Journal articles on the topic 'Approximately Rigid Formations'

Expression of α-smooth muscle actin (α-SMA) renders fibroblasts highly contractile and hallmarks myofibroblast differentiation. We identify α-SMA as a mechanosensitive protein that is recruited to stress fibers under high tension. Generation of this threshold tension requires the anchoring of stress fibers at sites of 8–30-μm-long “supermature” focal adhesions (suFAs), which exert a stress approximately fourfold higher (∼12 nN/μm2) on micropatterned deformable substrates than 2–6-μm-long classical FAs. Inhibition of suFA formation by growing myofibroblasts on substrates with a compliance of ≤11 kPa and on rigid micropatterns of 6-μm-long classical FA islets confines α-SMA to the cytosol. Reincorporation of α-SMA into stress fibers is established by stretching 6-μm-long classical FAs to 8.1-μm-long suFA islets on extendable membranes; the same stretch producing 5.4-μm-long classical FAs from initially 4-μm-long islets is without effect. We propose that the different molecular composition and higher phosphorylation of FAs on supermature islets, compared with FAs on classical islets, accounts for higher stress resistance.

Fast-start performance of rainbow trout (mass 0.187±0.022kg; mean±2S.E., N= 10) was measured in water of various depths. Relative water depth was defined as z/B, where z is the water depth measured from the air/water surface to the longitudinal midline of the body and B is the span of the caudal fin, 0.062±0.004m. Relative water depths (at absolute depths) tested were; 0.31 (at 0.05m), 1.11 (at 0.1m), 1.92 (at 0.15m), 2.73 (at 0.2m) and 7.56 (at 0.5m). Performance was defined in terms of the motion of the centre of mass as measured by the turning radius and the cumulative distance travelled in a given elapsed time. Turning radius was not affected by water depth and averaged 0.018±0.003m. Distance travelled was a positive function of water depth, although paired t-tests showed no significant effect of depth at 0.15 and 0.2 m after about 70 ms. Energy dispersion due to the formation of surface waves increased with decreasing relative water depth. The largest energy dispersion in wave formation at a relative water depth of 0.31 averaged about 70% of the useful mechanical work performed in deep water. Energy dispersion in wave generation was negligible for relative water depths larger than approximately 3. Energy dispersion is similar to that for rigid streamlined bodies moving at constant speed

Intramedullary (IM) nails are routinely used to stabilize long bone fractures. They can however lead to stress shielding, pain, migration, obstruct hematopoietic tissue, become a loci for infection, and require subsequent surgical retrieval. Novel intra-osseous scaffold (IOS™) prototypes for fracture healing have been developed to function as a regenerative scaffold to enhance callous formation under mechanically stabilized conditions then resorb. Prototype fixation pins and rod systems were formed from glass-reinforced-glass. Flexion, torsion and shear tests were performed to evaluate the composite pins and rods. A modular rod design was successfully deployed and dilated while in a deformable state. When fitted and gripping the intramedullary canal then set in a rigid state. An obliquely sectioned ovine femur was used as a long bone fracture model for deployment and mechanical verification. Flexural support provided by the intramedullary scaffold was superior to multiple k-wire fixation, while the k-wire approach was more stabilizing under torsional loads. Glass reinforced glass samples were mechanically tested after soaking for up to 4 weeks in saline. Strength and modulus of the composite was reduced to approximately 25% of initial values after 2 weeks.

Coffee husk, a major lignocellulosic waste derived from the coffee industry, was first ground into flour of fine particles of approximately 90 µm and then torrefied at 250 °C to make it more thermally stable and compatible with biopolymers. The resultant torrefied coffee husk flour (TCHF) was thereafter melt-compounded with polylactide (PLA) in contents from 20 to 50 wt% and the extruded green composite pellets were shaped by injection molding into pieces and characterized. Although the incorporation of TCHF reduced the ductility and toughness of PLA, filler contents of 20 wt% successfully yielded pieces with balanced mechanical properties in both tensile and flexural conditions and improved hardness. Contents of up to 30 wt% of TCHF also induced a nucleating effect that favored the formation of crystals of PLA, whereas the thermal degradation of the biopolyester was delayed by more than 7 °C. Furthermore, the PLA/TCHF pieces showed higher thermomechanical resistance and their softening point increased up to nearly 60 °C. Therefore, highly sustainable pieces were developed through the valorization of large amounts of coffee waste subjected to torrefaction. In the Circular Bioeconomy framework, these novel green composites can be used in the design of compostable rigid packaging and food contact disposables.

A multiharmonic quartz crystal microbalance (QCM) has been applied to study the viscoelastic properties of the aptamer-based sensing layers at the surface of a QCM transducer covered by neutravidin following interaction with bacteria Listeria innocua. Addition of bacteria in the concentration range 5 × 103–106 CFU/mL resulted in a decrease of resonant frequency and in an increase of dissipation. The frequency decrease has been lower than one would expect considering the dimension of the bacteria. This can be caused by lower penetration depth of the acoustics wave (approximately 120 nm) in comparison with the thickness of the bacterial layer (approximately 500 nm). Addition of E. coli at the surface of neutravidin as well as aptamer layers did not result in significant changes in frequency and dissipation. Using the Kelvin–Voight model the analysis of the viscoelastic properties of the sensing layers was performed and several parameters such as penetration depth, Γ, viscosity coefficient, η, and shear modulus, μ, were determined following various modifications of QCM transducer. The penetration depth decreased following adsorption of the neutravidin layer, which is evidence of the formation of a rigid protein structure. This value did not change significantly following adsorption of aptamers and Listeria innocua. Viscosity coefficient was higher for the neutravidin layer in comparison with the naked QCM transducer in a buffer. However, a further increase of viscosity coefficient took place following attachment of aptamers suggesting their softer structure. The interaction of Listeria innocua with the aptamer layer resulted in slight decrease of viscosity coefficient. The shearing modulus increased for the neutravidin layer and decreased following aptamer adsorption, while a slight increase of µ was observed after the addition of Listeria innocua.

Abstract The last glacial period is punctuated by abrupt changes in Northern Hemisphere temperatures that are known as Dansgaard–Oeschger (DO) events. A striking and largely unexplained feature of DO events is an interhemispheric asymmetry characterized by cooling in Antarctica during periods of warming in Greenland and vice versa—the bipolar seesaw. Methane-synchronized ice core records indicate that the Southern Hemisphere lags the Northern Hemisphere by approximately 200 years. Here, we propose a mechanism that produces observed features of both the bipolar seesaw and the phasing of DO events. The spatial pattern of sea ice formation and melt in the Southern Ocean imposes a rigid constraint on where water masses are modified: waters are made denser near the coast where ice forms and waters are made lighter farther north where ice melts. This pattern, coupled to the tilt of density surfaces across the Southern Ocean and the stratification of the ocean basins, produces two modes of overturning corresponding to different bipolar seesaw states. We present evolution equations for a simplified ocean model that describes the transient adjustment of the basin stratification, the Southern Ocean surface density distribution, and the overturning strength as the ocean moves between these states in response to perturbations in North Atlantic Deep Water formation, which we take as a proxy for Greenland temperatures. Transitions between different overturning states occur over a multicentennial time scale, which is qualitatively consistent with the observed Southern Hemisphere lag. The volume of deep density layers varies inversely with the overturning strength, leading to significant changes in residence times. Evidence of these dynamics in more realistic circulation models is discussed.

Complement control protein modules (CCPs) occur in numerous functionally diverse extracellular proteins. Also known as short consensus repeats (SCRs) or sushi domains each CCP contains approximately 60 amino acid residues, including four consensus cysteines participating in two disulfide bonds. Varying in length and sequence, CCPs adopt a β-sandwich type fold and have an overall prolate spheroidal shape with N- and C-termini lying close to opposite poles of the long axis. CCP-containing proteins are important as cytokine receptors and in neurotransmission, cell adhesion, blood clotting, extracellular matrix formation, haemoglobin metabolism and development, but CCPs are particularly well represented in the vertebrate complement system. For example, factor H (FH), a key soluble regulator of the alternative pathway of complement activation, is made up entirely from a chain of 20 CCPs joined by short linkers. Collectively, therefore, the 20 CCPs of FH must mediate all its functional capabilities. This is achieved via collaboration and division of labour among these modules. Structural studies have illuminated the dynamic architectures that allow FH and other CCP-rich proteins to perform their biological functions. These are largely the products of a highly varied set of intramolecular interactions between CCPs. The CCP can act as building block, spacer, highly versatile recognition site or dimerization mediator. Tandem CCPs may form composite binding sites or contribute to flexible, rigid or conformationally ‘switchable’ segments of the parent proteins.

The article discusses the view of a metropolis, due to the formation of metropolis identity. This identity is associated with a complex of sociocultural, socio-psychological processes, including the process of socialization in a big city. In a metropolis, patriarchal stereotypes are manifested to a lesser extent than in small cities, which contribute to a more rigid consolidation of gender roles. There is a smoothing of the gender aspects of consciousness. This situation is due to the fact that, on the one hand, the socialization of residents of megacities, as well as residents of other territories, occurs within the framework of gender culture. But, on the other hand, residents of megacities in everyday life are much more likely to encounter practices that go beyond the framework of the traditional socio-gender system. The paper provides empirical examples illustrating the characteristics of a metropolitan identity. Gender smoothing is taking place when evaluating the activities of educational and cultural institutions. Approximately equal shares of men and women assess the activities of educational and cultural institutions as high-level work. The low -level work of educational and cultural institutions is also estimated by men and women in approximately equal proportions. The results of the study show that men living in megacities stand in solidarity with women in their assessments. This may indicate that men and women are equally involved in raising children, which reflects the process of smoothing out gender stereotypes. No gender differences were also found when studying respondents' assessments of certain aspects of the social sphere. It is shown that the gender aspects of consciousness remain when assessing the sphere of health care. Significant differences in assessments of health care institutions exist when studying the question of satisfaction with the quality of state medical services, the availability of medical care and the work of ambulances. It is concluded that the smoothing of the gender aspects of consciousness is caused not only by personal characteristics but also by the individual living in a big city.

ABSTRACT The sheath of the filamentous, gliding cyanobacteriumPhormidium uncinatum was studied by using light and electron microscopy. In thin sections and freeze fractures the sheath was found to be composed of helically arranged carbohydrate fibrils, 4 to 7 nm in diameter, which showed a substantial degree of crystallinity. As in all other examined motile cyanobacteria, the arrangement of the sheath fibrils correlates with the motion of the filaments during gliding motility; i.e., the fibrils formed a right-handed helix in clockwise-rotating species and a left-handed helix in counterclockwise-rotating species and were radially arranged in nonrotating cyanobacteria. Since sheaths could only be found in old immotile cultures, the arrangement seems to depend on the process of formation and attachment of sheath fibrils to the cell surface rather than on shear forces created by the locomotion of the filaments. As the sheath in P. uncinatum directly contacts the cell surface via the previously identified surface fibril forming glycoprotein oscillin (E. Hoiczyk and W. Baumeister, Mol. Microbiol. 26:699–708, 1997), it seems reasonable that similar surface glycoproteins act as platforms for the assembly and attachment of the sheaths in cyanobacteria. InP. uncinatum the sheath makes up approximately 21% of the total dry weight of old cultures and consists only of neutral sugars. Staining reactions and X-ray diffraction analysis suggested that the fibrillar component is a homoglucan that is very similar but not identical to cellulose which is cross-linked by the other detected monosaccharides. Both the chemical composition and the rigid highly ordered structure clearly distinguish the sheaths from the slime secreted by the filaments during gliding motility.

A new method is proposed for the end-effector trajectory tracking control of flexible robot manipulators. The equations of motion are separated into two parts that represent the pseudostatic equilibrium and the deviations from it. The part of the control input for the pseudostatic equilibrium is determined algebraically, and the other part of the control input for the stabilization of the deviations is obtained by a state variable feedback law, by using strain, joint variable, and end-effector position measurements. The feedback gain matrix is determined online by continuously updated pole placement. The pseudostatic equilibrium is defined here as a hypothetical state, in which the velocity and acceleration of the end-effector have their desired values whereas the elastic deformations are instantaneously constant. In order to demonstrate the method, a planar two-link robot with a flexible forearm is taken into consideration. The elasticity of the forearm is approximately described by the first two modes, and a controller is designed by using this two-mode model. Furthermore, in order to investigate the effects of modelling discrepancies, a ‘submodel controller’ is designed by using a model with only the first mode and it is applied to the same system with the two-mode model. The performances of these two controllers are compared by means of simulations. The behaviour of the flexible robot is also simulated by using the computed torque method as if the robot is rigid in order to illustrate the importance of including the flexibility effects in the formation of an appropriate control law. The spillover effect that causes the dominant poles to approach towards the imaginary axis is inspected by monitoring the real parts of the dominant poles of the closed-loop system under the effect of the ‘submodel’ and ‘computed torque’ controllers.

Background: Peripheral nerve injuries are common, with approximately 9,000 cases in the UK annually. Young working individuals are predominantly affected, leading to significant health and social implications. Functional recovery is often poor with impaired hand sensation, reduced motor function and pain and cold intolerance. Where a nerve gap exists, nerve grafting remains the gold-standard treatment but creates a second surgical site, sensory deficit at the donor site, possible neuroma formation and has limited availability. Current commercially available synthetic and resorbable nerve conduit alternatives are reported to be rigid and inflexible. This study will set out to examine the first-in-man use of a new nerve conduit device ‘Polynerve’ to repair small nerve gaps in digital sensory nerves of the hand. Polynerve is a degradable co-polymer of poly-ε-caprolactone and poly-l-lactic acid, which is shaped as a cylinder that has greater tensile strength, flexibility and less acidic degradation compared with current commercially available synthetic nerve conduits. In addition, it has a novel micro-grooved internal lumen that aids Schwann cell ingress and alignment to improve nerve regeneration. Methods: In total, 17 eligible participants will be recruited to undergo repair of a transected sensory nerve of the hand using the Polynerve device. All participants that receive the nerve conduit device will be followed for a period of 12 months post-surgery. The primary endpoint is safety of the device and the secondary endpoint is degree of sensory nerve regeneration through the conduit assessed using standard sensory testing (2-PD, WEST monofilament testing and locognosia). Discussion: The ‘UMANC’ trial is a single-centre UK-based, prospective, unblinded, phase I clinical trial of a novel nerve conduit device. We aim to demonstrate the safety of Polynerve as a synthetic, biodegradable nerve conduit and improve the treatment options available to patients with significant nerve injuries. Registration: Clinicaltrials.gov: NCT02970864; EudraCT: 2016-001667-37.

Abstract How and when the Tibetan plateau developed has long been a puzzling question with implications for the current understanding of the behaviour of the continental lithosphere in convergent zones. We present and discuss recent data acquired in geology and geophysics and through igneous and metamorphic petrology and palaeo-altitude estimates. It appears from this research that Tibet initially resulted from the accretion of the Gondwana continental blocks to the southern Asian margin during the Palaeozoic and Mesozoic eras. These successive accretions have potentially favoured the creation of local landforms, particularly in southern Tibet, but no evidence exists in favour of the existence of a proto-Tibetan plateau prior to the Cenozoic. Moreover, before the India-Asia collision, the Tibetan crust had to be sufficiently cold and rigid to transfer the horizontal forces from India to northern Tibet and localize the deformation along the major strike-slip faults. However, these successive accretions associated with subductions have metasomatized the Tibetan lithospheric mantle and largely explain the potassium- and sodium-rich Cenozoic magmatism. Another consequence of this contamination by fluids is the softening of the Tibetan lithosphere, which favoured intra-continental subductions. The timing and the geochemical signatures of the magmatism and the palaeo-altitudes suggest the early growth of the Tibetan plateau. By the Eocene, the southern plateau and the northern portion of Himalaya would be at an altitude of approximately 4000 meters, while the central and northern Tibetan plateau was at altitudes of approximately 2000 to 3000 meters at the Eocene-Oligocene transition. From all of these data, we propose a model of the formation of the Tibetan plateau coupled with the formation of Himalaya, which accounts for more than 2500 km of convergence accommodated by the deformation of the continental lithospheres. During the early Eocene (55-45 Ma), the continental subduction of the high-strength Indian continental lithosphere dominates, ending with the detachment of the Indian slab. Between 45 and 35 Ma, the continental collision is established, resulting in the thickening of the internal Himalayan region and southern Tibet and the initiation of intra-tibetan subductions. By 35 Ma, the southward subduction of the intra-tibetan Songpan-Ganze terrane ends in slab break-off and is relayed by the oblique subduction of the Tarim the Athyn Tagh propagated northeastward beneath the Qilina Shan. Southward, the dextral Red River fault accommodated the southeastward extrusion of the Indochina block. During the Miocene, specifically, between 25 and 15 Ma, the Indian slab undergoes a second break-off, while the central part of Tibet is extruded eastward. Northward, the continental subduction beneath the Qilian Shan continues. Discontinuous periods of magmatic activity associated with slab detachments play a fundamental role in the convergence process. These periods lead locally to a softening of the mid-crust by magma heat transfer and to the granulitisation of the lower crust, which becomes more resistant. We propose that due to these alternating periods of softening and hardening of the Tibetan crust, the rheological behaviour of the convergence system evolves in space and time, promoting homogeneous thickening periods alternating with periods of localised crustal or lithospheric deformations.

The present work studies the effect of passive exit flexibility on a two-dimensional starting jet. The exit flexibility is introduced by attaching two flexible (deformable) flaps at the jet exit of a high aspect ratio rectangular duct with the flaps initially being parallel to the channel walls. A controlled piston motion is used to generate the starting jet, which is composed of a rapid acceleration to a constant velocity ($U_{p}$) that is maintained for a given duration of time, after which it is brought to rest impulsively. The parameters which are varied include the flexural rigidity ($EI$) of the flaps, flap length ($L_{f}$) and piston speed ($U_{p}$), with measurements of the flap kinematics and flow field in each case. The flaps initially bulge due to the acceleration of the piston from rest, with this bulge growing in size and moving downstream as the flow develops, culminating in a large opening at the flap exit. Subsequently, the flaps return to their initial parallel position and remain there as long as the piston is in motion. Once the piston stops, the flaps collapse inwards due to fluid deceleration causing additional flow out of the flap region in the form of a jet that adds to the net amount of fluid pushed by the piston. We find that the flap kinematics is affected by the flap $EI$ and $L_{f}$ besides $U_{p}$. We define a non-dimensional flexural rigidity $EI^{\ast }=EI_{eq}/(1/2\unicode[STIX]{x1D70C}U_{p}^{2}L_{f}^{2}d)$, where $EI_{eq}$ is an equivalent flexural rigidity which takes the self-weight of the flaps into account ($d=\text{channel width}$; $\unicode[STIX]{x1D70C}=$ fluid density). We find that across different $EI_{eq}$, $L_{f}$, and piston speeds, the maximum opening of the flap tip and the time taken to reach this maximum opening in terms of $L/L_{f}$ (where $L=\text{fluid slug length}$) fall on a single curve for all the cases studied, when plotted with $EI^{\ast }$. Particle image velocimetry measurements show that the motion of the flaps results in the formation of additional pairs of vortices when compared to the single vortex pair formed in the absence of flaps. The total final circulation coming out of the flap region remains nearly the same as that of the rigid exit case. However, the final fluid impulse is always found to be higher in the flap cases, with the fluid impulse in most flap cases being approximately two times the fluid impulse of the rigid exit case. This increase in impulse is shown to be linked to the fact that the centroids of vorticity get spread out more in the lateral direction due to the opening of the flaps. The increased impulse and the higher time rate of change of impulse, which is linked with force, suggest that introduction of flexible flaps can help improve thrust performance when looked at from a propulsion point of view.

We study the settling of rigid oblates in a quiescent fluid using interface-resolved direct numerical simulations. In particular, an immersed boundary method is used to account for the dispersed solid phase together with lubrication correction and collision models to account for short-range particle–particle interactions. We consider semi-dilute suspensions of oblate particles with aspect ratio $AR=1/3$ and solid volume fractions $\unicode[STIX]{x1D719}=0.5{-}10\,\%$. The solid-to-fluid density ratio $R=1.02$ and the Galileo number (i.e. the ratio between buoyancy and viscous forces) based on the diameter of a sphere with equivalent volume $Ga=60$. With this choice of parameters, an isolated oblate falls vertically with a steady wake with its broad side perpendicular to the gravity direction. At this $Ga$, the mean settling speed of spheres is a decreasing function of the volume $\unicode[STIX]{x1D719}$ and is always smaller than the terminal velocity of the isolated particle, $V_{t}$. On the contrary, in dilute suspensions of oblate particles (with $\unicode[STIX]{x1D719}\leqslant 1\,\%$), the mean settling speed is approximately 33 % larger than $V_{t}$. At higher concentrations, the mean settling speed decreases becoming smaller than the terminal velocity $V_{t}$ between $\unicode[STIX]{x1D719}=5\,\%$ and 10 %. The increase of the mean settling speed is due to the formation of particle clusters that for $\unicode[STIX]{x1D719}=0.5{-}1\,\%$ appear as columnar-like structures. From the pair distribution function we observe that it is most probable to find particle pairs almost vertically aligned. However, the pair distribution function is non-negligible all around the reference particle indicating that there is a substantial amount of clustering at radial distances between 2 and $6c$ (with $c$ the polar radius of the oblate). Above $\unicode[STIX]{x1D719}=5\,\%$, the hindrance becomes the dominant effect, and the mean settling speed decreases below $V_{t}$. As the particle concentration increases, the mean particle orientation changes and the mean pitch angle (the angle between the particle axis of symmetry and gravity) increases from $23^{\circ }$ to $47^{\circ }$. Finally, we increase $Ga$ from 60 to 140 for the case with $\unicode[STIX]{x1D719}=0.5\,\%$ and find that the mean settling speed (normalized by $V_{t}$) decreases by less than 1 % with respect to $Ga=60$. However, the fluctuations of the settling speed around the mean are reduced and the probability of finding vertically aligned particle pairs increases.

Abstract Terminal erythropoiesis involves differentiation of erythroblasts to enucleated reticulocytes, which further remove major organelles to become mature red blood cells. Several pieces of evidence indicate that the extrusion of the nucleus out of the orthochromatic erythroblasts is a fairly rapid process that lasts approximately 10 minutes. However, the detachment of the extruded nucleus from the nascent reticulocyte takes longer time, and possibly requires the aid of phagocyte to anchor the nucleus. The mechanism involved in this process is poorly understood. Previous studies have demonstrated that mDia2 is critical for erythroblast enucleation. Loss of mDia2 in mice lead to compromised cytokinesis in orthochromatic erythroblasts and decrease in enucleation. To further reveal the mechanism of the defect in enucleation in mDia2 deficient erythroid cells, we first monitored the enucleating erythroblasts using real-time microscopy. The wild type enucleating mouse erythroblast showed a dynamic motility to detach the nucleus, which can be facilitated by the macrophages. The mDia2 knockout erythroblasts retained the capacity to extrude the nucleus, even in the bi-nucleated cells. However, the nascent reticulocytes were rigid and lacked the dynamic movement to expel the nuclei. Since mDia2 is critical for linear actin polymerization, we next performed a Western blot assay of RBC ghost and found that actin and many other critical RBC cytoskeleton proteins were significantly decreased in mDia2 knockout mice (Fig 1A). Transmission electron microscope (TEM) analysis of RBC cytoskeleton revealed that spectrin filament connecting two junctional complexes was longer in mDia2 knockout RBCs (Fig 1B), which explains their rigidity and inefficient movement to detach the extruded nuclei. Further studies using stochastic optical reconstruction microscopy (STORM) revealed disorganized distribution of the major components of erythrocyte cytoskeleton, including actin (Fig 1C) and β-spectrin, in mDia2 knockout reticulocytes. The dynamic motility of the nascent reticulocytes is also required for the remodeling and removal of proteins to further mature into RBCs. We found an increase in proteins such as CD71 and CD44, as well as DNA/RNAs, in mDia2 knockout reticulocytes. Mechanistic studies revealed that mDia2 functions on vesicle trafficking through its interaction with Chmp5, one of the critical components of the ESCRT-III complex involved in vesicle formation and trafficking. This interaction stabilized Chmp5 since its level was dramatically reduced in mDia2 knockout erythroblasts and reticulocytes (Fig 1D-E). Our study reveals a critical role of the dynamic motility of the nascent reticulocyte in enucleation and maturation. Abnormal membrane cytoskeleton in mDia2 null mice compromises these processes. In one hand, mDia2 mediated actin polymerization ensures the flexibility of the erythrocyte cytoskeleton. On the other hand, mDia2 also involves vesicle biogenesis and discharging through the regulation of ESCRT complexes during reticulocyte maturation. Our study thus sheds lights on the understanding of reticulocyte maturation mechanisms. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

Background: CD22 is an attractive target for Chimeric Antigen Receptor (CAR) since it is expressed by most B-cell malignancies. However, CAR targeting of CD22 is challenging since CD22 has a long ectodomain of 300 Å, which is several times wider than the optimal immune synapse. Further, the ectodomain is rigid, so even targeting of membrane proximal domains may not allow effective synapse formation. Further still, CD22 is expressed at low density and dropping of antigen density has been described as a mode of escape. A previously described CD22 CAR based on the M971 antibody required a very short linker between single-chain VH-VL for sensitive function, presumably to allow CAR concatenation but which comes at the cost of basal signalling. Our aim was to engineer an anti-CD22 CAR which triggered not only killing, but proliferation in response to less than 1000 CD22 molecules per cell, without basal signalling. We conducted a functional screen for stable / high affinity binders recognizing the CD22 membrane proximal domains that function in a CAR against cells expressing low levels of CD22 target. Methods: Binders were generated in two campaigns. Hyperimmune mice were vaccinated with recombinant CD22 protein lacking the highly immunogenic N-terminal V-type domain. Similarly, Wistar rats were immunized via genetic vaccination using a modified gene encoding the 4 membrane proximal domains of CD22, cloned into a DNA vaccine plasmid designed to stimulate a humoral immune response. A total of 18 binders passed biophysical screening properties of stability, affinity and proximal binding. Binding affinity ranged between 1-36.5nM; the binders were cloned into 41BB-Zeta signalling CARs. We generated a panel of CD22 expressing SupT1 cell lines. Using expression cassettes with amber stop codons preceding the CD22 frame, we generated stable SuptT1 cell lines which express CD22 below the limit of amplified flow cytometry detection (<100 copies, CD22Und) and a cell line with 255 copies / cell (CD22Low). In addition, using conventional means, we generated cell lines expressing intermediate and high levels of CD22 expression (CD22Mid=3,444, CD22High=78,916 copies/cell). Results: The 18 CAR constructs went through an initial round of screening using primary T-cells as effectors and engineered SupT1 cells as targets. A threshold of >50% killing of CD22Und target cells at an effector:target (E:T) ratio of 1:4 at 72 hour was set for further characterization. Only one CAR derived from the hyperimmune murine binders, and two derived from the rat binders met this threshold. Further characterization of killing at lower E:T ratios, cytokine release and proliferation revealed that CAR based on the rat binder 9A8 had superior function in response to low density target cells compared with the other two CARs and was characterized further and compared with the M971 CAR. This comparison showed approximately 2-fold better killing of CD22Und 9A8, and approximately 4-fold increased proliferation with no basal signalling. Next, we tried to correlate binder characteristics with sensitivity to low CD22 density. No correlation was found between either affinity, epitope, or stability and sensitivity. In fact, two of the best candidates could be paired with CARs which recognized the same CD22 domain and had similar binding kinetics and stability but had much lower sensitivity to CD22. This suggests that some other as yet unappreciated binder characteristic leads to sensitivity and we are currently investigating this via a structural analysis of binder / target interaction. Finally, we are currently testing 9A8 co-expressed with the CAT19 CD19 CAR (AUTO1) (Blood 2017 130:806) in small animal models of B-ALL. Conclusion: A highly sensitive CD22 CAR could be selected by empiric screening of CARs derived from a set of binders which target the proximal domains of CD22. CAR concatenation was not required for a high-degree of sensitivity to CD22 antigen. No correlation was found between binder characteristics and function. Disclosures Thomas: Autolus: Employment, Equity Ownership. Cordoba:Autolus: Employment, Equity Ownership. Pule:Autolus: Employment, Equity Ownership, Patents & Royalties.

Dear Editor,
 
 Reconstruction of mandibular defects resulting from ablative surgery for benign and malignant tumors remains a reconstructive challenge. For the past decade, the fibular free flap has been the workhorse for large mandibular defects because of its length, versatility, and ability to be harvested with a skin paddle for soft tissue closure. Although its success rate has continuously improved to almost 95%, donor site morbidity remains a matter of concern.1,2 Bone grafts are already widely used in dental surgery but only as fillers for chipped or marginal defects and not for large segmental mandibular defects. We present a new technique of reconstructing segmental mandibular defects using bone grafts combined with autologous platelet-rich fibrin (PRF), a biomaterial derived intra-operatively from the patient that incorporates leukocytes, platelets, growth factors, and a wide range of glycoproteins in a dense fibrin matrix. Moreover, we describe the essential role of PRF in bone healing and regeneration that offers an invaluable reconstructive option that is free of donor site morbidity without sacrificing the main goal of reconstruction in restoring both form and function.
 
 Keywords: Mandibular reconstruction; segmental mandibular defect; bone graft; autologous Platelet-Rich Fibrin (PRF)
 
 MATERIALS AND METHODS
 
 Subject and Indications
 A 23-year-old male underwent reconstruction with allogenic bone graft in combination with autologous platelet-rich fibrin (PRF) for a large segmental angle to parasymphyseal mandibular defect. (Figure 1) As in this example, the authors’ technique for segmental mandibular defect reconstruction using bone grafts with PRF was best performed as a second stage procedure following tumor ablation to prevent contamination from oral cavity secretions. As with any elective procedure, a thorough review of the medical history, control of systemic disease and informed consent were necessary. Patients with contraindications for fibular free flaps, such as history of peripheral vascular disease, unfavorable imaging of the lower extremity, venous insufficiency, and anomalous lower extremity vasculature may benefit from this technique.3 Patients who had failed mandibular reconstruction with other methods such as those reconstructed with single alloplastic material, titanium plate, non-vascularized autologous bone graft, or free flaps are likewise candidates for this option.
 
 Procedure
 A submandibular incision was made and a sub-platysmal flap was raised to expose the entire length of the mandibular defect. Apart from the preservation of vital structures in the area, it was important not to violate the oral mucosa to prevent contamination of the reconstruction site. A cortico-cancellous allogenic bone graft (Maxgraft®, Botiss Medical AG , Berlin, Germany) was fitted to the mandibular defect and anchored with bicortical screws (2.5; 2.8 mm, lengths 14-20 mm) to a pre-bended 2.5 mm reconstruction titanium plate (Modus Reco 2.5, Medartis, Hochbergerstrasse Basel Switzerland). The remaining gaps between the inlaid grafts were filled with the remaining cancellous bone and biomimetic composite materials. (Figure 2) Although allogenic bone grafts with cortical and cancellous components are recommended for mandibular ramus and condylar reconstruction as these regions are composed of nearly 100% cortical bone, xenogenic (Cerabone®, Botiss Medical AG , Berlin, Germany) or combined alloplastic material- (Maxresorb®, Botiss Medical AG , Berlin, Germany) bone grafts may be used in other regions. (Figure 3)
 
 Meanwhile, venous blood was simultaneously drawn from the patient and placed in a 10 cc glass collecting tube for single centrifuge processing using a PC-O2 centrifuge (PC-O2, Process, Nice, France). The specific centrifuge processes 8 uncoated tubes using a standard protocol specially manufactured for processing PRF using 33° tube angulation at 2700 RPM’s, soft spin for 12 minutes.4 (Figure 4) At the end of the centrifugation process, three distinct fractions of blood components were produced where the intermediate fraction composed of dense PRF clot was used. The other blood components separated by the centrifugation process- serum or platelet-poor plasma (PPP) and red blood cell concentrates, were respectively situated in the superficial and bottom layers of the collecting tube. The PRF clots were then transferred to a PRF processing box (PRF Box®, Process, Nice, France) to prepare standardized membranes and harvest the PRF exudates in a sterile environment.5 (Figure 5) Collagen material of native pericardium (GTR/GBR) membrane (Jason® membrane, Botiss Medical AG, Berlin, Germany) was placed underneath the graft recipient site and the processed PRF membranes were layered over the graft recipient site to stimulate osteoblastic differentiation and neoangiogenesis.6 
 
 The entire recipient site was then enveloped with the collagen material, mechanically securing the autologous PRF in contact with the bone grafts. (Figure 6) This established a membrane barrier for guided bone regeneration (GBR) and guided tissue regeneration (GTR) by preventing growth of undesired cells inside the neomandible and allowing osteogenesis and angiogenesis.7 Commercially available collagen biomaterials vary from native collagen membrane to enhanced Ca/P collagen composite materials such as the 3D-stable collagen graft (Mucoderm®, Botiss Medical AG, Berlin, Germany) with larger available sizes for long mandibular defect coverage. The skin was closed in the usual manner and the patient was initially maintained on a liquid diet, progressing to a soft diet over 2-4 weeks. Plain panoramic radiographs after a week confirmed proper alignment of the bone grafts and monthly radiographic series was recommended for the first 6 months after reconstruction.
 
 
 RESULTS
 
 Monthly panoramic radiographs for the first 6 months after reconstruction showed absence of bone resorption. A 3D reconstruction CT imaging of the mandible was done after 10 months for placement of three osteo-integrated dental implants. (Figure 7) Bone biopsies were also taken in conjunction with placement of dental implants, and sent to the University of Bonn, Germany for histologic evaluation. (Figure 8) The trichrome-stained specimens showed new mineralized tissues consisting of woven bone characterized by high numbers of distributed osteocytes and irregularly arranged fiber bundles within the new bone matrix confirming bone regeneration. (Figure 9) The latest panoramic radiograph of the patient at 26 months after surgery showed absence of gaps between the bone grafts and their junction with the normal mandible, evincing complete bone regeneration and a successful mandibular reconstruction. (Figure 10) A total of 14 cases of segmental mandibular defects have been reconstructed by the authors using the particular technique from January 2011 to February 2013 with 100% success rate and will be reported as a series in the near future.
 
 
 DISCUSSION
 
 Advancements in mandibular reconstruction have continued to develop over the past decades. The use of alloplastic materials like titanium plating implants for repairing mandibular defects provided patients with rapid rigid mandibular restoration but was limited by numerous complications such as infection, plate extrusion, and subsequent failure. Recently, the concept of distraction osteogenesis, involving bone distraction with an external mechanical device and progressive lengthening of the bone to allow a gap of new bone during the consolidation phase has also been used for mandibular reconstruction but has been limited by poor scar formation, delayed return to function, and inadequate formation of desired bone length.8 The advent of microvascular reconstructive surgery enabled the transfer of vascularized osseous flaps with the most commonly used fibular free flap showing superior results over non-vascularized bone transfer and better quality of life outcome. However, it did not remain free of donor-site morbidities.9 
 
 Tissue engineering led to the development and use of bone grafts that hold promise for the future of head and neck repair.10 Numerous clinical studies demonstrated the utility of tissue engineering in developing bone grafts for mandibular defect reconstruction.11 Such have already been widely used over the past decades in oro-maxillary and dental reconstruction, including the recombinant bone morphogenetic protein (rhBMP-2) that is now used with great success in cleft palate repair, alveolar ridge augmentation, and sinus lift procedures.12 Autogenous bone grafts derived from the patient work through osteogenesis, osteoinduction and osteoconduction. However, such are not recommended because apart from enabling a donor site morbidity-free technique, they are best harvested as microvascular flaps. Allogenic bone grafts on the other hand are cadaveric processed grafts that may be cortical, trabecular, or combined in composition and have both osteoconductive and osteinductive properties. Xenografts or processed animal bone graft are a subgroup of the synthetically manufactured alloplasts known to form new bones from their osteoconductive activities.
 
 The use of autologous PRF is already widely used in combination with bone grafts for dental surgeries but not for large mandibular defects.13 Our reconstructive technique using bone grafts for large segmental mandibular defects emphasizes the important role of PRF with its intrinsic factors and leukocyte contents that release high amounts of growth factors such as TGBß1, PDGF-AB, VEGF and matrix glycoproteins.14 Collagen membrane used to envelop the entire recipient site creates a membrane barrier to prevent the growth of soft tissues and allow angiogenesis within the neomandible.15 Fascia lata may be used as a membrane barrier but defeats the authors’ goal of an absolute donor site morbidity-free procedure. Overall, this particular technique along with gentle tissue handling and avoidance of oral cavity contamination for reconstructing large mandibular defects has been found to enhance bone regeneration capable for osteo-integrated dental implantation. 
 
 Generally, the harvesting and processing of autologous PRF is simple and inexpensive. Its use with bone grafts is a good substitute for segmental mandibular reconstruction in patients with contraindications to free flap procedures or in cases where patients simply wish to be free from any donor-site morbidity. However, this technique is limited to defects secondary to trauma and ablation of benign conditions as bone regeneration is expected in approximately 6 to 9 months. Mandibular defects following resection of malignant oral neoplasms are still best reconstructed with fibular free flaps as radiation therapy is warranted at the soonest possible time. Histologic validation of bone regeneration and osteoblastic activity index for the 13 other cases performed by the authors using this particular technique necessitates bone research centers that are capable of advanced bone analysis, and none are locally-available at this time. Meanwhile, this technique of combining autologous PRF in bone grafting remains an innovative and invaluable option for mandibular reconstruction today.

Laryngeal stenosis is a partial or complete narrowing of the endolarynx and has many etiologies. Common causes of laryngeal stenosis are iatrogenic (prolonged intubation, laryngeal surgery), external neck trauma, congenital, burns, ingestions, infection, and inflammation (gastroesophageal reflux or Wegener’s). Laryngeal stenosis secondary to trauma usually affects the posterior endolaryngeal region in adults and the subglottic region in children.1
 Patients with mild to moderate laryngeal stenosis are usually asymptomatic and if otherwise, majority of the presenting signs and symptoms are mainly related to the airway, feeding and voice resulting to marked respiratory distress, dysphagia/odynophagia and altered voice, respectively.
 We present a case of hypopharyngeal, supraglottic and subglottic stenosis occurring 1 week after intubation.
 
 CASE REPORT
 A 3-year old boy from Ormoc City was admitted in our institution for dysphagia of 2 months.
 Three months prior to admission, he was treated for hypersensitivity reaction after eating shrimp and crab. The boy experienced sudden onset perioral swelling with bluish discoloration, dyspnea, severe drooling and vomiting of previously ingested food immediately after taking a vitamin supplement syrup that had been preceded by the dinner of crustaceans. He was immediately brought to a primary hospital in Ormoc City but was not relieved by nebulization and unrecalled intravenous medications.
 The boy was eventually transferred to a tertiary hospital in Ormoc City. During this time, perioral swelling, dyspnea and cyanosis with associated severe drooling persisted. He was also noted to have stridor, was intubated and subsequently admitted to the intensive care unit for 7 days with an impression of severe hypersensitivity reaction secondary to crustacean ingestion. He was fed via a nasogastric tube (NGT). His condition eventually improved and the endotracheal tube was removed after 7 days. According to the relatives, there was significant increase in expectoration of saliva hours after removal of the endotracheal tube, allegedly occurring almost every minute, accompanied by drooling. There was no fever, no difficulty of breathing, no aspiration, no vomiting episodes and no easy fatigability noted at this time. However, the boy was noted to have dysphagia associated with frequent coughing and expectoration of saliva on intake of both fluids and solid food following removal of the NGT. His relatives denied any episodes of dyspnea, vomiting, cyanosis, easy fatigability or fever, and he was subsequently discharged after 1 month of confinement.
 One month and three weeks prior to admission, he still presented with dysphagia, frequent spitting of saliva and now with associated wheezing and weight loss on follow-up at the hospital. He was referred to a pediatric pulmonologist in Cebu City for further evaluation and management.
 One month before admission, a thickened epiglottis was seen on neck and chest CT-scan and “acquired subglottic stenosis, post intubation” was diagnosed, for which direct laryngoscopy was recommended. The relatives did not consent, and the boy was discharged on Betamethasone + Dexchlorpheniramine syrup for 5 days, Montelukast Na oral granules for 30 days, and Amoxicillin suspension and Salbutamol syrup for 7 days.
 Nineteen days prior to admission, with persistence of the previously-mentioned symptoms, the boy was brought to our outpatient service and subsequently admitted.
 
 On admission, he was ambulatory and not in cardiorespiratory distress. He still had symptoms of increased expectoration and drooling with associated dysphagia for both liquids and solid foods. Because of difficulty inserting a nasogastric tube, he had to subsist on small, frequent sips of fluids consisting mostly of milk and water. Fluid thickeners improved swallowing. Initial flexible nasopharyngolaryngoscopy revealed a thickened epiglottic area obscuring the vocal cords. A modified barium swallow and airway fluoroscopy showed aryepiglottic fold thickening and non-persistent episodes of narrowing at the supraglottic and glottic areas. A trace of nasopharyngeal regurgitation was also noted without any gross tracheal aspiration.
 
 Flexible nasopharyngolaryngoscopy by a laryngologist revealed a normal nasopharynx, absent epiglottis, absent pyriform sinuses, stenotic hypopharynx and supraglottis, normal vocal cord structure and mobility with grade 1 subglottic stenosis. (Figures 1 A-D) Possible laser surgical release of fibrosis and removal of strictures was recommended, with close observation until then. Meanwhile, due to persistent dysphagia and significant weight loss, he underwent gastrostomy and was started on supplements for nutritional build up.
 
 
 
 DISCUSSION
 
 Laryngeal stenosis is a partial or complete cicatricial narrowing of the endolarynx and may be congenital or acquired.1 Trauma is the most common cause of acquired laryngeal stenosis, both in children and in adults, and is classified as external laryngeal trauma or internal laryngeal trauma. The latter is more commonly due to iatrogenic causes, especially prolonged endotracheal intubation.2 Approximately 90% of cases of acquired chronic subglottic stenosis in infants and children occur secondary to endotracheal intubation. The reported incidence of stenosis after intubation ranges from less than 1% to 8.3%.1 In our case, the patient initially presented with persistent dysphagia with associated excessive drooling and increased expectoration after intubation for 1 week.
 A study by Gallo et al. of 70 patients with laryngeal stenosis revealed that the causes of stenosis may be numerous (including intubation, autoimmune disease, iatrogenic) and multiple areas of the airway can be involved.3 The reported incidence of tracheal stenosis following laryngotracheal intubation ranges from 6% to 21%.3 They further explained that erosion and mucosal necrosis occur within hours of endotracheal intubation and full thickness injury exposes cartilage with development of perichondritis if the tube is not withdrawn within a week. Re-epithelialization of the edges of the ulceration follows and healing is completed within 4 weeks. The previous site of the ulceration is usually marked with fibrosis and metaplastic squamous epithelium. The risk of tissue damage and development of laryngotracheal stenosis increases depending on the severity of the ulceration and if the healing process is delayed by secondary infection.3 Duration of intubation and size of the endotracheal tube are the most important factors in the development of laryngeal stenosis, but no definite safe time limit for endotracheal intubation has been established. Severe injury has been reported after 17 hours of intubation in adults and 1 week after intubation in neonates. The area most commonly injured in children is the subglottic region.1
 Initial evaluation when suspecting laryngeal stenosis includes radiographic evaluation to aid in assessing the degree and length of stenosis. Computed tomography scanning (CT) and magnetic resonance imaging (MRI) scanning are not standard techniques to assess the laryngotracheal airway but may be used as an adjunctive diagnostic technique to help determine the length of the stenosis or concurrent vascular compression.4 Initial Computed Tomography (CT) scans prior to admission revealed only thickening of the epiglottis with narrowing of the subglottic region. The extent of involvement was not determined until flexible nasopharyngolaryngoscopy revealed absence of the epiglottis and pyriform sinuses, hypopharyngeal and supraglottic stenosis and grade 1 subglottic stenosis with normal vocal cord structure and mobility. Flexible and rigid endoscopy should be a part of assessment as they allow direct inspection of the dynamic laryngeal and hypopharyngeal airway.4 As illustrated in this case, fluoroscopy is also helpful in studying tracheal dynamics.1 
 The basic techniques for management of laryngeal stenosis include endoscopic and external methods. Wiatrak suggested that conservative management or a “wait-and-see” approach may be considered.4 The management of laryngeal stenosis in infants and young children should be conservative, since in the majority of cases, the stenosis will improve with laryngeal growth.5 While such management may be considered in our case, it is rarely successful for acquired laryngeal stenosis. Endoscopic methods including balloon dilatation and laser assisted excision are options, although the former is only beneficial in cases of early, soft stenosis, before mature, firm stenosis has developed.4
 Open surgical methods include expansion and resection surgery. Open surgical procedures should only be recommended when it has been established by careful endoscopic assessment that the laryngeal lumen has not increased in size.5 According to Gallo et al., tracheal resection and anastomosis is considered the treatment of choice for tracheal stenosis.3 However, this approach may not be applicable when the glottis and/or the subglottis are also involved. Moreover, it may not be feasible due to the extent of the stenosis, underlying disease and general health of the patient.3 While grade 1 stenosis may be managed by open surgery, it may also be amenable to endoscopic techniques. The challenge for this case includes correction of the laryngeal area, ensuring stability of airway and improving general status and health with the least invasive management possible. The use of stents offers another management option for laryngeal stenosis. Alshammari and Monnier used laryngotracheal stents on 65 patients during open surgery and endoscopy to keep the airway expanded after surgical reconstruction or trauma. However, they also reiterate that stents should be avoided unless absolutely necessary since there are potential risks for mucosal injuries, ulcerations, granulation tissue formation and subsequent restenosis.6 According to Zanetta et al., there is no ideal stent for the treatment of subglottic stenosis in children and that it can act as a foreign body in the reconstructed airway causing difficulties for feeding and in voice production.7
 Our proposed method for addressing the laryngeal stenosis is to attempt laser excision to correct the affected areas and hopefully improve the feeding status while ensuring stability of the airway. At present, nutritional build up is the initial target in preparation for the contemplated procedure.
 Laryngeal stenosis in the pediatric population is one of the most controversial topics in pediatric otolaryngology. There are various techniques available for management of laryngeal stenosis. Therapeutic procedures range from repeated dilatation, prolonged laryngeal stenting with or without the use of steroids, the use of carbon dioxide laser to create an airway with or without tracheostomy (through a laryngeal mask airway), to early tracheostomy and open surgery.5,8 However, feasibility of the technique, invasiveness, as well as possible outcome are some of the problems a physician may encounter. We should always consider individualizing our management according to pathologic findings, patient’s age, degree and consistency of stenosis and importantly, the general condition of the patient. Echoing Evans, one could at least give the parents of pediatric patients a reasonably accurate prognosis, and the hope that their child can be restored to normality.5

Three of the five thrust fault systems defining the boundaries of four lithotectonic terranes of the Himalaya and involved in controversies related to their positions and nomenclature, are the objects of discussion in this paper. Youngest of the five terrane-defining faults, the Himalayan Frontal Fault (HFF) is a series of reverse faults that demarcates the boundary of the Siwalik front of the Himalayan province with the alluvial expanse of the Indo-Gangetic Plains. Over large tracts, it is either concealed under younger sediments or has as yet not reached the ground surface and is therefore a blind fault. The nature of this frontal fault varies along its length. Where the hidden ridges of the Indo-Gangetic basement impinge the Himalaya, the mountain front is ruptured and the HFF is repeatedly reactivated. In the sectors intervening these ridges, it is not expressed on the surface, but the ground of the adjoining Indo-Gangetic Plain is sinking, the rivers are shifting their courses and large tracts of land are waterlogged and characterized by The Vaikrita Thrust is the plane that marks pronounced metamorphic break and abrupt change in style and orientation of structures within the succession of crystalline rocks that build the bulk of the snowy ranges in the Kumaun Himalaya. Not only is there a jump of pressure of the order of 4 kb and a temperature rise of >200 oC, but also is there a conspicuous change of neodymium isotope value across the tectonic plane that separates the low-grade metarnorphics in the lower part from the high-grade metamorphic rocks of the upper part of the Great Himalayan succession. The Vaikrita Thrust is therefore recognised as the Main Central Thrust (MCT). While the basal low-grade metamorphic assemblage comprises 1900±100 Ma old highly tectonised porphyritic granite characterised by low initial strontium isotope ratio, the upper high -grade metamorphic group is intruded by 20±1 Ma old anatectic granites characterised by garnet, kyanite, sillimanite and cordierite, and a high but variable value of strontium isotope ratio. Moreover, the anatectic Lower Miocene granites are singularly absent in the succession of the Lesser Himalayan nappes. Probably it is this thrust that has flexed downwards the plane of decoupling and displacement between the under thrusting Indian plate and the overlying Himalayan mass.
 The terrane-defining fault between the high-grade metamorphics with granitic rocks of the Himadri (i.e., Great Himalaya) and the Tethyan sedimentary pile was recognised as the Malari Thrust Fault in the northern Kumaun Himalaya in the early seventies, as the South Tibetan Detachment System in southern Tibet adjoining north-eastern Nepal in the early eighties and as the Zanskar Shear Zone in north-western Himachal Pradesh in the late eighties. Not only is there an abrupt change in the metamorphic grade across the tectonic plane, but also an attenuation and wholesale elimination of some lithostratigraphic formations of the hanging wall besides the difference in the style of deformation. Exhibiting predominant dip-slip movement in the central sector of the Himalayan arc, the Trans-Himadri Fault (T-HF) was formed as a consequence of the Tethyan sedimentary cover detaching from its rigid foundation of the basement complex that was squeezed up following blocking or slowing down of tectonic movements related to India-Asia convergence. The sedimentary cover lagging behind the thrust­ up basement complex slid down and toppled over northward and gave rise to back-folds and back-thrusts. In Kashmir, western Himachal Pradesh, central Nepal and north-western Bhutan, in sharp contrast, there was very strong compression, so that the Tethyan sedimentary rocks-along with a slice of the low-grade metamorphic basement in the hanging wall advanced southwards across the Himadri and were emplaced as nappes and klippen south of the Main Central Thrust. The T-HF movement occurred approximately around 20.9 Ma, although the movement had started quite earlier in some places. Quaternary reactivation resulted in river ponding and development of huge lakes such as the Garbyang palaeolake in the Kali valley and the ~ 40,000 year-old Goting palaeolake in the Western Dhauli Valley.

Vegetation in river floodplains has significant influence on the flood hydraulics and fate of suspended
 sediments, nutrients and contaminants. In the present, work preliminary 3-D calculations were
 performed to examine the effect of vegetation on the mean flow in open channels using the CFD
 model CFX-12.1, employing the RANS k-epsilon turbulence model. Calculated flow velocity
 distributions were compared against an experiment of free surface uniform flow in a vegetated
 experimental channel, filled with cylindrical submerged elements representing vegetation; these
 elements were rigid and arranged in a staggered pattern.
 Four unstructured numerical grids were employed, ranging from approximately 9.5 to 27.5 millions of
 tetrahedral elements. The main characteristics of the flow were (a) the formation of small recirculation
 regions in the wakes of the cylinders and (b) the relative uniform flow conditions
 throughout the length of the channel. Low flow velocities were observed in the vegetated region,
 implying the resistance due to vegetation, and higher velocities close to the free surface. The best
 agreement with experimental data was achieved for the finest grid that also included grid refinement
 at the top of the cylinders. Grid independence behaviour using relatively very fine grids was rather
 surprising and requires further detailed investigation.