[1] Toward understanding the relationship between strain accumulation and strain release in the context of the mechanics of the earthquake and mountain building process and quantifying the seismic hazard associated with the globes largest continental thrust system, we describe the late Quaternary expression and paleoseismic evidence for great surface rupture earthquakes at six sites along the Himalayan Frontal Thrust (HFT) system of India. Our observations span a distance of $250 km along strike of the HFT. Uplifted and truncated fluvial terrace deposits resulting from the Holocene displacements on the HFT are preserved along canyons of the Ghaggar, Markanda, Shajahanpur, and Kosi Rivers. Dividing the elevation of the bedrock straths at each site by their ages yields estimates of the vertical uplift rate of $4-6 mm/yr, which when assumed to be the result of slip on an underlying thrust dipping at $20°-45°are equivalent to fault slip rates of $6-18 mm/yr or shortening rates of $4-16 mm/yr. Trench exposures reveal the HFT to fold and break late Holocene surface sediments near the cities and villages of Chandigarh, Kala Amb, Rampur Ganda, Lal Dhang, and Ramnagar. Radiocarbon ages of samples obtained from the displaced sediments indicate surface rupture at each site took place after $A.D. 1200 and before $A.D. 1700. Uncertainties attendant to the radiocarbon dating currently do not allow an unambiguous definition of the capping bound on the age of the displacement at each site and hence whether or not the displacements at all sites were contemporaneous. Trench exposures and vertical separations measured across scarps at Rampur Ganda, Lal Dhang, and Ramnagar are interpreted to indicate single-event displacements of $11-38 m. Dividing the observed single-event vertical components of displacement by the estimated longer-term uplift rates indicates $1330-3250 or more years should be required to accumulate the slip sufficient to produce similar sized displacements. Surface rupture appears to not have occurred during the historical 1905 Kangra (M w = 7.7), 1934 Bihar-Nepal (M w = 8.1), and 1950 Assam (M w = 8.4) earthquakes, which also occurred along the Himalayan front. Yet we observe clear evidence of fault scarps and displacements in young alluvium and progressive and continued offset of fluvial terrace deposits along the HFT. We suggest on this basis and the size and possible synchroneity of displacements recorded in the trenches that there exists the potential for earthquakes larger than recorded in the historical record and with the potential to rupture lengths of the HFT greater than the $250 km we have studied.

The ∼2500 km long Himalayan arc has experienced three large to great earthquakes of Mw 7.8 to 8.4 during the past century, but none produced surface rupture. Paleoseismic studies have been conducted during the last decade to begin understanding the timing, size, rupture extent, return period, and mechanics of the faulting associated with the occurrence of large surface rupturing earthquakes along the ∼2500 km long Himalayan Frontal Thrust (HFT) system of India and Nepal. The previous studies have been limited to about nine sites along the western two‐thirds of the HFT extending through northwest India and along the southern border of Nepal. We present here the results of paleoseismic investigations at three additional sites further to the northeast along the HFT within the Indian states of West Bengal and Assam. The three sites reside between the meizoseismal areas of the 1934 Bihar‐Nepal and 1950 Assam earthquakes. The two westernmost of the sites, near the village of Chalsa and near the Nameri Tiger Preserve, show that offsets during the last surface rupture event were at minimum of about 14 m and 12 m, respectively. Limits on the ages of surface rupture at Chalsa (site A) and Nameri (site B), though broad, allow the possibility that the two sites record the same great historical rupture reported in Nepal around A.D. 1100. The correlation between the two sites is supported by the observation that the large displacements as recorded at Chalsa and Nameri would most likely be associated with rupture lengths of hundreds of kilometers or more and are on the same order as reported for a surface rupture earthquake reported in Nepal around A.D. 1100. Assuming the offsets observed at Chalsa and Nameri occurred synchronously with reported offsets in Nepal, the rupture length of the event would approach 700 to 800 km. The easternmost site is located within Harmutty Tea Estate (site C) at the edges of the 1950 Assam earthquake meizoseismal area. Here the most recent event offset is relatively much smaller (<2.5 m), and radiocarbon dating shows it to have occurred after A.D. 1100 (after about A.D. 1270). The location of the site near the edge of the meizoseismal region of the 1950 Assam earthquake and the relatively lesser offset allows speculation that the displacement records the 1950 Mw 8.4 Assam earthquake. Scatter in radiocarbon ages on detrital charcoal has not resulted in a firm bracket on the timing of events observed in the trenches. Nonetheless, the observations collected here, when taken together, suggest that the largest of thrust earthquakes along the Himalayan arc have rupture lengths and displacements of similar scale to the largest that have occurred historically along the world's subduction zones.

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Abstract. Along the Himalayan thrust front in northwestern India, terrace deposits exposed 20 to 30 m above modern stream level are interpreted to have been uplifted by displacement on the underlying Himalayan Frontal Thrust. A radiocarbon age limits the age of the terrace to _< 1665 + 215 calendar BC (_< 3663 + 215 radiocarbon years before present), yielding a vertical uplift rate of _> 6.9 + 1.8 mm/yr. In combination with published studies constraining the dip of the Himalayan Frontal Thrust fault to about 30 ø in the study area, the observed uplift rate equates to horizontal shortening across the Himalayan Frontal Thrust of > 11.9 + 3.1 mm/yr and the slip rate of the Himalayan Frontal Thrust of > 13.8 + 3.6 mm/yr. This is similar to previously reported rate estimates along the Himalayan arc based on displacement of older PlioMiocene age rocks, or the much shorter records of geodesy and historical seismicity. The similarity is consistent with the idea that convergence across the Himalayan front has occurred at a relatively steady rate through time. The seismic expression of this deformation includes several great (M-8) historical earthquakes which, due to lack of surface rupture during those events, have been attributed to their occurrence on blind thrusts. Yet, the occurrence of a possible fault scarp in the field area indicates that past earthquakes have been sufficiently large to rupture to the surface and produce coseismic scarps. These observations suggest a potential for earthquakes along the Himalayan Frontal Thrust larger than those observed historically.

The Black Mango fault is a structural discontinuity that transforms motion between two segments of the active Himalayan Frontal Thrust (HFT) in northwestern India. The Black Mango fault displays evidence of two large surface rupture earthquakes during the past 650 years, subsequent to 1294 A.D. and 1423 A.D., and possibly another rupture at about 260 A.D. Displacement during the last two earthquakes was at minimum 4.6 meters and 2.4 to 4.0 meters, respectively, and possibly larger for the 260 A.D. event. Abandoned terraces of the adjacent Markanda River record uplift due to slip on the underlying HFT of 4.8 +/- 0.9 millimeters per year or greater since the mid-Holocene. The uplift rate is equivalent to rates of fault slip and crustal shortening of 9.6(-3.5)(+7.0) millimeters per year and 8.4(-3.6)(+7.3) millimeters per year, respectively, when it is assumed that the HFT dips 30 degrees +/- 10 degrees.

Increasing evidence suggests that the process of alpha‐synuclein (α‐syn) aggregation from monomers into amyloid fibrils and Lewy bodies, via oligomeric intermediates plays an essential role in the pathogenesis of different synucleinopathies, including Parkinson's disease (PD), multiple system atrophy and dementia with Lewy bodies (DLB). However, the nature of the toxic species and the mechanisms by which they contribute to neurotoxicity and disease progression remain elusive. Over the past two decades, significant efforts and resources have been invested in studies aimed at identifying and targeting toxic species along the pathway of α‐syn fibrillization. Although this approach has helped to advance the field and provide insights into the biological properties and toxicity of different α‐syn species, many of the fundamental questions regarding the role of α‐syn aggregation in PD remain unanswered, and no therapeutic compounds targeting α‐syn aggregates have passed clinical trials. Several factors have contributed to this slow progress, including the complexity of the aggregation pathways and the heterogeneity and dynamic nature of α‐syn aggregates. In the majority of experiment, the α‐syn samples used contain mixtures of α‐syn species that exist in equilibrium and their ratio changes upon modifying experimental conditions. The failure to quantitatively account for the distribution of different α‐syn species in different studies has contributed not only to experimental irreproducibility but also to misinterpretation of results and misdirection of valuable resources. Towards addressing these challenges and improving experimental reproducibility in Parkinson's research, we describe here a simple centrifugation‐based filtration protocol for the isolation, quantification and assessment of the distribution of α‐syn monomers, oligomers and fibrils, in heterogeneous α‐syn samples of increasing complexity. The protocol is simple, does not require any special instrumentation and can be performed rapidly on multiple samples using small volumes. Here, we present and discuss several examples that illustrate the applications of this protocol and how it could contribute to improving the reproducibility of experiments aimed at elucidating the structural basis of α‐syn aggregation, seeding activity, toxicity and pathology spreading. This protocol is applicable, with slight modifications, to other amyloid‐forming proteins.

Semen enhances HIV infection in vitro, but how long it retains this activity has not been carefully examined. Immediately postejaculation, semen exists as a semisolid coagulum, which then converts to a more liquid form in a process termed liquefaction. We demonstrate that early during liquefaction, semen exhibits maximal HIV-enhancing activity that gradually declines upon further incubation. The decline in HIV-enhancing activity parallels the degradation of peptide fragments derived from the semenogelins (SEMs), the major components of the coagulum that are cleaved in a site-specific and progressive manner upon initiation of liquefaction. Because amyloid fibrils generated from SEM fragments were recently demonstrated to enhance HIV infection, we set out to determine whether any of the liquefaction-generated SEM fragments associate with the presence of HIVenhancing activity. We identify SEM1 from amino acids 86 to 107 [SEM1(86-107)] to be a short, cationic, amyloidogenic SEM peptide that is generated early in the process of liquefaction but that, conversely, is lost during prolonged liquefaction due to the activity of serine proteases. Synthetic SEM1(86-107) amyloids directly bind HIV-1 virions and are sufficient to enhance HIV infection of permissive cells. Furthermore, endogenous seminal levels of SEM1(86-107) correlate with donor-dependent variations in viral enhancement activity, and antibodies generated against SEM1(86-107) recognize endogenous amyloids in human semen. The amyloidogenic potential of SEM1(86-107) and its virus-enhancing properties are conserved among great apes, suggesting an evolutionarily conserved function. These studies identify SEM1(86-107) to be a key, HIV-enhancing amyloid species in human semen and underscore the dynamic nature of semen's HIV-enhancing activity. IMPORTANCESemen, the most common vehicle for HIV transmission, enhances HIV infection in vitro, but how long it retains this activity has not been investigated. Semen naturally undergoes physiological changes over time, whereby it converts from a gel-like consistency to a more liquid form. This process, termed liquefaction, is characterized at the molecular level by site-specific and progressive cleavage of SEMs, the major components of the coagulum, by seminal proteases. We demonstrate that the HIV-enhancing activity of semen gradually decreases over the course of extended liquefaction and identify a naturally occurring semenogelin-derived fragment, SEM1(86-107), whose levels correlate with virus-enhancing activity over the course of liquefaction. SEM1(86-107) amyloids are naturally present in semen, and synthetic SEM1(86-107) fibrils bind virions and are sufficient to enhance HIV infection. Therefore, by characterizing dynamic changes in the HIV-enhancing activity of semen during extended liquefaction, we identified SEM1(86-107) to be a key virus-enhancing component of human semen. Human semen is a complex biological fluid that begins as a gelatinous structure and, over time, undergoes regulated changes in consistenc...

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