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Grain-size analysis of the sediments in borehole M0079A, located in the Corinth Rift, was used to explore hydrodynamic conditions and provenance in the Late Pleistocene Corinth Rift. Grain-size populations that were sensitive to the sedimentary environments were characterized by frequency distribution, particle size–standard deviation and probability cumulative curves. Our results indicate the grain-size population component in the range 0.15–0.25 µm may be used as a sensitive proxy for hyperpycnal flows, which have commonly been triggered by river floods from the southern margin of the rift since c. 0.593–0.613 Ma. The high-density plumes derived from the longer rivers of the southern rift that were prevalent before c. 0.593–0.613 Ma. When sediment is supplied as hemipelagic deposition, the proportion of the total grain-size population that is in the 0.3–0.5 µm range becomes an index for suspension fall-out deposits. The core shows coarser sediments during the marine periods, and this may be linked to the current circulation related to the Ishtmia Strait opening. The study thus illustrates how the establishment of interbasinal straits can influence the details of sedimentary hydrodynamics in the deep-water axis of an adjacent depocentre.

Over 500 clinical trials are investigating combination radiotherapy and immune checkpoint blockade (ICB) as cancer treatments; however, the majority of trials have found no positive interaction. Here we perform a comprehensive molecular analysis of a randomized phase I clinical trial of patients with non-small cell lung cancer (NSCLC) treated with concurrent or sequential ablative radiotherapy and ICB. We show that concurrent treatment is superior to sequential treatment in augmenting local and distant tumor responses and in improving overall survival in a subset of patients with immunologically cold, highly aneuploid tumors, but not in those with less aneuploid tumors. In addition, radiotherapy alone decreases intratumoral cytotoxic T cell and adaptive immune signatures, whereas radiotherapy and ICB upregulates key immune pathways. Our findings challenge the prevailing paradigm that local ablative radiotherapy beneficially stimulates the immune response. We propose the use of tumor aneuploidy as a biomarker and therapeutic target in personalizing treatment approaches for patients with NSCLC treated with radiotherapy and ICB.

To evaluate the clinical impact of molecular tumor profiling (MTP) with targeted sequencing panel tests, pediatric patients with extracranial solid tumors were enrolled in a prospective observational cohort study at 12 institutions. In the 345-patient analytical population, median age at diagnosis was 12 years (range 0-27.5); 298 patients (86%) had 1 or more alterations with potential for impact on care. Genomic alterations with diagnostic, prognostic or therapeutic significance were present in 61, 16 and 65% of patients, respectively. After return of the results, impact on care included 17 patients with a clarified diagnostic classification and 240 patients with an MTP result that could be used to select molecularly targeted therapy matched to identified alterations (MTT). Of the 29 patients who received MTT, 24% had an objective response or experienced durable clinical benefit; all but 1 of these patients received targeted therapy matched to a gene fusion. Of the diagnostic variants identified in 209 patients, 77% were gene fusions. MTP with targeted panel tests that includes fusion detection has a substantial clinical impact for young patients with solid tumors.

DNA double strand breaks (DSBs), neuroinflammation, and vascular alterations in the brain are all associated with neurodegenerative disorders. However, the interconnections between these neuropathological changes and how they act synergistically to promote irreversible neurodegeneration remain unclear. Here we show that abrogating the BRCA1-associated protein Brap in cerebral cortical neurons, as opposed to vascular endothelium cells, causes cerebrovascular defects. This non-cell autonomous effect is mediated by cellular senescence resulting from persistent neuronal DSBs. We show that in the state of senescence, there is a massive upregulation of genes involved in cell secretion, inflammatory responses, and vascular changes, which coincides with cerebral microclots and microbleeds. The vascular lesions intertwine with neuroinflammation and exacerbate neuronal DSBs, culminating in oxidative stress, metabolic alteration, and downregulation of genes essential for neuronal function. By demonstrating the cerebrovascular impact of cortical neuronal DSBs, our data suggest that senescence-associated secretory phenotype can initiate brain-wide neurodegeneration.

Large earthquakes in the Tibetan Plateau generally occur on block-boundary faults and produce coseismic surface ruptures that indicate the sense of block movement. However, seismic hazard in the block is less concerned. The Mw 7.3 Maduo earthquake on 22 May 2021 hit the internal Bayan Har block, which provides a rare opportunity to study the deformation features of the intra-block tectonics in central Tibet and related kinematics implications. We developed the high-resolution survey via the DJI drone of Phantom 4 Pro RTK and detailed field observations, to sum up the typical characteristics of the Maduo coseismic surface rupture zone. Then we classified these surface ruptures based on rupture orientation, spatial distribution, and stress state and analyzed their kinematic mechanisms. Our results indicate that (1) the typical surface ruptures of the Maduo earthquake are shear fractures, tensional cracks, and mole tracks, which follow the Riedel shear model; (2) the Riedel shear structures reveal a sinistral strike-slip movement sense for the seismogenic fault, accordant with regional tectonics; (3) seismic potential on minor faults in the interior block should be emphasized highly. This study will not provide insights into the kinematics of surface ruptures on a strike-slip fault but will strengthen the understanding of seismic hazards on an intra-block active fault.

PURPOSE Multiple FGFR inhibitors are currently in clinical trials enrolling adults with different solid tumors, while very few enroll pediatric patients. We determined the types and frequency of FGFR alterations ( FGFR1-4) in pediatric cancers to inform future clinical trial design. METHODS Tumors with FGFR alterations were identified from two large cohorts of pediatric solid tumors subjected to targeted DNA sequencing: The Dana-Farber/Boston Children's Profile Study (n = 888) and the multi-institution GAIN/iCAT2 (Genomic Assessment Improves Novel Therapy) Study (n = 571). Data from the combined patient population of 1,395 cases (64 patients were enrolled in both studies) were reviewed and cases in which an FGFR alteration was identified by OncoPanel sequencing were further assessed. RESULTS We identified 41 patients with tumors harboring an oncogenic FGFR alteration. Median age at diagnosis was 8 years (range, 6 months-26 years). Diagnoses included 11 rhabdomyosarcomas, nine low-grade gliomas, and 17 other tumor types. Alterations included gain-of-function sequence variants (n = 19), amplifications (n = 10), oncogenic fusions ( FGFR3:: TACC3 [n = 3], FGFR1:: TACC1 [n = 1], FGFR1:: EBF2 [n = 1], FGFR1:: CLIP2 [n = 1], and FGFR2:: CTNNA3 [n = 1]), pathogenic-leaning variants of uncertain significance (n = 4), and amplification in combination with a pathogenic-leaning variant of uncertain significance (n = 1). Two novel FGFR1 fusions in two different patients were identified in this cohort, one of whom showed a response to an FGFR inhibitor. CONCLUSION In summary, activating FGFR alterations were found in approximately 3% (41/1,395) of pediatric solid tumors, identifying a population of children with cancer who may be eligible and good candidates for trials evaluating FGFR-targeted therapy. Importantly, the genomic and clinical data from this study can help inform drug development in accordance with the Research to Accelerate Cures and Equity for Children Act.

We propose an on-axis deflectometric system for the accurate measurement of freeform surfaces with large slope ranges. A miniature plane mirror is attached on the illumination screen to fold the optical path and achieve the on-axis deflectometric testing. Due to the existence of the miniature folding mirror, the deep-learning method is applied to recover the missing surface data in a single measurement. Low sensitivity to the calibration error of system geometry and high testing accuracy can be achieved with the proposed system. The feasibility and accuracy of the proposed system have been validated. The system is low in cost and simple in configuration, and it provides a feasible way for the flexible and general testing of freeform surfaces, with a significant potential of the application in on-machine testing.

Key roles of bisulfite (HSO3–) in food quality assurance and human health necessitate a reliable analytical method for rapid, sensitive, and selective detection of HSO3–. Herein, a new red-emitting ratiometric fluorescence probe, BIQ, is reported for sensitive and selective detection of HSO3– in food samples and live animals. Probe BIQ recognizes HSO3– via a 1,4-nucleophilic addition reaction. As a result of this specific reaction, emission intensities at 625 and 475 nm are dramatically changed, allowing the detection of HSO3– in a ratiometric fluorescence model in an aqueous solution. The obvious changes of solution color from pink to transparent and fluorescence color from rose-red to cyan allow the detection of HSO3– by naked eyes. Furthermore, probe BIQ has fast response in color and fluorescence (

The Araniko and Pasang Lhamu highways are two critical trading routes connecting Nepal and China that are experiencing and are threatened by landsliding. The April 25 Mw 7.8 Gorkha earthquake and its May 12 Mw 7.3 aftershock in 2015 significantly increased landsliding along these highways. Multi-temporal remote sensing images (pre-seismic to December 2017) on Google Earth, aerial photography acquired in 2018 using an unmanned aerial vehicle (UAV), and field investigations and surveys in June 2015, November–December 2017, and April–May 2018 quantify the development of selected landslides after the earthquake along the two highways. These include detailed studies of 39 and 30 landslide locations in 2017 and 2018, respectively, with 14 locations common to both the 2017 and 2018 studies. Only the landslides in five locations showed a slight decrease in activity after the earthquake, and most landslides continued to move and enlarge. More than five new landslides were triggered by monsoon rainfalls in the summers of 2017 and 2018. All the landslides pose significant challenges for infrastructure reconstruction and hazard reduction in the area affected by the Gorkha earthquake, especially along the Araniko and Pasang Lhamu highways. Comparison of landslide debris volume, pre- and post- earthquake rainfalls, and earthquakes that occurred before and after the 2015 Gorkha earthquake with the 1999 Chi-Chi, 2005 Kashmir, and 2008 Wenchuan earthquakes show that continuing rainfall after earthquakes and strong aftershock shaking are key factors affecting continued landsliding in these earthquake-effected areas.

The seismic cycle model is roughly constrained by limited offset data sets from the eastern Altyn Tagh fault with a low slip rate. The recent availability of high-resolution topographic data from the eastern Altyn Tagh fault provides an opportunity to obtain distinctly improved quantitative, dense measurements of fault offsets. In this paper, we used airborne light detection and ranging data and unmanned aircraft vehicle photogrammetry to evaluate fault offsets. To better constrain the large earthquake recurrence model, we acquired dense data sets of fault displacements using the LaDiCaoz_v2.1 software. A total of 321 offset measurements below 30 m highlight two new observations: (1) surface-slip of the most recent earthquake and multiple events exhibit both short-wavelength (m-scale) and long-wavelength (km-scale) variability; and (2) synthesis of offset frequency analysis and coefficient of variation indicate regular slip events with ∼6 m slip increment on fault segments to the west of the Shulehe triple junction. The distribution of offsets and paleoseismological data reveal that the eastern Altyn Tagh fault exhibits characteristic slip behavior, with the characteristic slip of ∼6 m and a recurrence period ranging from 1170 to 3790 years. Paleoearthquake recurrence intervals and slip increments yield mean horizontal slip-rate estimates of 2.1–2.6 mm/yr for fault segments to the west of the Shulehe triple junction. Assuming a 10 km rupture depth and a 30 GPa shear modulus, we estimated a characteristic slip event moment magnitude (Mw) of ∼7.6. Finally, we discuss the interaction mechanism between Altyn Tagh fault (strike fault) and the NW-trending thrust faults (reverse faults) that caused the sudden decrease of sinistral slip rate at the Shulehe and Subei triple junctions; our results support the eastward “lateral slip extrusion” model.

PURPOSE Molecular tumor profiling is becoming a routine part of clinical cancer care, typically involving tumor-only panel testing without matched germline. We hypothesized that integrated germline sequencing could improve clinical interpretation and enhance the identification of germline variants with significant hereditary risks. MATERIALS AND METHODS Tumors from pediatric patients with high-risk, extracranial solid malignancies were sequenced with a targeted panel of cancer-associated genes. Later, germline DNA was analyzed for a subset of these genes. We performed a post hoc analysis to identify how an integrated analysis of tumor and germline data would improve clinical interpretation. RESULTS One hundred sixty participants with both tumor-only and germline sequencing reports were eligible for this analysis. Germline sequencing identified 38 pathogenic or likely pathogenic variants among 35 (22%) patients. Twenty-five (66%) of these were included in the tumor sequencing report. The remaining germline pathogenic or likely pathogenic variants were single-nucleotide variants filtered out of tumor-only analysis because of population frequency or copy-number variation masked by additional copy-number changes in the tumor. In tumor-only sequencing, 308 of 434 (71%) single-nucleotide variants reported were present in the germline, including 31% with suggested clinical utility. Finally, we provide further evidence that the variant allele fraction from tumor-only sequencing is insufficient to differentiate somatic from germline events. CONCLUSION A paired approach to analyzing tumor and germline sequencing data would be expected to improve the efficiency and accuracy of distinguishing somatic mutations and germline variants, thereby facilitating the process of variant curation and therapeutic interpretation for somatic reports, as well as the identification of variants associated with germline cancer predisposition.

Gut epithelial morphogenesis is maintained by intestinal stem cells. Here, we report that depletion of N

BACKGROUND COVID-19, which emerged in December 2019, has spread rapidly around the world and has become a serious public health event endangering human life. With regard to COVID-19, there are still many unknowns, such as the exact case fatality rate (CFR). OBJECTIVE The main objective of this study was to explore the value of the discharged CFR (DCFR) to make more accurate forecasts of epidemic trends of COVID-19 in Italy. METHODS We retrieved the epidemiological data of COVID-19 in Italy published by the John Hopkins Coronavirus Resource Center. We then used the proportion of deaths to discharged cases（including deaths and recovered cases） to calculate the total DCFR (tDCFR), monthly DCFR (mDCFR), and stage DCFR (sDCFR). Furthermore, we analyzed the trend in the mDCFR between January and December 2020 using joinpoint regression analysis, used ArcGIS version 10.7 to visualize the spatial distribution of the epidemic CFR, and assigned different colors to each province based on the CFR or tDCFR. RESULTS We calculated the numbers and obtained the new indices of the tDCFR and mDCFR for calculating the fatality rate. The results showed that the tDCFR and mDCFR fluctuated greatly from January to May. They first showed a rapid increase followed by a rapid decline after reaching the peak. The map showed that the provinces with a high tDCFR were Emilia-Romagna, Puglia, and Lombardia. The change trend of the mDCFR over time was divided into the following 2 stages: the first stage (from January to May) and the second stage (from June to December). With regard to worldwide COVID-19 statistics, among 6 selected countries, the United States had the highest tDCFR (4.26%), while the tDCFR of the remaining countries was between 0.98% and 2.72%. CONCLUSIONS We provide a new perspective for assessing the fatality of COVID-19 in Italy, which can use ever-changing data to calculate a more accurate CFR and scientifically predict the development trend of the epidemic.

Background COVID-19, which emerged in December 2019, has spread rapidly around the world and has become a serious public health event endangering human life. With regard to COVID-19, there are still many unknowns, such as the exact case fatality rate (CFR). Objective The main objective of this study was to explore the value of the discharged CFR (DCFR) to make more accurate forecasts of epidemic trends of COVID-19 in Italy. Methods We retrieved the epidemiological data of COVID-19 in Italy published by the John Hopkins Coronavirus Resource Center. We then used the proportion of deaths to discharged cases（including deaths and recovered cases） to calculate the total DCFR (tDCFR), monthly DCFR (mDCFR), and stage DCFR (sDCFR). Furthermore, we analyzed the trend in the mDCFR between January and December 2020 using joinpoint regression analysis, used ArcGIS version 10.7 to visualize the spatial distribution of the epidemic CFR, and assigned different colors to each province based on the CFR or tDCFR. Results We calculated the numbers and obtained the new indices of the tDCFR and mDCFR for calculating the fatality rate. The results showed that the tDCFR and mDCFR fluctuated greatly from January to May. They first showed a rapid increase followed by a rapid decline after reaching the peak. The map showed that the provinces with a high tDCFR were Emilia-Romagna, Puglia, and Lombardia. The change trend of the mDCFR over time was divided into the following 2 stages: the first stage (from January to May) and the second stage (from June to December). With regard to worldwide COVID-19 statistics, among 6 selected countries, the United States had the highest tDCFR (4.26%), while the tDCFR of the remaining countries was between 0.98% and 2.72%. Conclusions We provide a new perspective for assessing the fatality of COVID-19 in Italy, which can use ever-changing data to calculate a more accurate CFR and scientifically predict the development trend of the epidemic.

Aspiration secondary to impaired swallow function, or dysphagia, is one of the major causes of mortality in patients with Parkinson’s disease (PD). Dysphagia usually does not respond well to medications. Despite its effectiveness on motor fluctuation, dyskinesia and tremor in patients with PD, deep brain stimulation (DBS) is not as effective on axial symptoms of balance, freezing of gait (FOG), speech and swallow function. Studies even raise concerns about axial symptoms under usual high-frequency stimulation (HFS) of the subthalamic nucleus (STN), particularly ON medication.1 STN DBS has various effects on swallow function.2–4 Swallowing involves multiple phases, with oral and pharyngeal phases most critical for bolus clearance and airway protection. However, the impact of different oral textures on aspiration with or without DBS in patients with PD has not been studied.2 Fast-flowing liquids may be more likely to aspirate before and during the swallow, although with less risk of post-swallow aspiration of residue compared with more viscous solids. Dynamic changes in swallow parameters have not been well characterised either.2 A comprehensive evaluation in a randomised double-blind study under various DBS conditions over time is therefore of significant importance. We hypothesised that liquids would more likely yield aspiration than solids, regardless of DBS conditions and assessment timing, and that swallowing measures could worsen in a year. ### Standard protocol approval, registrations and patient consents The study was approved by the institutional review board, with written consents by patients.3 Unlike our previous publications in which only the whole aspiration events (a combination of liquid and solid bolus) were reported using the Penetration-Aspiration Scale (PAS) on the videofluoroscopic swallow study (VFSS),3 the current study (1) further delineated the impact of different oral textures (liquid vs solid bolus) on aspiration and (2) characterised the swallow dynamics across oral and pharyngeal phases, based on the previously obtained VFSS …

The Eastern Himalayan Syntaxis (EHS), as one of the most tectonically active regions on the Earth, is one of the best places to explore the relationship between tectonics and surface exhumation process. The uplift and exhumation history are often by one of two leading models: a stationary or localized “tectonic aneurysm” or a northeasterly “migrating crustal antiform”. Previous researchers have placed great emphasis on the core zone of Namche Barwa antiform. However, the Dongjiu-Milin Fault Zone (DMFZ), which forms the northwestern boundary of the antiform and plays an important role for deformation process in the EHS, is still poorly understood. In this study, we focus on differential late-Cenozoic uplift across the DMFZ. We collected 10 bedrock samples in two vertical transects, one on the northwest side of the DMFZ on the Lhasa block and one on the southeast side on the Namche Barwa antiform, and conducted apatite fission track and zircon fission track analyses. Ten samples collected from the two vertical transects yield AFT ages between 3.2 million years ago (Ma) and 10.3 Ma and ZFT ages between 9.9 Ma and 12.9 Ma. A finite-element analysis reveals that the two sides of the DMFZ have undergone quite different uplift histories and processes in the late-Cenozoic: The Lhasa block is uniformly uplifted, while the Namche Barwa antiform is nonuniformly uplifted similar to a buckle fold. The phenomenon revealed in this study is best explained by a mechanism whereby the EHS is characterized by the northeasterly migration of an antiform.

Searching for an efficient non‑platinum electrocatalyst for oxygen reduction reaction (ORR) is of great significance for some energy conversion devices. In this work, Pd‒Ni‒P hybrid nanocatalysts loaded on nitrogen-doped carbon supports (defined as Pd‒Ni‒P@NC) are prepared by simply reacting Pd(II)/Ni(II)-dimethylglyoxime with NaH2PO2 at 500 °C. Compared with Pd‒P@NC and Ni‒P@NC counterparts, the Pd‒Ni‒P@NC exhibits a more positive onset potential and higher specific/mass activity towards ORR due to the interfacial coupling interaction between Pd3P0.8 and Ni2P. Moreover, it has a higher catalytic durability and better methanol tolerance than commercial Pt/C catalyst. The surface valence state analysis and electrochemistry characterization reveals that the enhanced electrocatalytic performance of Pd‒Ni‒P@NC is attributed to the modified Pd 3d electronic structure and improved charge transfer character, originating from the incorporation of Ni2P component. Our study provides an alternative non‑platinum electrocatalyst for ORR in fuel cell and metal-air battery.

Oncogenic FGFR alterations in the form of activating mutations, amplifications, and fusions are detected in a variety of solid tumors, including those in children. Major advances in FGFR-targeted drug development have led to investigation of multiple generations of FGFR inhibitors in adult clinical trials. In contrast, there are few clinical trials of FGFR inhibitors enrolling children. There is a need to identify and characterize molecular targets including oncogenic FGFR alterations in pediatric cancers so that drug development can occur in accordance with the RACE (Research to Accelerate Cures and Equity) for Children Act. The goal of this study was to determine the frequency and types of FGFR alterations in pediatric cancers to inform future clinical trial design. Tumors with FGFR alterations were identified from two large cohorts of pediatric solid tumors subjected to targeted DNA sequencing: The Dana-Farber/Boston Children’s Profile Study (n=888) and the multi-institution GAIN/iCAT2 (Genomic Assessment Improves Novel Therapy) Study (n=571). Data from the combined patient population of 1,395 cases (64 patients were enrolled in both studies) were reviewed and cases in which an FGFR alteration was identified by OncoPanel sequencing were further assessed. We identified 42 patients with tumors harboring an oncogenic or possibly oncogenic FGFR alteration (FGFR1 in 22; FGFR2 in 4; FGFR3 in 5; FGR4 in 11). Median age at diagnosis was 8 years (range 6 months-26 years old). Diagnoses included 11 rhabdomyosarcomas, 8 low-grade gliomas, 3 high-grade gliomas, and 16 other tumor types. We identified 20 patients with a gain-of-function (GoF) mutation, 10 patients with amplifications (copy number ≥7), 7 patients with fusions, 4 patients with a variant of uncertain significance (VUS) assessed and determined to be possibly oncogenic, and 1 patient with an amplification and VUS. Four of the fusion cases had oncogenic FGFR3-TACC3 (n=3) and FGFR1-TACC1 (n=1) fusions previously reported in the literature. Three cases had novel fusions (FGFR1-EBF2, FGFR1-CLIP2, FGFR2-CTNNA3) found in a spindle cell sarcoma and two low-grade gliomas. Tumors with an FGFR missense mutation were primarily those with oncogenic hotspot mutations in FGFR1 [N546K (n= 5); K656E (n=4)] and FGFR4 [N535K/D (n=2); V550L/E (n=5)]. In summary, this study identified oncogenic FGFR alterations in 42 of 1395 patients (3%) with solid and brain tumors sequenced through the Profile and GAIN/iCAT2 studies who would potentially be eligible for clinical trials evaluating FGFR-targeted therapy. Citation Format: Lorena Lazo De La Vega, Alanna J. Church, Hannah Comeau, Wenjun Kang, AeRang Kim, Navin R. Pinto, Margaret E. Macy, Luke D. Maese, Steven G. DuBois, Bruce E. Johnson, Katherine A. Janeway, Suzanne J. Forrest. Rare FGFR oncogenic alterations in sequenced pediatric solid and brain tumors suggest FGFR is a relevant molecular target in childhood cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3893.

Three-dimensional (3D) printing technology has evolved tremendously in recent years, but due to stringent requirements on surface finish and limited material selection for optical performance purposes, 3D printing optics is still lagging behind. This paper reports on a quantitative study on the printing process of optical lenses using acrylic and cationic combined commercial hybrid material. By utilizing its unique curing property with digital light process technology, we demonstrate the concept of continuous printing in the top-down light projection setup. Also, an equal thickness and equal arc combo method has been proposed and evaluated to further help smooth the surface finish. Millimeter-level spherical lenses have been successfully fabricated, and their optical performance has also been discussed.