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Abstract While high circulating tumor DNA (ctDNA) levels are associated with poor survival for multiple cancers, variant-specific differences in the association of ctDNA levels and survival have not been examined. Here we investigate KRAS ctDNA (ctKRAS) variant-specific associations with overall and progression-free survival (OS/PFS) in first-line metastatic pancreatic ductal adenocarcinoma (mPDAC) for patients receiving chemoimmunotherapy (“PRINCE”, NCT03214250), and an independent cohort receiving standard of care (SOC) chemotherapy. For PRINCE, higher baseline plasma levels are associated with worse OS for ctKRAS G12D (log-rank p = 0.0010) but not G12V (p = 0.7101), even with adjustment for clinical covariates. Early, on-therapy clearance of G12D (p = 0.0002), but not G12V (p = 0.4058), strongly associates with OS for PRINCE. Similar results are obtained for the SOC cohort, and for PFS in both cohorts. These results suggest ctKRAS G12D but not G12V as a promising prognostic biomarker for mPDAC and that G12D clearance could also serve as an early biomarker of response.

Abstract The demand for open data and open science is on the rise, fueled by expectations from the scientific community, calls to increase transparency and reproducibility in research findings, and developments such as the Final Data Management and Sharing Policy from the U.S. National Institutes of Health and a memorandum on increasing public access to federally funded research, issued by the U.S. Office of Science and Technology Policy. This paper explores the pivotal role of data repositories in biomedical research and open science, emphasizing their importance in managing, preserving, and sharing research data. Our objective is to familiarize readers with the functions of data repositories, set expectations for their services, and provide an overview of methods to evaluate their capabilities. The paper serves to introduce fundamental concepts and community-based guiding principles and aims to equip researchers, repository operators, funders, and policymakers with the knowledge to select appropriate repositories for their data management and sharing needs and foster a foundation for the open sharing and preservation of research data.

Abstract Submarine groundwater discharge (SGD) supplies nutrients, carbon, metals, and radionuclide tracers to estuarine and coastal waters. One aspect of SGD that is poorly recognized is its direct effect on dissolved oxygen (DO) demand in receiving waters, denoted here as SGD-OD. Sulfate-mediated oxidation of organic matter in salty coastal aquifers produces numerous reduced byproducts including sulfide, ammonia, dissolved organic carbon and nitrogen, methane, and reduced metals. When these byproducts are introduced to estuarine and coastal systems by SGD and are oxidized, they may substantially reduce the DO concentration in receiving waters and impact organisms living there. We consider six estuarine and coastal sites where SGD derived fluxes of reduced byproducts are well documented. Using data from these sites we present a semiquantitative model to estimate the effect of these byproducts on DO in the receiving waters. Without continued aeration with atmospheric oxygen, the study sites would have experienced periodic hypoxic conditions due to SGD-OD. The presence of H2S supplied by SGD could also impact organisms. This process is likely prevalent in other systems worldwide.

Background: Ketamine has emerged as one of the most promising therapies for treatment-resistant depression. However, inter-individual variability in response to ketamine is still not well understood and it is unclear how ketamine’s molecular mechanisms connect to its neural and behavioral effects. Methods: We conducted a single-blind placebo-controlled study, with participants blinded to their treatment condition. 40 healthy participants received acute ketamine (initial bolus 0.23 mg/kg, continuous infusion 0.58 mg/kg/hr). We quantified resting-state functional connectivity via data-driven global brain connectivity and related it to individual ketamine-induced symptom variation and cortical gene expression targets. Results: We found that: (i) both the neural and behavioral effects of acute ketamine are multi-dimensional, reflecting robust inter-individual variability; (ii) ketamine’s data-driven principal neural gradient effect matched somatostatin (SST) and parvalbumin (PVALB) cortical gene expression patterns in humans, while the mean effect did not; and (iii) behavioral data-driven individual symptom variation mapped onto distinct neural gradients of ketamine, which were resolvable at the single-subject level. Conclusions: These results highlight the importance of considering individual behavioral and neural variation in response to ketamine. They also have implications for the development of individually precise pharmacological biomarkers for treatment selection in psychiatry. Funding: This study was supported by NIH grants DP5OD012109-01 (A.A.), 1U01MH121766 (A.A.), R01MH112746 (J.D.M.), 5R01MH112189 (A.A.), 5R01MH108590 (A.A.), NIAAA grant 2P50AA012870-11 (A.A.); NSF NeuroNex grant 2015276 (J.D.M.); Brain and Behavior Research Foundation Young Investigator Award (A.A.); SFARI Pilot Award (J.D.M., A.A.); Heffter Research Institute (Grant No. 1–190420) (FXV, KHP); Swiss Neuromatrix Foundation (Grant No. 2016–0111) (FXV, KHP); Swiss National Science Foundation under the framework of Neuron Cofund (Grant No. 01EW1908) (KHP); Usona Institute (2015 – 2056) (FXV). Clinical trial number: NCT03842800

Abstract Macromolecular damage leading to cell, tissue and ultimately organ dysfunction is a major contributor to aging. Intracellular reactive oxygen species (ROS) resulting from normal metabolism cause most damage to macromolecules and the mitochondria play a central role in this process as they are the principle source of ROS. The relationship between naturally occurring variations in the mitochondrial (MT) genomes leading to correspondingly less or more ROS and macromolecular damage that changes the rate of aging associated organismal decline remains relatively unexplored. MT complex I, a component of the electron transport chain (ETC), is a key source of ROS and the NADH dehydrogenase subunit 5 (ND5) is a highly conserved core protein of the subunits that constitute the backbone of complex I. Using Daphnia as a model organism, we explored if the naturally occurring sequence variations in ND5 correlate with a short or long lifespan. Our results indicate that the short-lived clones have ND5 variants that correlate with reduced complex I activity, increased oxidative damage, and heightened expression of ROS scavenger enzymes. Daphnia offers a unique opportunity to investigate the association between inherited variations in components of complex I and ROS generation which affects the rate of aging and lifespan.

Detection and identification of species, subspecies or stocks of whales, dolphins and porpoises at sea remain challenging, particularly for cryptic or elusive species like beaked whales (Family: Ziphiidae). Here we investigated the potential for using an acoustically assisted sampling design to collect environmental (e)DNA from beaked whales on the U.S. Navy's Atlantic Undersea Test and Evaluation Center (AUTEC) in The Bahamas. During 12 days of August 2019, we conducted 9 small-boat surveys and collected 56 samples of seawater (paired subsamples of 1L each, including controls) using both a spatial collection design in the absence of visual confirmation of whales, and a serial collection design in the proximity of whales at the surface. There were 7 sightings of whales, including 11 Blainville's beaked whales (Mesoplodon densirostris). All whales were located initially with the assistance of information from a bottom-mounted acoustic array available on the AUTEC range. Quantification by droplet digital (dd)PCR from the four spatial design collections showed no samples of eDNA above the threshold of detection and none of these 20 samples yielded amplicons for conventional or next-generation sequencing. Quantification of the 31 samples from four serial collections identified 11 likely positive detections. eDNA barcoding by conventional sequencing and eDNA metabarcoding by next-generation sequencing confirmed species identification for 9 samples from three of the four serial collections. We further resolved five intra-specific variants (i.e., haplotypes), two of which showed an exact match to previously published haplotypes and three that have not been reported previously to the international repository, GenBank. A minimum spanning network of the five eDNA haplotypes, with all other published haplotypes of Blainville's beaked whales, suggested the potential for further resolution of differences between oceanic populations.

Primary rectal squamous cell carcinoma is rare compared to adenocarcinoma, which is the predominant histologic type most commonly discovered at the time of colorectal carcinoma diagnosis. Due to the infrequent nature of this malignancy, data on tumor pathogenesis and risk factors remains sparse. Moreover, no standardized therapeutic regimen exists. This report describes a case of advanced rectal squamous cell carcinoma diagnosed in a 46-year-old female who initially presented with abdominal pain. Her clinical course was uncomplicated and she responded well to the selected therapy. Much work remains to be accomplished for patients with rectal squamous cell carcinoma.

Abstract The Global Alliance of Disaster Research Institutes held its 3rd Global Summit of Research Institutes for Disaster Risk Reduction at the Disaster Prevention Research Institute, Kyoto University, Japan, 19–21 March, 2017. The Global Alliance seeks to contribute to enhancing disaster risk reduction (DRR) and disaster resilience through the collaboration of research organizations around the world. The summit aim was to expand the platform for bridging science and policy making by evaluating the evidence base needed to meet the expected outcomes and actions of the Sendai Framework for Disaster Risk Reduction 2015–2030 and its Science and Technology Roadmap. The summit reflected the international nature of collaborative research and action. A pre-conference questionnaire filled out by Global Alliance members identified 323 research projects that are indicative of current research. These were categorized to support seven parallel discussion sessions related to the Sendai Framework priorities for action. Four discussion sessions focused on research that aims to deepen the understanding of disaster risks. Three cross-cutting sessions focused on research that is aimed at the priorities for action on governance, resilience, and recovery. Discussion summaries were presented in plenary sessions in support of outcomes for widely enhancing the science and policy of DRR.

Telomeres, comprised of short repetitive sequences, are essential for genome stability and have been studied in relation to cellular senescence and aging. Telomerase, the enzyme that adds telomeric repeats to chromosome ends, is essential for maintaining the overall telomere length. A lack of telomerase activity in mammalian somatic cells results in progressive shortening of telomeres with each cellular replication event. Mammals exhibit high rates of cell proliferation during embryonic and juvenile stages but very little somatic cell proliferation occurs during adult and senescent stages. The telomere hypothesis of cellular aging states that telomeres serve as an internal mitotic clock and telomere length erosion leads to cellular senescence and eventual cell death. In this report, we have examined telomerase activity, processivity, and telomere length in Daphnia, an organism that grows continuously throughout its life. Similar to insects, Daphnia telomeric repeat sequence was determined to be TTAGG and telomerase products with five-nucleotide periodicity were generated in the telomerase activity assay. We investigated telomerase function and telomere lengths in two closely related ecotypes of Daphnia with divergent lifespans, short-lived D. pulex and long-lived D. pulicaria. Our results indicate that there is no age-dependent decline in telomere length, telomerase activity, or processivity in short-lived D. pulex. On the contrary, a significant age dependent decline in telomere length, telomerase activity and processivity is observed during life span in long-lived D. pulicaria. While providing the first report on characterization of Daphnia telomeres and telomerase activity, our results also indicate that mechanisms other than telomere shortening may be responsible for the strikingly short life span of D. pulex.

Exposure to traffic is an established risk factor for the triggering of myocardial infarction (MI). Particulate matter, mainly emitted by diesel vehicles, appears to be the most important stressor. However, the possible influence of benzene from gasoline-fueled cars has not been explored so far.We conducted a case-crossover study from 2,134 MI cases recorded by the local Coronary Heart Disease Registry (2000-2007) in the Strasbourg Metropolitan Area (France). Available individual data were age, gender, previous history of ischemic heart disease and address of residence at the time of the event. Nitrogen dioxide, particles of median aerodynamic diameter

The cerebellar vermis (lobules VI-VII) has been implicated in both postmortem and neuroimaging studies of autism spectrum disorders (ASD). This region maintains the consistent accuracy of saccadic eye movements and plays an especially important role in correcting systematic errors in saccade amplitudes such as those induced by adaptation paradigms. Saccade adaptation paradigms have not yet been used to study ASD. Fifty-six individuals with ASD and 53 age-matched healthy controls performed an intrasaccadic target displacement task known to elicit saccadic adaptation reflected in an amplitude reduction. The rate of amplitude reduction and the variability of saccade amplitude across 180 adaptation trials were examined. Individuals with ASD adapted slower than healthy controls, and demonstrated more variability of their saccade amplitudes across trials prior to, during and after adaptation. Thirty percent of individuals with ASD did not significantly adapt, whereas only 6% of healthy controls failed to adapt. Adaptation rate and amplitude variability impairments were related to performance on a traditional neuropsychological test of manual motor control. The profile of impaired adaptation and reduced consistency of saccade accuracy indicates reduced neural plasticity within learning circuits of the oculomotor vermis that impedes the fine-tuning of motor behavior in ASD. These data provide functional evidence of abnormality in the cerebellar vermis that converges with previous reports of cellular and gross anatomic dysmorphology of this brain region in ASD.

Spermine synthase (SMS) is a key enzyme controlling the concentration of spermidine and spermine in the cell. The importance of SMS is manifested by the fact that single missense mutations were found to cause Snyder-Robinson Syndrome (SRS). At the same time, currently there are no non-synonymous single nucleoside polymorphisms, nsSNPs (harmless mutations), found in SMS, which may imply that the SMS does not tolerate amino acid substitutions, i.e. is not mutable.To investigate the mutability of the SMS, we carried out in silico analysis and in vitro experiments of the effects of amino acid substitutions at the missense mutation sites (G56, V132 and I150) that have been shown to cause SRS. Our investigation showed that the mutation sites have different degree of mutability depending on their structural micro-environment and involvement in the function and structural integrity of the SMS. It was found that the I150 site does not tolerate any mutation, while V132, despite its key position at the interface of SMS dimer, is quite mutable. The G56 site is in the middle of the spectra, but still quite sensitive to charge residue replacement.The performed analysis showed that mutability depends on the detail of the structural and functional factors and cannot be predicted based on conservation of wild type properties alone. Also, harmless nsSNPs can be expected to occur even at sites at which missense mutations were found to cause diseases.

BACKGROUND: BCG vaccination, combined with adenoviral-delivered boosts, represents a reasonable strategy to augment, broaden and prolong immune protection against tuberculosis (TB). We tested BCG (SSI1331) (in 6 animals, delivered intradermally) and a recombinant (rBCG) AFRO-1 expressing perfringolysin (in 6 animals) followed by two boosts (delivered intramuscullary) with non-replicating adenovirus 35 (rAd35) expressing a fusion protein composed of Ag85A, Ag85B and TB10.4, for the capacity to induce antigen-specific cellular immune responses in rhesus macaques (Macaca mulatta). Control animals received diluent (3 animals). METHODS AND FINDINGS: Cellular immune responses were analyzed longitudinally (12 blood draws for each animal) using intracellular cytokine staining (TNF-alpha, IL-2 and IFN-gamma), T cell proliferation was measured in CD4(+), CD8alpha/beta(+), and CD8alpha/alpha(+) T cell subsets and IFN-gamma production was tested in 7 day PBMC cultures (whole blood cell assay, WBA) using Ag85A, Ag85B, TB10.4 recombinant proteins, PPD or BCG as stimuli. Animals primed with AFRO-1 showed i) increased Ag85B-specific IFN-gamma production in the WBA assay (median >400 pg/ml for 6 animals) one week after the first boost with adenoviral-delivered TB-antigens as compared to animals primed with BCG (