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We established a split nanoluciferase complementation assay to rapidly screen for inhibitors that interfere with binding of the receptor binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein with its target receptor, angiotensin-converting enzyme 2 (ACE2). After a screen of 1,200 US Food and Drug Administration (FDA)-approved compounds, we identified bifonazole, an imidazole-based antifungal agent, as a competitive inhibitor of RBD-ACE2 binding. Mechanistically, bifonazole binds ACE2 around residue K353, which prevents association with the RBD, affecting entry and replication of spike-pseudotyped viruses as well as native SARS-CoV-2 and its variants of concern (VOCs). Intranasal administration of bifonazole reduces lethality in K18-hACE2 mice challenged with vesicular stomatitis virus (VSV)-spike by 40%, with a similar benefit after live SARS-CoV-2 challenge. Our screen identified an antiviral agent that is effective against SARS-CoV-2 and VOCs such as Omicron that employ the same receptor to infect cells and therefore has high potential to be repurposed to control, treat, or prevent coronavirus disease 2019 (COVID-19).

The coronavirus disease 2019 (COVID-19) pandemic requires the continued development of safe, long-lasting, and efficacious vaccines for preventive responses to major outbreaks around the world, and especially in isolated and developing countries. To combat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), we characterize a temperature-stable vaccine candidate (TOH-Vac1) that uses a replication-competent, attenuated vaccinia virus as a vector to express a membrane-tethered spike receptor binding domain (RBD) antigen. We evaluate the effects of dose escalation and administration routes on vaccine safety, efficacy, and immunogenicity in animal models. Our vaccine induces high levels of SARS-CoV-2 neutralizing antibodies and favorable T cell responses, while maintaining an optimal safety profile in mice and cynomolgus macaques. We demonstrate robust immune responses and protective immunity against SARS-CoV-2 variants after only a single dose. Together, these findings support further development of our novel and versatile vaccine platform as an alternative or complementary approach to current vaccines., Graphical abstract, To combat SARS-CoV-2, we characterize a novel vaccine candidate (TOH-Vac1) that uses a replication-competent, attenuated vaccinia virus as a vector to express a membrane-tethered spike receptor binding domain antigen. We evaluate the effects of dose escalation and administration routes on vaccine safety, efficacy, and immunogenicity in mice and cynomolgus macaques.

ABO blood groups are associated with genetically predisposed variations in von Willebrand factor (VWF) resulting in higher risks of thrombotic events in non-O blood types and bleeding complications in blood type O. The role of ABO blood groups in progression of traumatic intracranial hemorrhage (TICH) is unknown. Given statistically lower VWF levels in blood type O in the general population, we hypothesized that blood type O patients have a higher risk of such progression. A retrospective review of adult trauma patients with isolated TICH admitted to a Level 1 trauma center over eight years was conducted. Patients were categorized with blood type O and non-O (types A, B, AB) delineation. The primary outcome was radiological progression of TICH during the first 24 h. Secondary outcomes included surgical intervention after follow-up computed tomography (CT), complications, days on mechanical ventilation (DMV), intensive care unit (ICU) length of stay (LOS), hospital LOS, and mortality. Of 949 patients, 432 (45.5%) had blood type O. When comparing O and non-O groups, no significant differences were found in gender, age, race, admission vital signs, Glasgow Coma Scale, coagulation profile, TICH type, or Injury Severity Score. No difference in TICH progression was found between O and non-O groups: 73 (17%) vs 80 (15%), respectively, p = 0.55. Blood type O mortality was 12 (3% vs. 23 (4%), p = 0.174). Rate of TICH surgical intervention after follow-up CT, DMV, complications, and ICU and hospital LOS did not differ. No association between ABO blood types and radiological progression of TICH was identified.

Background While modern techniques allow midline fascial closure for most abdominal hernias, a bridge repair with mesh may be the only alternative in very large defects. When the risk of infection is high, the use of prosthetic mesh is controversial. We aim to examine outcomes after bridge repair of very large abdominal hernias at high risk for postoperative infection with a second-generation biologic mesh. Methods Prospective, multicenter, single-arm study of patients with very large abdominal hernias who received bridge repair with a neonatal bovine dermis mesh. Primary outcome was hernia recurrence, as identified on computed tomography 1 year after the operation. Secondary outcomes included mesh laxity, surgical site occurrences, and any other mesh-related complications. Independent risk factors of the outcomes were determined by univariate and multivariable analyses. Results A total of 117 bridge repair patients were enrolled with a mean defect size of 442.5 ± 254.2 cm2. The patients were predominantly obese (mean body mass index 36.5 ± 10.5) and with multiple comorbidities (Charlson comorbidity index 3 ± 2.5). Hernia recurrence was identified in 24 (20.5%) patients. An infected mesh at the index operation was an independent predictor of hernia recurrence, whereas obesity was an independent predictor of the pooled endpoint of recurrence and mesh laxity. Surgical site occurrences were recorded in 36.8% of the patients, and no independent risk factors were identified. Conclusion In patients with very large abdominal hernias and at high risk for postoperative infection, who cannot undergo midline fascial closure, a bridge repair with neonatal bovine dermis mesh offers an acceptable profile in terms of hernia recurrence and wound occurrences.

West Virginia (WV) is situated at the epicenter of the opioid epidemic with the highest rates of overdose deaths and some of the lowest rates of access to life saving evidence-based medication assisted treatment (MAT) for patients with opioid use disorder (OUD). WV used a modified hub-and-spoke model to build organizational capacity for facilities to use buprenorphine to treat patients with OUD and to provide ongoing case consultation. The purpose of this study is to 1) describe the group-base model of buprenorphine treatment and the model used to build organizational capacity, 2) to describe the preliminary results of buprenorphine expansion in WV and 3) to report preliminary data describing and comparing the characteristics of the patients served across five hubs. A single Coordinating Center uses video conferencing to train hubs and provide ongoing case consultation, as well as clinical support. Hubs were trained to deliver a buprenorphine treatment model that is multi-disciplinary and includes group-based medication management and psychosocial therapy. Five regional hubs independently treat patients and are leading MAT expansion in their local areas by training and mentoring spokes (n = 13). As a result of the WV STR funding, 14 health care facilities have started to use buprenorphine, 56 health professionals were trained and 196 patients with OUD have been treated. There were few sociodemographic characteristic differences across patients treated at the five hubs, while there were differences in self-reported alcohol and drug use in the 30 days prior to intake. Additional research is needed to determine whether the WV modified hub-and-spoke model resulted in statistically significant improvements in buprenorphine treatment capacity; there is a need to address MAT stigma and regulatory barriers in order to ensure the long-term sustainability of the buprenorphine expansion.

Multicomponent reactive transport modeling using PHREEQC of a Ni-sulfide tailings deposit was undertaken to assess how effective locally-obtained mineral dissolution rates in simulating long-term kinetic testing results of the tailings material. Forsterite and pyrrhotite were used as proxies for the chemical reactions occuring within the tailings. The dissolution rates of forsterite and pyrrhotite were obtained based on the actual kinetic testing data and PHREEQC inverse modeling. BET (Brunauer Emmet Teller) and geometric surface area-derived rates were used in the kinetic test data simulation and long-term prediction for 100 years. Results indicate that the geochemical models for both the BET and geometric surface area-derived rates are generally consistent with the actual pH, Mg, SO4 and Ni of the kinetic testing data. Long term prediction of effluent chemistry suggests that pH will continue to increase until a stable pH of 8 is achieved while the predicted Mg, SO4 and Ni concentrations will be stable and will be close to the concentrations observed towards the end of the kinetic test. This method of using locally-obtained mineral dissolution rates in multicomponent reactive transport modeling of a kinetic test data has proven to be reliable as compared to using literature dissolution rate values. This method can then be used for a quick and cost-effective way for future effluent chemistry prediction rather than conducting long and expensive kinetic tests.

Quantifying both the lethal and non-lethal (or “risk”) effects of predation has emerged as a major research focus in carnivore-ungulate systems. While numerous studies have examined predation risk and risk effects in recent decades, a lack of standardization in approaches has impeded progress in the field. We provide an overview of five major study design considerations involved in assessing predation risk and responses of prey in carnivore-ungulate systems, highlighting how different design choices can impact the strength and scope of inference. First, we stress the importance of distinguishing measures of predation risk (probability of being killed) from measures of risk effects (costs of antipredator behaviors in response to risk). Second, we recommend explicit consideration of spatial and temporal scales using a standardized framework to facilitate cross-study comparisons. Third, ungulates use visual, auditory, and olfactory sensory pathways to evaluate predation risk. Experiments that manipulate signals of risk (e.g., auditory playbacks or application of predator scent) can be powerful approaches, but the dosages and types of cues need to be carefully considered. Fourth, ungulates usually face threats from multiple predators simultaneously, and we highlight the potential for remote cameras and structural equation modeling to help address this challenge. Fifth, emerging technologies may substantially improve our ability to assess risk. We discuss several promising technologies, such as animal-borne video, unmanned aerial vehicles, and physiological sensors. We conclude with general recommendations for study design, which may improve the utility of predation risk research for the conservation and management of carnivore-ungulate systems.

While pharmacological and/or behavioral treatments are effective in managing symptoms for many patients with psychiatric diagnoses and disorders with behavioral/cognitive manifestations, a subset of individuals are treatment-refractory, unable to achieve appreciable benefit or symptom relief from traditional methods. In recent years, neuromodulation has gained momentum as an adjunctive treatment for improving outcomes in patients who are treatment-refractory. One form of neuromodulation, deep brain stimulation (DBS), has been investigated for the treatment of various psychiatric disorders and behavioral/cognitive symptoms. The following article provides a review of DBS investigations for several psychiatric and behavioral-related disorders, including depression, obsessive-compulsive disorder, substance use disorder, Alzheimer's disease, anorexia, obesity, schizophrenia, and posttraumatic stress disorder. PubMed, PsycINFO, Scopus, Ovid MEDLINE, and Web of Science were used to identify published articles, and Clinicaltrials.gov was used to identify currently ongoing or planned studies. Findings revealed the potential utility of DBS in improving outcomes for various psychiatric and behavioral/cognitive-related disorders. While promising, there are several limitations present in the available literature, and further well-designed clinical trials are necessary before conclusive decisions regarding the utility of DBS for the treatment of these psychiatric/behavioral/cognitive-related disorders can be made. Regardless, the studies included in this review demonstrate positive preliminary findings for the potential benefit of DBS for treatment of a variety of psychiatric disorders, and further research is warranted to better determine the potential utility of DBS for those who are treatment-refractory and unable to achieve symptom relief with standard care.

Relatively little is known of how the world's largest vegetation transition zone – the Forest Tundra Ecotone (FTE) – is responding to climate change. Newly available, satellite-derived time-series of the photochemical reflectance index (PRI) across North America and Europe could provide new insights into the physiological response of evergreen trees to climate change by tracking changes in foliar pigment pools that have been linked to photosynthetic phenology. However, before implementing these data for such purpose at these evergreen dominated systems, it is important to increase our understanding of the fine scale mechanisms driving the connection between PRI and environmental conditions. The goal of this study is thus to gain a more mechanistic understanding of which environmental factors drive changes in PRI during late-season phenological transitions at the FTE – including factors that are susceptible to climate change (i.e., air- and soil-temperatures), and those that are not (photoperiod). We hypothesized that late-season phenological changes in foliar pigment pools captured by PRI are largely driven by photoperiod as opposed to less predictable drivers such as air temperature, complicating the utility of PRI time-series for understanding climate change effects on the FTE. Ground-based, time-series of PRI were acquired from individual trees in combination with meteorological variables and photoperiod information at six FTE sites in Alaska. A linear mixed-effects modeling approach was used to determine the significance (α = 0.001) and effect size (i.e., standardized slope b*) of environmental factors on late-seasonal changes in the PRI signal. Our results indicate that photoperiod had the strongest, significant effect on late-season changes in PRI (b* = 0.08, p

The dissolution rates of forsterite and pyrrhotite in a mine tailings deposit as a function of pH were obtained using kinetic testing (leaching test) and PHREEQC inverse modeling. Leach columns containing nickel sulfide mine tailings from four locations in a tailings deposit were subjected to weekly flushing with distilled water. The dissolved moles of forsterite and pyrrhotite were obtained based on the assumption that bulk of the M g 2 + and S O 4 2 − present in the leachate come from the dissolution of forsterite and pyrrhotite, respectively. The moles dissolved during a steady-state dissolution period were normalized by the BET and geometric surface areas. The dissolution rate with respect to pH was obtained by regressing the plot of log(rate) and log( H + ). This relatively simple method of obtaining dissolution rate of minerals from a heterogeneous material such as mine tailings can be applied to other settings as long as proper mineralogical characterization and modeling constraints are taken into account. The obtained dissolution rates can then be used in reactive transport modeling for the prediction of long-term leachate chemistry of the tailings.

Pin1 is a two-domain human protein that catalyzes the cis–trans isomerization of phospho-Ser/Thr–Pro (pS/T–P) motifs in numerous cell-cycle regulatory proteins. These pS/T–P motifs bind to Pin1's peptidyl-prolyl isomerase (PPIase) domain in a catalytic pocket, between an extended catalytic loop and the PPIase domain core. Previous studies showed that post-translational phosphorylation of S71 in the catalytic loop decreases substrate binding affinity and isomerase activity. To define the origins for these effects, we investigated a phosphomimetic Pin1 mutant, S71E-Pin1, using solution NMR. We find that S71E perturbs not only its host loop but also the nearby PPIase core. The perturbations identify a local network of hydrogen bonds and salt bridges that is more extended than previously thought, and includes interactions between the catalytic loop and the α2/α3 turn in the PPIase core. Explicit-solvent molecular dynamics simulations and phylogenetic analysis suggest that these interactions act as conserved “latches” between the loop and PPIase core that enhance binding of phosphorylated substrates, as they are absent in PPIases lacking pS/T–P specificity. Our results suggest that S71 is a hub residue within an electrostatic network primed for phosphorylation, and may illustrate a common mechanism of phosphorylation-mediated allostery.

Background Chimeric antigen receptor (CAR) T cells targeting BCMA have resulted in deep responses in patients with relapsed MM however most remissions are not sustained. While cellular and molecular mediators of relapse post CAR T therapy are not fully delineated, current data suggest three possible mechanisms including the lack of persistence of the CAR T cell product, acquired exhaustion and less commonly loss of BCMA expression. Methods Using CITE-seq we measured the expansion of variable T cell subsets, T cell specific activation and inhibitor markers and their functional states in serial blood and marrow samples (n=10) collected from patients treated with anti BCMA CAR T cells. Results CAR T cells were identified by the expression of the chimeric CAR T cell transcript. With the exception of one patient where biallelic loss of BCMA was identified at relapse, CAR T cells of resistant patients were enriched with terminally exhausted CD45RA+ cells with loss of CD28, low BCL2L1 (gene encoding BclxL) expression, high CD57 with co-expression of checkpoint inhibitors (LAG3, TIGIT and PD1). The lack of persistence of the CAR T cells product was notable in all relapsing patients consistent with an activation induced cells death (AICD). Conclusions Cognizant of the role BclxL plays in T cells survival in response to CD28 co-stimulatory signaling, we postulated that increasing BclxL expression is a feasible strategy to enhance CAR T cell resistant to AICD, improve their persistence and anti-BCMA reactivity. To this goal, we designed a 2nd generation lentiviral CAR construct where the anti-BCAM scFV-41BBz CAR and the BCL2L1 cDNA were linked with self-cleaving 2A sequence. The efficiency in eradicating MM cells of this BclxL armored CAR (BCL2L1_CAR) was compared to that of non-unarmored CAR (BCMA_CAR) in vitro and in vivo studies. While BCL2L1_CAR and BCMA_CAR were equally cytotoxic to OPM2 MM cells, in MM cell lines expressing the FAS death receptor ligand FASLG (MM1S, OCMY5 and H929) BCL2L1_CAR viability and cytotoxic activity was significantly superior to that of unarmored BCMA_CAR. Of note, the expression of FASLG was upregulated in H929 cells when co-cultured with CAR T cells. Importantly, under chronic antigenic stimulation conditions, where CAR T cells were stimulated every 2 days over a 28 days period with irradiated OPM2 cells, we found no phenotypic difference between BCL2L1_CAR and BCMA_CAR with respect to the composition of Tem cells (CCR7–CD45RO+CD45RA–) or Tcm cells (CCR7+CD45RO+CD45RA–). However, under these chronic antigenic stimulation conditions, the CAR T cells viability, proliferation and anti-MM cytotoxic activities of the BCMA_CAR were dramatically reduced compared to that of the BCL2L1 armored CAR. Therefore BCL2L1 blockade of AICD not only enhanced the viability and cytotoxicity of CAR-T cells but surprisingly also reduced their functional exhaustion. Our findings provide a novel approach for CAR-T optimization and overcoming relapse resulting from lack of persistence.

Background Non-fatal opioid-related overdoses have increased significantly over the past two decades and there have been increasing reports of brain injuries and/or neurocognitive impairments following overdose events. Limited preclinical research suggests that opioid overdoses may cause brain injury; however, little is known about such injuries in humans. The purpose this systematic review is to summarize existing studies on neurocognitive impairments and/or brain abnormalities associated with an opioid-related overdose in humans. Methods PubMed, Web of Science, Ovid MEDLINE and PsyINFO were searched, without year restrictions, and identified 3099 articles. An additional 24 articles were identified by reviewing references. Articles were included if they were published in English, reported study findings in humans, included individuals 18 years of age or older, and reported an objective measure of neurocognitive impairments and/or brain abnormalities resulting from an opioid-related overdose. Six domains of bias (selection, performance, attrition, detection (two dimensions) and reporting were evaluated and themes were summarized. Results Seventy-nine journal articles, published between 1973–2020, were included in the review. More than half of the articles were case reports (n = 44) and there were 11 cohort studies, 18 case series, and 6 case-control studies. All of the studies were categorized as at-risk of bias, few controlled for confounding factors, and methodological differences made direct comparisons difficult. Less than half of the studies reported toxicology results confirming an opioid-related overdose; 64.6 % reported brain MRI results and 27.8 % reported results of neuropsychological testing. Only two studies had within subject comparative data to document changes in the brain possibly associated with an overdose. Despite these limitations, existing publications suggest that brain injuries and neurocognitive impairments are associated with opioid overdose. Additional research is needed to establish the incidence of overdose-related brain injuries and the potential impact on functioning, as well as engagement in treatment of substance use disorders. Conclusions Respiratory depression is a defining characteristic of opioid overdose and prolonged cerebral hypoxia may cause brain injuries and/or neurocognitive impairments. The onset, characteristics, and duration of such injuries is variable and additional research is needed to understand their clinical implications.

AREVA Resources Canada operates the McClean Lake Operation (MLO), a uranium mine and processing facility located in northern Saskatchewan. Uranium-containing ores processed at the MLO contain high concentrations of arsenic that is oxidized to soluble arsenite and arsenate species when leaching and recovering uranium. To reduce the environmental impact of AREVA's mining operations, AREVA has developed a tailings preparation process designed to trap arsenic in a mineral form before the tailings are permanently deposited in the JEB Tailings Management Facility (TMF). Scorodite (FeAsO 4 ·2H 2 O) is predicted to be the primary arsenic species produced from the tailings preparation process. However, scorodite has never been observed in aged tailings samples. Confirming the presence of scorodite in the tailings is important in verifying that the tailings preparation process at the MLO can isolate high concentrations of arsenic from the environment in the form of stable minerals. Herein, X-ray Absorption Near-Edge Structure (XANES) spectroscopy was used to investigate arsenic speciation in a series of samples collected from the JEB TMF in 2013. Arsenic K-edge XANES analysis confirmed that most (86 wt%) of the arsenic content in the tailings samples consisted of iron-containing arsenates. Of these, crystalline scorodite was the most abundant arsenate species followed by poorly crystalline arsenates in the form of poorly crystalline ferric arsenate (FeAsO 4 ·xH 2 O) and arsenate adsorbed on ferrihydrite (AsO 4 –FeOOH). Arsenite adsorbed on ferrihydrite (AsO 3 –FeOOH), and gersdorffite (NiAsS) were also identified as minor arsenic species in the tailings samples. The abundance and distribution of scorodite in the TMF suggests that it is the major arsenic species produced in the tailings preparation process.

To investigate the associations between the Neuro-Quality of Life (NQOL) Depression and Anxiety measures with an objective emotional inventory (Personality Assessment Inventory; PAI), and demonstrate the clinical utility of the NQOL as screening measures for depression and anxiety in persons with epilepsy (PWE).PWE (N=72) were concurrently administered the NQOL Depression and Anxiety measures and the PAI. Pearson product moment correlations were used to determine the relationships between the NQOL measures and the respective PAI scales (i.e., depression, anxiety). One-way ANOVAs were conducted comparing NQOL scores between patients with elevated levels of depression and anxiety (T-score≥65 on the PAI) to profiles that were within normal limits. Using sensitivity and specificity analyses, optimal cut-scores on the NQOL measures were determined.Participants were primarily Caucasian (89%), female (60%), and ~35 years old. The NQOL Depression measure was significantly correlated with the PAI Depression total score (r=.747; p0.001) and its subscales (p's0.001). Similarly, the NQOL Anxiety measure was significantly correlated with the PAI Anxiety total score (r=.750; p0.001) and its subscales (p's0.001). Compared to profiles that were within normal limits, individuals with elevated depressive symptoms on the PAI had significantly higher NQOL Depression scores (F(1,71)=48.2, p0.001, d=1.6). Similarly, those who endorsed elevated anxiety on the PAI had significantly higher NQOL Anxiety scores (F(1,71)=32.2, p0.001, d=1.5). Cut-off scores of 19 on the NQOL Depression and 24 on the NQOL Anxiety measures adequately detected depression (sensitivity=0.67; specificity=0.93; PPV=0.91; NPV=0.74) and anxiety symptoms (sensitivity=0.77; specificity=0.82; PPV=0.81; NPV=0.78) in PWE.The NQOL Depression and Anxiety measures evidenced strong associations with the PAI Depression and Anxiety scales and may be effective in detecting depressive and anxiety symptoms in PWE using the provided cut-scores.

OBJECTIVE: Funding to address the current opioid epidemic has focused on treatment of opioid use disorder (OUD); however, rates of other substance use disorders (SUDs) remain high and non-opioid related overdoses account for nearly 30% of overdoses. This study assesses the prevalence of co-occurring substance use in West Virginia (WV) to inform treatment strategies. The objective of this study was to assess the prevalence of, and demographic and clinical characteristics (including age, gender, hepatitis C virus (HCV) status) associated with, co-occurring substance use among patients with OUD in WV. METHODS: This retrospective study utilized the West Virginia Clinical and Translation Science Institute Integrated Data Repository, comprised of Electronic Medical Record (EMR) data from West Virginia University Medicine. Deidentified data were extracted from inpatient psychiatric admissions and emergency department (ED) healthcare encounters between 2009 and 2018. Eligible patients were those with OUD who had a positive urine toxicology screen for opioids at the time of their initial encounter with the healthcare system. Extracted data included results of comprehensive urine toxicology testing during the study timeframe. RESULTS: 3,127 patients met the inclusion criteria of whom 72.8% had co-occurring substance use. Of those who were positive for opioids and at least one additional substance, benzodiazepines were the most common co-occurring substances (57.4% of patients yielded a positive urine toxicology screen for both substances), followed by cannabis (53.1%), cocaine (24.5%) and amphetamine (21.6%). Individuals who used co-occurring substances were younger than those who were positive for opioids alone (P < 0.001). There was a higher prevalence of individuals who used co-occurring substances that were HCV positive in comparison to those who used opioids alone (P < 0.001). There were limited gender differences noted between individuals who used co-occurring substances and those who used opioids alone. Among ED admissions who were positive for opioids, 264 were diagnosed with substance toxicity/overdose, 78.4% of whom had co-occurring substance use (benzodiazepines: 65.2%; cannabis: 44.4%; cocaine: 28.5%; amphetamine: 15.5%). Across the 10-year timespan, the greatest increase for the entire sample was in the rate of co-occurring amphetamine and opioid use (from 12.6% in 2014 to 47.8% in 2018). CONCLUSIONS: These data demonstrate that the current substance use epidemic extends well beyond opioids, suggesting that comprehensive SUD prevention and treatment strategies are needed, especially for those substances which do not yet have any evidence-based and/or medication treatments available.

We report a familial case of Simpson-Golabi-Behmel syndrome type 1 (SGBS1) with prenatal ultrasound findings of bilateral ventriculomegaly and polyhydramnios and postnatal findings of macroglossia, macrosomia and other dysmorphic features. Oligonucleotide array comparative genomic hybridization (aCGH) analysis and further polymerase chain reaction (PCR) sequencing identified a 167.071 kb hemizygous deletion including the entire TFDP3 gene and exons 3–9 of the GPC4 (Glypican 4) gene, and a 86.943 kb deletion including exon 3 of the GPC3 (Glypican 3) gene. Joined sequences at the breakpoints indicate that the deletion of TFDP3 and GPC4 is likely caused by microhomology-mediated end joining while the deletion within the GPC3 gene is due to non-homology end joining. Both deletions are considered loss of function due to the loss of large portions of coding sequences. The prenatal ultrasound findings of the affected male fetuses in this family are comparable with two previously reported cases with large deletions of the GPC3 and GPC4 genes. Further investigation of more cases with genetic defects of both GPC3 and GPC4 genes is needed for assessing the genotype-phenotype correlation.

The sagittal plane relationship of the first to second ray is a primary determinant of proper alignment in Lapidus midfoot fusion as assessed both clinically and on postoperative weightbearing lateral radiographs. The traditional approach to intraoperative fluoroscopic imaging allows for accurate assessment of fixation placement and intermetatarsal angle correction but only a crude evaluation of final sagittal plane alignment. Surgeons have used various methods in an attempt to load the foot during lateral imaging. This had led to inconsistent results and the potential for poor outcome. Skepticism exists regarding the ability of simulated weightbearing fluoroscopy to predict the final outcome, and evidence is lacking to support this practice. A prospective investigation was performed to assess the correlation of the first to second ray sagittal plane alignment as demonstrated on intraoperative simulated weightbearing lateral foot imaging studies and the 10-week postoperative lateral weightbearing radiograph. A consistent simulated weightbearing technique was used prospectively with 50 consecutive cases of Lapidus midfoot fusion with the goal of achieving parallel sagittal plane alignment of the first and second metatarsals with no divergence. Although 47 cases had no divergence and 3 had divergence with mild first ray elevatus, all 50 cases demonstrated a direct correlation between the intraoperative simulated and postoperative full weightbearing images. In conclusion, we believe the findings from our intraoperative imaging technique are a reliable predictor of first ray sagittal plane alignment in Lapidus midfoot fusion.

Heterotopic bone growth is a common finding after partial foot amputation that can predispose to recurrent wounds, osteomyelitis, and reamputation. Heterotopic ossification is the formation of excessive mature lamellar bone in the soft tissues adjacent to bone that is exacerbated by trauma or surgical intervention. The relevance of heterotopic ossification is dependent on its anatomic location. Its occurrence as a sequela of partial foot amputation can lead to prominence on the plantar aspect of the foot that can predispose the patient to recurrent neuropathic ulceration or preclude appropriate wound healing. Reulceration puts the high-risk patient who has already undergone local amputation at greater risk of recurrent infection and further amputation. The present study aimed to assess the incidence and risk factors for heterotopic ossification to further evaluate its role in partial foot amputation. A retrospective analysis of 72 consecutive patients who had undergone partial metatarsal resection was performed, with 90% of the cohort having peripheral neuropathy and 88% diabetes mellitus. Our findings revealed a heterotopic ossification incidence of 75% diagnosed radiographically. The initial onset of heterotopic ossification was not appreciated >10 weeks postoperatively. Ten patients (18.5%) exhibited heterotopic ossification-associated ulceration. The incidence of heterotopic ossification was 30% less in patients with peripheral vascular disease. These results indicate that heterotopic ossification is a common sequela of partial ray resection in an already high-risk patient population. The perioperative use of pharmacologic or radiation prophylaxis in an attempt to minimize amputation-related morbidity should be considered.

Given the high prevalence of individuals diagnosed with substance use disorder, along with the elevated rate of relapse following treatment initiation, investigating novel approaches and new modalities for substance use disorder treatment is of vital importance. One such approach involves neuromodulation which has been used therapeutically for neurological and psychiatric disorders and has demonstrated positive preliminary findings for the treatment of substance use disorder. The following article provides a review of several forms of neuromodulation which warrant consideration as potential treatments for substance use disorder. PubMed, PsycINFO, Ovid MEDLINE, and Web of Science were used to identify published articles and clinicaltrials.gov was used to identify currently ongoing or planned studies. Search criteria for Brain Stimulation included the following terminology: transcranial direct current stimulation, transcranial magnetic stimulation, theta burst stimulation, deep brain stimulation, vagus nerve stimulation, trigeminal nerve stimulation, percutaneous nerve field stimulation, auricular nerve stimulation, and low intensity focused ultrasound. Search criteria for Addiction included the following terminology: addiction, substance use disorder, substance-related disorder, cocaine, methamphetamine, amphetamine, alcohol, nicotine, tobacco, smoking, marijuana, cannabis, heroin, opiates, opioids, and hallucinogens. Results revealed that there are currently several forms of neuromodulation, both invasive and non-invasive, which are being investigated for the treatment of substance use disorder. Preliminary findings have demonstrated the potential of these various neuromodulation techniques in improving substance treatment outcomes by reducing those risk factors (e.g. substance craving) associated with relapse. Specifically, transcranial magnetic stimulation has shown the most promise with several well-designed studies supporting the potential for reducing substance craving. Deep brain stimulation has also shown promise, though lacks well-controlled clinical trials to support its efficacy. Transcranial direct current stimulation has also demonstrated promising results though consistently designed, randomized trials are also needed. There are several other forms of neuromodulation which have not yet been investigated clinically but warrant further investigation given their mechanisms and potential efficacy based on findings from other studied indications. In summary, given promising findings in reducing substance use and craving, neuromodulation may provide a non-pharmacological option as a potential treatment and/or treatment augmentation for substance use disorder. Further research investigating neuromodulation, both alone and in combination with already established substance use disorder treatment (e.g. medication treatment), warrants consideration.

The North American beaver (Castor canadensis) is a classic ecosystem engineer, creating and expanding wetlands throughout their vast range. As important as their impacts on aquatic ecosystems, beaver as central place foragers restructure the surrounding forest community by their selective cutting of preferred woody species and size classes. These effects, which have been studied in several regions of North America, are still poorly understood within forests of the northeastern United States, where beaver populations are rebounding following regional extirpation. Here, beaver represent a key disturbance agent in a region where other drivers such as fire and timber cutting have been greatly reduced over the last century. Understanding their specific impacts on forest composition and structure is needed to manage these forests and their multiple ecosystem services. In this context, we assessed beaver foraging preferences throughout New York’s Adirondack State Park, a vast northern wooded region, to model their impacts on forest structure and composition. Across 19 sites distributed throughout the Park, beavers preferentially harvested stems

Existing research has demonstrated that patients in treatment for an opioid use disorder (OUD) have high rates of adverse childhood experiences (ACE) compared to community-based samples. While research has documented important gender differences in ACEs in patients with OUD receiving treatment in urban areas, research has not shown whether these findings would generalize to rural and Appalachian areas, which are known to have lower ACE scores. We conducted a secondary analysis of existing clinical data, utilizing intake assessment data from a rural Appalachian outpatient buprenorphine program. We restricted the sample to patients with an OUD who presented for treatment between June 2018 and June 2019 (n = 173). The clinical intake assessment included a modified 17-item ACE instrument that patients self-administered. More than half (54.3%) of patients reported having experienced 4+ categories of adverse childhood experiences. On average, females endorsed 4.5 categories of adverse experiences, whereas males endorsed 3.3 (p < 0.00); female patients were significantly more likely to have experienced sexual abuse (42.4% versus 10.6%, p < 0.00). Alarmingly, 25.9% of females and 8.2% of males reported being forced to have sex before age 18. Disproportionately high rates of childhood adversities, particularly among females, may partially explain despair in rural Appalachian areas. OUD treatment programs should conduct clinical assessments of trauma and integrate trauma-informed care into drug treatment, especially for female patients residing in rural Appalachia.

Background The United States continues to experience an opioid epidemic of unprecedented proportions despite FDA approval of life saving medications, such as buprenorphine. This paper describes a novel group-based buprenorphine treatment model and summarizes patient characteristics and treatment retention. This model, known as the Comprehensive Opioid Addiction Treatment (COAT) program, was developed in West Virginia, the epicenter of the opioid epidemic. Methods Data on 454 patients actively enrolled in the COAT program were extracted from an administrative clinical data set and electronic medical records and analyzed using descriptive and quantitative analysis to determine long-term retention in treatment using frequencies and means. Results The characteristics of the 454 patients are as follows: average age of 39, 53% female, predominantly white (94%) and Medicaid was the primary insurance provider (68%). Analysis of retention showed 37.8% of patents were retained less than one year and 14.7% were retained 10 or more years. Initiating treatment at a younger age was associated with long-term retention. Conclusion Opioid use disorder is a chronic relapsing disease and treatment models that retain patients long-term have the greatest benefit. The COAT model has been successful in retaining patients long-term in a rural setting where barriers to treatment are many.

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SummaryPin1 is a modular peptidyl-prolyl isomerase specific for phosphorylated Ser/Thr-Pro (pS/T-P) motifs, typically within intrinsically disordered regions of signaling proteins. Pin1 consists of two flexibly linked domains: an N-terminal WW domain for substrate binding and a larger C-terminal peptidyl-prolyl isomerase (PPIase) domain. Previous studies showed that binding of phosphopeptide substrates to Pin1 could alter Pin1 interdomain contact, strengthening or weakening it depending on the substrate sequence. Thus, substrate-induced changes in interdomain contact may act as a trigger within the Pin1 mechanism. Here, we investigate this possibility via nuclear magnetic resonance studies of several Pin1 mutants. Our findings provide new mechanistic insights for those substrates that reduce interdomain contact. Specifically, the reduced interdomain contact can allosterically enhance PPIase activity relative to that when the contact is sustained. These findings suggest Pin1 interdomain contact can negatively regulate its activity.

Pramipexole is a D3 dopamine receptor-preferring agonist indicated for the treatment of Parkinson disease. Studies associate pramipexole with pathological gambling and impulse control disorders suggesting a role for D3 receptors in reinforcement processes. Clinical studies showed pramipexole decreased cocaine craving and reversed central deficits in individuals with cocaine use disorder. Preclinical studies have shown acute administration of pramipexole increases cocaine’s reinforcing effects whereas other reports suggest chronic pramipexole produces tolerance to cocaine. In a randomized, double-blind, placebo-controlled study we examined the impact of pramipexole treatment on the subjective effects produced by cocaine in volunteers with cocaine use disorder. Volunteers received pramipexole titrated up to 3.0 mg/d or placebo over 15 days. Participants then received intravenous cocaine (0, 20 and 40 mg) on day 15. Cardiovascular and subjective effects were obtained with visual analog scales at time points across the session. Pramipexole alone increased peak heart rate following saline and diastolic blood pressure following cocaine. Pramipexole produced upwards of two-fold increases in positive subjective effects ratings following cocaine. These results indicate that chronic D3 receptor activation increases the subjective effects of cocaine in humans. Caution should be used when prescribing pramipexole to patients that may also use cocaine.

This study aimed to develop a three dimensional culture platform for aggregates of human embryonic stem cell (hESC)-derived pancreatic progenitors that enables long-term culture, maintains aggregate size and morphology, does not adversely affect differentiation and provides a means for aggregate recovery. A platform was developed with poly(ethylene glycol) hydrogels containing collagen type I, for cell-matrix interactions, and peptide crosslinkers, for facile recovery of aggregates. The platform was first demonstrated with RIN-m5F cells, showing encapsulation and subsequent release of single cells and aggregates without adversely affecting viability. Aggregates of hESC-derived pancreatic progenitors with an effective diameter of 82 (15)μm were either encapsulated in hydrogels or cultured in suspension for 28 days. At day 14, aggregate viability was maintained in the hydrogels, but significantly reduced (88%) in suspension culture. However by day 28, viability was reduced under both culture conditions. Aggregate size was maintained in the hydrogels, but in suspension was significantly higher (∼ 2-fold) by day 28. The ability to release aggregates followed by a second enzyme treatment to achieve single cells enabled assessment by flow cytometry. Prior to encapsulation, there were 39% Pdx1(+)/Nkx6.1(+) cells, key endocrine markers required for β-cell maturation. The fraction of doubly positive cells was not affected in hydrogels but was slightly and significantly lower in suspension culture by 28 days. In conclusion, we demonstrate that a MMP-sensitive PEG hydrogel containing collagen type I is a promising platform for hESC-derived pancreatic progenitors that maintains viable aggregates, aggregate size, and progenitor state and offers facile recovery of aggregates.

Spreading depolarizations (SD) are mass depolarizations of neurons and astrocytes that occur spontaneously in acute brain injury and mediate time-dependent lesion growth. Glutamate excitotoxicity has also been extensively studied as a mechanism of neuronal injury, although its relevance to in vivo pathology remains unclear. Here we hypothesized that excitotoxicity in acute lesion development occurs only as a consequence of SD. Using glutamate-sensitive microelectrodes, we found that SD induced by KCl in normal rat cortex elicits increases in extracellular glutamate (11.6±1.3μM) that are synchronous with the onset, sustainment, and resolution of the extracellular direct-current shift of SD. Inhibition of glutamate uptake with d,l-threo-β-benzyloxyaspartate (TBOA, 0.5 and 1mM) significantly prolonged the duration of the direct-current shift (148% and 426%, respectively) and the glutamate increase (167% and 374%, respectively) in a dose-dependent manner (P0.05). These prolonged events produced significant cortical lesions as indicated by Fluoro-Jade staining (P0.05), while no lesions were observed after SD in control conditions or after cortical injection of 1mM glutamate (extracellular increase: 243±50.8μM) or 0.5mM TBOA (glutamate increase: 8.5±1.6μM) without SD. We then used an embolic focal ischemia model to determine whether glutamate elevations occur independent of SD in the natural evolution of a cortical lesion. In both the ischemic core and penumbra, glutamate increased only in synchrony with anoxic terminal SD (6.1±1.1μM) and transient SDs (11.8±2.4μM), and not otherwise. Delayed terminal SDs were also observed in two animals at 98 and 150min after ischemic onset and induced similar glutamate elevations. Durations of SDs and glutamate increases were significantly correlated in both normal and ischemic animals (P0.05). These data suggest that pathologically prolonged SDs are a required mechanism of acute cortical lesion development and that glutamate elevations and the mass electrochemical changes of SD and are merely different facets of the same pathophysiologic process.

Monosodium methylarsenate (MSMA) is an organic arsenical herbicide currently utilized in turfgrass and cotton systems. In recent years, concerns over adverse impacts of arsenic (As) from MSMA applications have emerged; however, little research has been conducted in controlled field experiments using typical management practices. To address this knowledge gap, a field lysimeter experiment was conducted during 2012–2013 to determine the fate of As following MSMA applications to a bareground and an established turfgrass system. Arsenic concentrations in soil, porewater, and aboveground vegetation, were measured through one yr after treatment. Aboveground vegetation As concentration was increased compared to nontreated through 120 d after initial treatment (DAIT). In both systems, increased soil As concentrations were observed at 0–4 cm at 30 and 120 DAIT and 0–8 cm at 60 and 365 DAIT, suggesting that As was bound in shallow soil depths. Porewater As concentrations in MSMA-treated lysimeters from a 30-cm depth (22.0–83.8 μg L −1 ) were greater than those at 76-cm depth (0.4–5.1 μg L −1 ). These results were combined with previous research to devise management considerations in systems where MSMA is utilized. MSMA should not be applied if rainfall is forecasted within 7 DAIT and/or in areas with shallow water tables. Further, disposing of MSMA-treated turfgrass aboveground vegetation in a confined area – a common management practice for turfgrass clippings – may be of concern due to As release to surface water or groundwater as the vegetation decomposes. Finally, long-term MSMA use may cause soil As accumulation and thus downward migration of As over time; therefore, MSMA should be used in rotation with other herbicides.

The goal of this project was to evaluate the relationship between self-reported sleep habits, daytime sleepiness, and drug use variables in individuals with cocaine and methamphetamine (METH) use disorders. Participants with a cocaine or meth use disorder completed questionnaires, including the Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), and a Demographic/Drug use form. Participants with a cocaine (N=51) or meth use disorder (N=85) were separated into those with either high or low sleep deficits. In participants with a cocaine use disorder, ANOVA revealed significantly higher ESS scores among those defined as “poor sleepers” (with a PSQI score >5) when compared to those defined as “good sleepers” (with a PSQI score ≤5). In addition, poor sleepers reported using cocaine for more days out of the past 30 when compared to good sleepers. Interestingly, good sleepers reported using more grams of cocaine/day compared to poor sleepers. In participants with a METH use disorder, ANOVA revealed significantly higher ESS scores among poor sleepers when compared to good sleepers. Finally, individuals with a METH use disorder that endorsed elevated daytime sleepiness also had significantly higher PSQI scores when compared to those with normal daytime sleepiness. The results indicate that drug use variables, such as recent and daily use, may affect sleep quality and daytime sleepiness in individuals with stimulant use disorders; however, further investigations (i.e. in cocaine and METH users that do not meet criteria for a cocaine or METH use disorder) must be conducted in order to provide more conclusive evidence of the impact these usage variables may have on these sleep characteristics.

Shatsky Rise, an early Cretaceous igneous oceanic plateau in the NWPacific, comprises characteristics that could be attributed to either formation by shallow, plate tectonic-controlled processes or to an origin by a mantle plume(head). The plateauwas drilled during Integrated Ocean Drilling Program(IODP) Expedition 324. Complementary to a recent trace element study (Sano et al., 2012) this work presents Nd, Pb and Hf isotope data of recovered lava samples cored from the three major volcanic edifices of the Shatsky Rise. Whereas lavas from the oldest edifice yield fairly uniform compositions, awider isotopic spread is found for lavas erupted on the younger parts of the plateau, suggesting that the Shatsky magma source became more heterogeneous with time. At least three isotopically distinct components can be identified in the magma source: 1) a volumetrically and spatially most common, moderately depleted component of similar composition to modern East Pacific Ridge basalt but with low 3He/4He, 2) an isotopically very depleted component which could represent local, early Cretaceous (entrained) depleted upper mantle, and 3) an isotopically enriched component, indicating the presence of (recycled) continental material in the magma source. The majority of analyzed Shatsky lavas, however, possess Nd–Hf–Pb isotope compositions consistent with a derivation from an early depleted, non-chondritic reservoir. By comparing these results with petrological and trace element data of mafic volcanic rock samples from all three massifs (Tamu, Ori, Shirshov), we discuss the origin of Shatsky Rise magmatism and evaluate the possible involvement of a mantle plume (head).

We sought to compare measurements of circulating cell-free DNA as well as Down syndrome test results in women with naturally conceived pregnancies with those conceived using assisted reproductive technologies.Data regarding assisted reproductive technologies were readily available from seven enrollment sites participating in an external clinical validation trial of nested case/control design. Measurements of circulating cell-free fetal and total DNA, fetal fraction (ratio of fetal to total DNA), chromosome-specific z-scores, and karyotype results were available for analysis.Analyses were restricted to 632 euploid (5.2% assisted reproductive technologies) and 73 Down syndrome (13.7% assisted reproductive technologies), including 16 twin pregnancies. No differences were found for fetal or total circulating cell-free DNA, or for the fetal fraction in euploid (P = 0.70) or Down syndrome (P = 0.58) pregnancies by method of conception. There appeared to be systematic z-score reductions for chromosomes 21, 18, and 13 in assisted reproductive technologies versus natural euploid pregnancies (P = 0.048, 0.0032, and 0.36, respectively).Assisted reproductive technologies and naturally conceived pregnancies contribute similar levels of circulating cell-free DNA into maternal circulation. Small differences in the z-scores of pregnancies achieved by assisted reproductive technologies were observed and do not appear to be test-related artifacts. However, the findings need confirmation before any consideration of changes to testing and reporting protocols.

The primary objective of this study was to determine the safety of lofexidine, an α2 receptor agonist, alone and concurrent with cocaine in non-treatment seeking cocaine-dependent or cocaine-abusing participants. After screening, eligible participants received double-blind, randomized infusions of saline and 20 mg of cocaine on Day 1, and saline and 40 mg of cocaine on Day 2. Subjects were randomized and started receiving daily administration of placebo (N=4) or lofexidine on Day 3 and continued on this schedule until Day 7. Two dosing regimens for lofexedine were investigated: 0.8 QID (N=3) and 0.2 mg QID (N=11). On Days 6 and 7, subjects received double-blind infusions of saline and 20 mg of cocaine on Day 6, and saline and 40 mg of cocaine on Day 7. The data reveal a notable incidence of hemodynamic-related AEs over the course of the study. Two of the three participants at the 0.8 mg dose level discontinued, and five of 11 participants at the 0.2 mg dose level were withdrawn (or voluntarily discontinued) after hemodynamic AEs. Subjective effects and cardiovascular data were derived from all participants who were eligible to receive infusions (i.e., did not meet stopping criteria) on Days 6 and 7 (6 received lofexidine 0.2 mg, QID and 4 received placebo, QID). As expected, cocaine significantly increased heart rate and blood pressure, as well as several positive subjective effects. There was a trend for lofexidine to decrease cocaine-induced cardiovascular changes and cocaine-induced ratings for "Any Drug Effect", "Good Effects", and “Desire Cocaine”, but sample size issues limit the conclusions that can be drawn. Despite the trends to reduce cocaine-induced subjective effects, cardiovascular AEs may limit future utility of lofexidine as a treatment for this population.

Long-term cocaine use is a risk factor for the onset of neurocognitive impairment. This study sought to determine whether the cholinesterase inhibitor rivastigmine could improve neurocognitive performance in cocaine-dependent individuals. Cocaine-dependent individuals who were not seeking treatment at the time of enrollment in the study were randomly assigned to receive placebo (n = 16), rivastigmine 3 mg (n = 13), or rivastigmine 6 mg (n = 12). The baseline neurocognitive assessment, which included measures of attention/information processing (as measured by the Continuous Performance Task-II (CPT-II)), verbal learning/episodic memory (as measured by the Hopkins Verbal Learning Test-Revised (HVLT-R)), and working memory (as measured by the Dual N-Back Task), was conducted prior to the administration of study medication (Day 0). The follow-up assessment was conducted on Day 8 after the participants had received rivastigmine or placebo for 7 days (Day 2–8). Rivastigmine administration significantly improved performance on one measure of working memory span (mean n-back span). This study provides additional data showing that cocaine-associated neurocognitive impairment, specifically working memory deficits, can be remediated, at least to some degree.

Electron probe analyses of clinopyroxenes from several areas of the Deccan and Rajmahal Traps consisting mostly of subalkalic and alkalic basalts, picritic basalts and a few dolerite dykes have been obtained. Evaluation of the data indicate the absence of pigeonite from subalkalic basalts that occur in close spatial association with mild or strongly alkalic basalts in areas such as Rajpipla, Navagam and central Kachchh. Co-existence of augite and pigeonite, however, has been noticed in subalkalic basalts/dykes and picritic basalts from a number of Deccan localities such as Sagar, Igatpuri, Kalsubai, Triambak, Pavagarh and Girnar besides the one sample from Rajmahal. Diopside, salite, and wollastonite-rich compositions dominate the basanites and foidites of Kachchh whereas chrome-diopside and salite are the main types in the picrite basalt samples from Anila, Botad and Paliyad in Saurashtra akin to those found in contiguous areas in the east from borehole flows at Dhandhuka and Wadhwan studied in detail previously. Compositional variations in zoned clinopyroxenes indicate differentiation of the parental magma and also mixing of different magma types (subalkalic and alkalic) from areas such as Igatpuri, Rajpipla and Kachchh. Based on host-rock chemistry, total alkalis-silica plot, CIPW norms, estimated temperatures of eruption and augite – pigeonite thermometry, it has been inferred that clinopyroxene compositions, especially the incidence of pigeonite, appear to be very sensitive to bulk chemistry of host rocks, especially their Na 2 O, K 2 O, SiO 2 , total iron and TiO 2 contents. Non-quadrilateral cationic components in the clinopyroxenes, such as Al in tetrahedral and octahedral positions together with Si, Na, Ti and Cr abundances have been found to be useful to discriminate clinopyroxenes from alkalic and subalkalic basalt types besides inferences on the ferric iron component in them. Evaluation of host-rock compositions in the ternary olivine–clinopyroxene-quartz plot indicate polybaric conditions of crystallization and evolution especially in samples that are picritic (e.g. Pavagarh, Anila and Kachchh) and which could also breach the olivine–clinopyroxene-plagioclase thermal divide that exists in part between alkalic and subalkalic basalts under atmospheric conditions.

Sr, Nd and Pb isotopic compositions, and major and trace element abundances of lavas in five central Deccan Traps sections are generally very similar to those of lavas in the southwestern Deccan (Western Ghats escarpment). The combination of strong isotopic and chemical similarities between lavas of the two regions indicates that they shared a closely similar petrogenesis. Our results indicate that, unlike many lavas in the northeastern Deccan, most of the lavas studied in the central Deccan sections can be grouped into different stratigraphic members and chemical types (CTs) belonging to four formations (Thakurvadi, Bhimashankar, Khandala, and Poladpur) present in the type sections of the Western Ghats. Bhimashankar- and Thakurvadi-type lavas are found in a section near Outram, whereas only Khandala-type lavas make up the Mhaishmal, Ellora and Ajanta sections to the east, and only Poladpur-type lavas are present in the easternmost section at Lonar. This west-east sequence is the same as that seen going upward in the Western Ghats stratigraphy, except that Bushe-type lavas, which are located stratigraphically between the Khandala and Poladpur formations in the Western Ghats, have not been found in this study. Overall, our results indicate that the Khandala and Poladpur formations extend over west-east distances of more than 300 km, and some individual members (e.g., the Dhak Dongar) may extend over as much as 500 km. The regional dip from Igatpuri in the southwest to Lonar in the east-central Deccan is less than 0.5° to the east, which is similar to the southward regional dip in the southwestern Deccan. Near-horizontal flows in the central and southwestern Deccan areas suggest that post-Deccan tectonic activity has had limited effects on the studied area. Large volumes of basaltic lavas derived from eruptive centers in the western Deccan may have covered both the central and southwestern Deccan areas.

Summary The mechanistic target of rapamycin (mTOR) is a central regulator of cellular metabolic processes. Dysregulation of this kinase complex can result in a variety of human diseases. Rapamycin and its analogs target mTORC1 directly; however, chronic treatment in certain cell types and in vivo results in the inhibition of both mTORC1 and mTORC2. We have developed a high-throughput cell-based screen for the detection of phosphorylated forms of the mTORC1 (4E-BP1, S6K1) and mTORC2 (Akt) substrates and have identified and characterized a chemical scaffold that demonstrates a profile consistent with the selective inhibition of mTORC1. Stable isotope labeling of amino acids in cell culture-based proteomic target identification revealed that class I glucose transporters were the primary target for these compounds yielding potent inhibition of glucose uptake and, as a result, selective inhibition of mTORC1. The link between the glucose uptake and selective mTORC1 inhibition are discussed in the context of a yet-to-be discovered glucose sensor.

Previous studies of Ontong Java Plateau (OJP) basalts reveal that they are products of 20–30% degree of melting and possess ocean-island-like Pb, Nd, and Sr isotopic signatures that fall within a limited range yet define two distinct isotopic groups represented by the Kroenke- and Kwaimbaita-type basalts and by the Singgalo-type basalts. The origin of the two groups is not clear, although the Kroenke–Kwaimbaita-type signature has been suggested to represent the plateauʼs main mantle source, probably originating from the lower mantle. In this study, samples from central Malaita, Solomon Islands and Ocean Drilling Program (ODP) Sites 807, 1185B, and 1187 were analyzed for Os and Hf isotopic composition to further investigate the origin of the bimodal isotopic composition of OJP basalts. The Kroenke-type basalts, which are parental to Kwaimbaita-type basalts, show the least effect of post-emplacement alteration on their Os isotopic composition and have e Hf ( t ) = + 10.8 to +13.3, Os = 118–174 ppt, Re = 161–1111 ppt, and near-chondritic ( Os 187 / Os 188 ) t = 0.1322 ± 0.0029 [ γ Os ( t ) = 2.7 ± 2.2 and 4.3 ± 2.3 ( n = 6 ; 1σ) relative to primitive upper mantle (PUM) and average chondrite values, respectively], suggesting a near-primitive mantle source for the OJP. Up to 25% assimilation of altered Jurassic Pacific MORB crust into fractionating Kroenke-type magma could explain the lower, 11–51 ppt, Os contents and more radiogenic, ( Os 187 / Os 188 ) t = 0.1395 ± 0.0020 [ γ Os ( t ) = 8.4 ± 1.5 and 10.0 ± 1.5 ( n = 3 ; 1σ)], composition of some Kwaimbaita-type basalts. These compositions are markedly different from those of the least altered Singgalo-type basalts with e Hf ( t ) = + 10.2 to +11.5 and ( Os 187 / Os 188 ) t = 0.3301 ± 0.0175 [ γ Os ( t ) = 156 ± 14 and 160 ± 14 ( n = 8 , 1σ)] and low, 21–37 ppt, Os contents that are lower oceanic crust-like. Despite the scatter in the Re–Os isotope data, meaningful isochron ages and initial values were obtained. These ages are 121.4 ± 4.6 Ma for Malaitan Kwaimbaita Fm. basalts and 123 ± 24 Ma for Singgalo-type basalts, with initial 187Os/188Os of 0.129 ± 0.025 and 0.325 ± 0.098 , respectively. The Re–Os ages agree very well with the average ∼122 Ma 40Ar–39Ar age for the OJP. The Re–Os and Lu–Hf results reinforce the interpretation of a two-component mantle source for the OJP consisting of a dominant near-primitive mantle similar to that involved in the sources of several ocean islands, represented by the Kroenke- and Kwaimbaita-type basalts, and old, recycled lower continental crustal material expressed subtly in the isotopic signature of the Singgalo-type basalts. A lower crustal influence may be explained by incorporation of ancient, delaminated mafic continental crust into a thermochemical plume; incorporation could provisionally involve dense ex-crustal material that had accumulated in the lower mantle or less dense material that had stagnated at mid-mantle depths.

We model the dynamics and melting of a ridge-centered mantle plume, and predict the geochemical composition of magma at the surface. The mantle source is a fine-scale mixture of a small fraction of hydrous peridotite that is relatively enriched in incompatible elements (“EC”) and is embedded in a drier peridotite (“DC”) matrix. We assume all magma erupts at the ridge and calculate the contribution of EC and DC to the pooled composition along the ridge. If viscosity increases as melting dehydrates the mantle, EC contributes more to the pooled magma at the hotspot center than anywhere else along the ridge. The magnitude of this EC anomaly increases with Rayleigh number, and the along-axis distance to normal ridge composition increases with Rayleigh number, plume radius, and thermal buoyancy flux. A subset of model calculations designed to simulate the Iceland hotspot and Mid-Atlantic Ridge predict variations in crustal thickness, 87Sr/86Sr, and La/Sm with magnitudes and widths along the ridge that are comparable to, but less than, those observed. Improved fits to the observations require the innermost plume mantle to be compositionally distinct from the ambient asthenosphere; for example, by having a slightly higher mass fraction of EC (13–16%), or with DC having slightly higher 87Sr/86Sr and La/Sm. The inferred bulk plume 87Sr/86Sr composition, however, is within the predicted range of the source of normal mid-ocean ridge basalts worldwide. The broader implication is that the source of the Iceland plume is more similar in composition to the ambient upper mantle than previously thought, as a large part of the variation in ridge basalt composition can be attributed to the dynamics of mantle flow and melting.