Search

Abstract Vast alteration of the biosphere by humans is causing a sixth mass extinction, driven in part by an increase in infectious diseases. The emergence of the lethal fungal pathogen Batrachochytrium dendrobatidis (Bd) has devastated global amphibian biodiversity. Given the lack of any broadly applicable methods to reverse these impacts, the future of many amphibians appears grim. The Sierra Nevada yellow-legged frog (Rana sierrae) is highly susceptible to Bd infection and most R. sierrae populations are extirpated following disease outbreaks. However, some populations persist and eventually recover, and frogs in these recovering populations have increased resistance against infection. Here, we conduct a 15-year reintroduction study and show that frogs collected from recovering populations and reintroduced to vacant habitats can reestablish populations despite the presence of Bd. In addition, the likelihood of establishment is influenced by site, cohort, and frog attributes. Results from viability modeling suggest that many reintroduced populations have a low probability of extinction over 50 years. These results provide a rare example of how reintroduction of resistant individuals can allow the landscape-scale recovery of disease-impacted species, and have broad implications for amphibians and other taxa that are threatened with extinction by novel pathogens.

AbstractThe study aimed to compare the growth-promoting and innate immune gene expression of phyto-biotics powder; moringa leaf, ginger, garlic, and a combination of the three, as well as a control diet fed to Clarias gariepinus. Relative to the juveniles in the control diet, growth and nutrient utilization indices of juveniles in phyto-additive diets increased, with fish fed with garlic having higher growth and feed utilization in terms of weight gain: 381.6 ± 71, feed conversion ratio: 2.7 ± 0.39, specific growth rate: 0.849 ± 1.72 and relative growth rate: 2.932 ± 0.23 when compared to the control fish fed diet as well as moringa and a combination of the phyto-biotics fed supplements. The expression of the innate immune gene TnF-α was observed to be downregulated in C. gariepinus fed with phyto-biotics fed supplements; moringa, ginger, garlic, and their combination having a fold change of; 0.124 ± 0.034, 0.196 ± 0.145, 0.288 ± 0.088, 0.097 ± 0.30, respectively while upregulated in fish fed with a control fish-fed diet having a fold change of 1.436 ± 0.791. This finding indicates that the use of garlic and ginger supplements can enhance growth performance and nutrient utilization while providing anti-inflammatory benefits in Clarias gariepinus.

Abstract Objective While risk factors for osteoarthritis (OA) are well known, it is not well understood why certain individuals maintain high mobility and joint health throughout their life while others demonstrate OA at older ages. The purpose of this study was to assess which demographic, clinical and MRI quantitative and semi-quantitative factors are associated with preserving healthy knees in older individuals. Methods This study analyzed data from the OA Initiative (OAI) cohort of individuals at the age of 65 years or above. Participants without OA at baseline (BL) (Kellgren-Lawrence (KL) ≤ 1) were followed and classified as incident cases (KL ≥ 2 during follow-up; n = 115) and as non-incident (KL ≤ 1 over 96-month; n = 391). Associations between the predictor-variables sex, age, BMI, race, clinical scoring systems, T2 relaxation times and Whole-Organ Magnetic Resonance Imaging-Score (WORMS) readings at BL and the preservation of healthy knees (KL ≤ 1) during a 96-month follow-up period were assessed using logistic regression models. Results Obesity and presence of pain showed a significant inverse association with maintaining radiographically normal joints in patients aged 65 and above. T2 relaxation times of the lateral femur and tibia as well as the medial femur were also significantly associated with maintaining radiographically normal knee joints. Additionally, absence of lesions of the lateral meniscus and absence of cartilage lesions in the medial and patellofemoral compartments were significantly associated with maintaining healthy knee joints. Conclusion Overall, this study provides protective clinical parameters as well as quantitative and semi-quantitative MR-imaging parameters associated with maintaining radiographically normal knee joints in an older population over 8 years.

Abstract Background Obesity influences the development of osteoarthritis via low-grade inflammation. Progression of local inflammation (= synovitis) increased with weight gain in overweight and obese women compared to stable weight. Synovitis could be associated with subcutaneous fat (SCF) around the knee. Purpose of the study was to investigate the effect of weight loss on synovitis progression and to assess whether SCF around the knee mediates the relationship between weight loss and synovitis progression. Methods We included 234 overweight and obese participants (body mass index [BMI] ≥ 25 kg/m2) from the Osteoarthritis Initiative (OAI) with > 10% weight loss (n = 117) or stable overweight (

Abstract Background Natural cytokines are poorly suited as therapeutics for systemic administration due to suboptimal pharmacological and pharmacokinetic (PK) properties. Recombinant human interleukin-2 (rhIL-2) has shown promise for treatment of autoimmune (AI) disorders yet exhibits short systemic half-life and opposing immune responses that negate an appropriate therapeutic index. Methods A semi-synthetic microbial technology platform was used to engineer a site-specifically pegylated form of rhIL-2 with enhanced PK, specificity for induction of immune-suppressive regulatory CD4 + T cells (Tregs), and reduced stimulation of off-target effector T and NK cells. A library of rhIL-2 molecules was constructed with single site-specific, biorthogonal chemistry-compatible non-canonical amino acids installed near the interface where IL-2 engages its cognate receptor βγ (IL-2Rβγ) signaling complex. Biorthogonal site-specific pegylation and functional screening identified variants that retained engagement of the IL-2Rα chain with attenuated potency at the IL-2Rβγ complex. Results Phenotypic screening in mouse identifies SAR444336 (SAR’336; formerly known as THOR-809), rhIL-2 pegylated at H16, as a potential development candidate that specifically expands peripheral CD4+ Tregs with upregulation of markers that correlate with their suppressive function including FoxP3, ICOS and Helios, yet minimally expands CD8 + T or NK cells. In non-human primate, administration of SAR’336 also induces dose-dependent expansion of Tregs and upregulated suppressive markers without significant expansion of CD8 + T or NK cells. SAR’336 administration reduces inflammation in a delayed-type hypersensitivity mouse model, potently suppressing CD4+ and CD8 + T cell proliferation. Conclusion SAR’336 is a specific Treg activator, supporting its further development for the treatment of AI diseases.

Abstract Background Meniscal root tears can lead to early knee osteoarthritis and pain. This study aimed (1) to compare clinical and radiological outcomes between patients who underwent arthroscopic meniscal root repair after meniscal root tears and those who received non-surgical treatment, and (2) to identify whether baseline MRI findings could be potential predictors for future treatment strategies. Methods Patients with meniscal root tears were identified from our picture archiving and communication system from 2016 to 2020. Two radiologists reviewed radiographs and MRI studies using Kellgren-Lawrence (KL) grading and a modified Whole Organ MRI Scoring (WORMS) at baseline and follow-up. The median (interquartile range [IQR]) of follow-up radiographs and MRI studies were 134 (44–443) days and 502 (260–1176) days, respectively. MR images were assessed for root tear-related findings. Pain scores using visual analogue scale (VAS) and management strategies (non-surgical vs. arthroscopic root repair) were also collected. Chi-squared tests and independent t-tests were used to assess differences regarding clinical and imaging variables between treatment groups. Logistic regression analyses were performed to evaluate the associations between baseline MRI findings and each future treatment. Results Ninety patients were included. VAS pain scores were significantly (p

Background and Aims: Definitive peroral endoscopic treatment of pancreaticobiliary pathology in patients with surgically altered anatomy has recently been made more feasible by the use of lumen-apposing metal stents (LAMS) to create bowel-to-bowel anastomoses. We aim to demonstrate 4 cases of non–gastric bypass Roux-en-Y anatomy for which an enteroenterostomy was created under EUS guidance to facilitate complex peroral ERCP. Methods: Akin to EUS-directed transgastric ERCP, the approach to EUS-directed transenteric ERCP involves identification and expansion of the target bowel before transmural puncture and stent placement. Bowel irrigation is used to opacify and distend the pancreaticobiliary limb in reasonable proximity to the papilla or biliary-enteric anastomosis, which facilitates enteroenterostomy creation via LAMS placement. Peroral ERCP can be performed through anastomosis, generally using a therapeutic gastroscope, once the transmural tract has matured. Results: In 4 cases of biliary obstruction, peroral ERCP was successfully performed after creation of an enteroenterostomy. In 3 of the 4 cases, target bowel opacification and distention were achieved by continuous irrigation through a previously placed percutaneous transhepatic cholangiography tube. In one case, a gastro-jejunostomy was created after irrigation of the target bowel loop via antegrade catheter advanced through a prior hepaticogastrostomy. No major adverse events occurred. In 2 of the 4 patients, the endoscopic objective (stone clearance) was met and the transenteric LAMS was removed. The other 2 patients are still undergoing serial ERCP. Conclusions: EUS-guided enteroenterostomy permits safe and effective peroral ERCP, allowing for more efficient and effective treatment of pancreaticobiliary pathology in patients with surgically altered anatomy.

ABSTRACT Transmission of Yersinia pestis by fleas depends on the formation of condensed bacterial aggregates embedded within a gel-like matrix that localizes to the proventricular valve in the flea foregut and interferes with normal blood feeding. This is essentially a bacterial biofilm phenomenon, which at its end stage requires the production of a Y. pestis exopolysaccharide that bridges the bacteria together in a cohesive, dense biofilm that completely blocks the proventriculus. However, bacterial aggregates are evident within an hour after a flea ingests Y. pestis, and the bacterial exopolysaccharide is not required for this process. In this study, we characterized the biochemical composition of the initial aggregates and demonstrated that the yersinia murine toxin (Ymt), a Y. pestis phospholipase D, greatly enhances rapid aggregation following infected mouse blood meals. The matrix of the bacterial aggregates is complex, containing large amounts of protein and lipid (particularly cholesterol) derived from the flea’s blood meal. A similar incidence of proventricular aggregation occurred after fleas ingested whole blood or serum containing Y. pestis, and intact, viable bacteria were not required. The initial aggregation of Y. pestis in the flea gut is likely due to a spontaneous physical process termed depletion aggregation that occurs commonly in environments with high concentrations of polymers or other macromolecules and particles such as bacteria. The initial aggregation sets up subsequent binding aggregation mediated by the bacterially produced exopolysaccharide and mature biofilm that results in proventricular blockage and efficient flea-borne transmission.IMPORTANCEYersinia pestis, the bacterial agent of plague, is maintained in nature in mammal-flea-mammal transmission cycles. After a flea feeds on a mammal with septicemic plague, the bacteria rapidly coalesce in the flea’s digestive tract to form dense aggregates enveloped in a viscous matrix that often localizes to the foregut. This represents the initial stage of biofilm development that potentiates transmission of Y. pestis when the flea later bites a new host. The rapid aggregation likely occurs via a depletion-aggregation mechanism, a non-canonical first step of bacterial biofilm development. We found that the biofilm matrix is largely composed of host blood proteins and lipids, particularly cholesterol, and that the enzymatic activity of a Y. pestis phospholipase D (Ymt) enhances the initial aggregation. Y. pestis transmitted by flea bite is likely associated with this host-derived matrix, which may initially shield the bacteria from recognition by the host's intradermal innate immune response.

ABSTRACTHuman immunodeficiency virus type 1 typically requires a high density of CD4 for efficient entry as a mechanism to target CD4+ T cells (T-tropic), with CCR5 being used most often as the coreceptor. When target T cells are limiting, the virus can evolve to infect cells with a low density of CD4 such as macrophages (M-tropic). The entry phenotype is known to be encoded in the viral Env protein on the surface of the virus particle. Using data showing a dose response for infectivity based on CD4 surface density, we built a model consistent with T-tropic viruses requiring multiple CD4 molecules to mediate infection, whereas M-tropic viruses can infect cells using a single CD4 receptor molecule interaction. We also found that T-tropic viruses bound to the surface of cells with a low density of CD4 are released more slowly than M-tropic viruses which we modeled to be due to multiple interactions of the T-tropic virus with multiple CD4 molecules to allow the initial stable binding. Finally, we found that some M-tropic Env proteins, as the gp120 subunit, possess an enhanced affinity for CD4 compared with their T-tropic pair, indicating that the evolution of macrophage tropism can be reflected both in the closed Env trimer conformation on the virion surface and, in some cases, also in the open confirmation of gp120 Env. Collectively, these studies reveal differences in the stoichiometry of interaction of T-tropic and M-tropic viruses with CD4 and start to identify the basis of binding differences at the biochemical level.IMPORTANCEHuman immunodeficiency virus type 1 normally targets CD4+ T cells for viral replication. When T cells are limiting, the virus can evolve to infect myeloid cells. The evolutionary step involves a change from requiring a high surface density of CD4 for entry to being able to infect cells with a low density of CD4, as is found on myeloid lineage cells such as macrophage and microglia. Viruses able to infect macrophages efficiently are most often found in the CNS late in the disease course, and such viruses may contribute to neurocognitive impairment. Here, we examine the CD4 binding properties of the viral Env protein to explore these two different entry phenotypes.

Abstract The salivary glands of hematophagous arthropods contain pharmacologically active molecules that interfere with host hemostasis and immune responses, favoring blood acquisition and pathogen transmission. Exploration of the salivary gland composition of the rat flea, Xenopsylla cheopis, revealed several abundant acid phosphatase-like proteins whose sequences lacked one or two of their presumed catalytic residues. In this study, we undertook a comprehensive characterization of the tree most abundant X. cheopis salivary acid phosphatase-like proteins. Our findings indicate that the three recombinant proteins lacked the anticipated catalytic activity and instead, displayed the ability to bind different biogenic amines and leukotrienes with high affinity. Moreover, X-ray crystallography data from the XcAP-1 complexed with serotonin revealed insights into their binding mechanisms.

Abstract Background Tension-type headache (TTH) is the most prevalent primary headache disorder. Neck pain is commonly associated with primary headaches and the trigemino-cervical complex (TCC) refers to the convergence of trigeminal and cervical afferents onto neurons of the brainstem, thus conceptualizes the emergence of headache in relation to neck pain. However, no objective biomarkers exist for the myofascial involvement in primary headaches. This study aimed to investigate the involvement of the trapezius muscles in primary headache disorders by quantitative magnetic resonance imaging (MRI), and to explore associations between muscle T2 values and headache frequency and neck pain. Methods This cohort study prospectively enrolled fifty participants (41 females, age range 20–31 years): 16 subjects with TTH only (TTH-), 12 with mixed-type TTH plus migraine (TTH+), and 22 healthy controls (HC). The participants completed fat-suppressed T2‐prepared three-dimensional turbo spin-echo MRI, a headache diary (over 30 days prior to MRI), manual palpation (two weeks before MRI), and evaluation of neck pain (on the day of MRI). The bilateral trapezius muscles were manually segmented, followed by muscle T2 extraction. Associations between muscle T2 and the presence of neck pain as well as the number of days with headache (considering the 30 days prior to imaging using the headache calendar) were analyzed using regression models (adjusting for age, sex, and body mass index). Results The TTH+ group demonstrated the highest muscle T2 values (right side: 31.4 ± 1.2 ms, left side: 31.4 ± 0.8 ms) as compared to the TTH- group or HC group (p

We present the Fire Inventory from National Center for Atmospheric Research (NCAR) version 2.5 (FINNv2.5), a fire emissions inventory that provides publicly available emissions of trace gases and aerosols for various applications, including use in global and regional atmospheric chemistry modeling. FINNv2.5 includes numerous updates to the FINN version 1 framework to better represent burned area, vegetation burned, and chemicals emitted. Major changes include the use of active fire detections from the Visible Infrared Imaging Radiometer Suite (VIIRS) at 375 m spatial resolution, which allows smaller fires to be included in the emissions processing. The calculation of burned area has been updated such that a more rigorous approach is used to aggregate fire detections, which better accounts for larger fires and enables using multiple satellite products simultaneously for emissions estimates. Fuel characterization and emissions factors have also been updated in FINNv2.5. Daily fire emissions for many trace gases and aerosols are determined for 2002–2019 (Moderate Resolution Imaging Spectroradiometer (MODIS)-only fire detections) and 2012–2019 (MODIS + VIIRS fire detections). The non-methane organic gas emissions are allocated to the species of several commonly used chemical mechanisms. We compare FINNv2.5 emissions against other widely used fire emissions inventories. The performance of FINNv2.5 emissions as inputs to a chemical transport model is assessed with satellite observations. Uncertainties in the emissions estimates remain, particularly in Africa and South America during August–October and in southeast and equatorial Asia in March and April. Recommendations for future evaluation and use are given.

Introduction: Fracture risk is elevated in type 2 diabetes (T2D) despite normal or even high bone mineral density (BMD). Microvascular disease (MVD) is a diabetic complication, but also associated with other diseases, for example chronic kidney disease. We hypothesize that increased fracture risk in T2D could be due to increased cortical porosity (Ct.Po) driven by expansion of the vascular network in MVD. The purpose of this study was to investigate associations of T2D and MVD with cortical microstructure and intracortical vessel parameters. Methods: The study group consisted of 75 participants (38 with T2D and 37 without T2D). High-resolution peripheral quantitative CT (HR-pQCT) and dynamic contrast-enhanced MRI (DCE-MRI) of the ultra-distal tibia were performed to assess cortical bone and intracortical vessels (outcomes). MVD was defined as ≥1 manifestation including neuropathy, nephropathy, or retinopathy based on clinical exams in all participants. Adjusted means of outcomes were compared between groups with/without T2D or between participants with/without MVD in both groups using linear regression models adjusting for age, sex, BMI, and T2D as applicable. Results: MVD was found in 21 (55 %) participants with T2D and in 9 (24 %) participants without T2D. In T2D, cortical pore diameter (Ct.Po.Dm) and diameter distribution (Ct.Po.Dm.SD) were significantly higher by 14.6 μm (3.6 %, 95 % confidence interval [CI]: 2.70, 26.5 μm, p = 0.017) and by 8.73 μm (4.8 %, CI: 0.79, 16.7 μm, p = 0.032), respectively. In MVD, but not in T2D, cortical porosity was significantly higher by 2.25 % (relative increase = 12.9 %, CI: 0.53, 3.97 %, p = 0.011) and cortical BMD (Ct.BMD) was significantly lower by −43.6 mg/cm3 (2.6 %, CI: −77.4, −9.81 mg/cm3, p = 0.012). In T2D, vessel volume and vessel diameter were significantly higher by 0.02 mm3 (13.3 %, CI: 0.004, 0.04 mm3, p = 0.017) and 15.4 μm (2.9 %, CI: 0.42, 30.4 μm, p = 0.044), respectively. In MVD, vessel density was significantly higher by 0.11 mm−3 (17.8 %, CI: 0.01, 0.21 mm−3, p = 0.033) and vessel volume and diameter were significantly lower by −0.02 mm3 (13.7 %, CI: −0.04, −0.004 mm3, p = 0.015) and − 14.6 μm (2.8 %, CI: −29.1, −0.11 μm, p = 0.048), respectively. Conclusions: The presence of MVD, rather than T2D, was associated with increased cortical porosity. Increased porosity in MVD was coupled with a larger number of smaller vessels, which could indicate upregulation of neovascularization triggered by ischemia. It is unclear why higher variability and average diameters of pores in T2D were accompanied by larger vessels.

People with HIV-1 (PWH) on antiretroviral therapy (ART) can maintain undetectable virus levels, but a small pool of infected cells persists. This pool is largely comprised of defective proviruses that may produce HIV-1 proteins but are incapable of making infectious virus, with only a fraction (~10%) of these cells harboring intact viral genomes, some of which produce infectious virus following ex vivo stimulation (i.e. inducible intact proviruses). A majority of the inducible proviruses that persist on ART are formed near the time of therapy initiation. Here we compared proviral DNA (assessed here as 3' half genomes amplified from total cellular DNA) and inducible replication competent viruses in the pool of infected cells that persists during ART to determine if the original infection of these cells occurred at comparable times prior to therapy initiation. Overall, the average percent of proviruses that formed late (i.e. around the time of ART initiation, 60%) did not differ from the average percent of replication competent inducible viruses that formed late (69%), and this was also true for proviral DNA that was hypermutated (57%). Further, there was no evidence that entry into the long-lived infected cell pool was impeded by the ability to use the CXCR4 coreceptor, nor was the formation of long-lived infected cells enhanced during primary infection, when viral loads are exceptionally high. We observed that infection of cells that transitioned to be long-lived was enhanced among people with a lower nadir CD4+ T cell count. Together these data suggest that the timing of infection of cells that become long-lived is impacted more by biological processes associated with immunodeficiency before ART than the replication competency and/or cellular tropism of the infecting virus or the intactness of the provirus. Further research is needed to determine the mechanistic link between immunodeficiency and the timing of infected cells transitioning to the long-lived pool, particularly whether this is due to differences in infected cell clearance, turnover rates and/or homeostatic proliferation before and after ART.

Abstract Background and Aims The two most common interventions used to treat painless jaundice from pancreatic cancer are endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous transhepatic biliary drainage (PTBD). Our study aimed to characterize the geographic distribution of ERCP‐performing hospitals among patients with pancreatic cancer in the United States and the association between geographic accessibility to ERCP‐performing hospitals and biliary interventions patients receive. Methods This is a retrospective cohort study using the Surveillance, Epidemiology, and End Results (SEER)‐Medicare database for pancreatic cancer from 2005 to 2013. Multilevel models were used to examine the association between accessibility to ERCP hospitals within a 30‐ and 45‐min drive from the patient's residential ZIP Code and the receipt of ERCP treatment. A two‐step floating catchment area model was used to calculate the measure of accessibility based on the distribution across SEER regions. Results 7464 and 782 patients underwent ERCP and PTBD, respectively, over the study period. There were 808 hospitals in which 8246 patients diagnosed with pancreatic cancer in SEER regions from 2005 to 2013 received a procedure. Patients with high accessibility within both 30‐ and 45‐min drive to an ERCP‐performing hospital were more likely to receive an ERCP (30‐min adjusted odds ratio [aOR]: 1.53, 95% confidence interval [CI]: 1.17–2.01; 45‐min aOR: 1.31, 95% CI: 1.01–1.70). Furthermore, in the adjusted model, Black patients (vs. White) and patients with stage IV disease were less likely to receive ERCP than PTBD. Conclusions Patients with pancreatic cancer and high accessibility to an ERCP‐performing hospital were more likely to receive ERCP. Disparities in the receipt of ERCP persisted for Black patients regardless of their access to ERCP‐performing hospitals.

One of the most difficult tasks faced by the firms during the COVID19 period is managing work processes while permitting workers to work remotely is indifference, which has rarely piqued the attention of researchers. This research explores the influence of extended remote working on employee indifference to the workplace. A quantitative research approach has been used to accomplish the objectives. The data was obtained through well-structured questionnaires distributed to 369 IT employees in Kerala, India. To test the research hypotheses, regression analysis, and moderator analysis were used. Extended remote working positively correlates to employee indifference to the workplace and gender acts as a moderator for this relationship. This study is likely to lead to research insights in the area of remote working and employee indifference to the workplace. The study explored the existence of indifference to the workplace and also found that extended remote working positively influences indifference to the workplace.

BackgroundThere is growing interest in developing impedance planimetry as a tool to enhance the clinical outcomes for endoscopic and surgical management of achalasia. The primary aim of this study was to determine whether impedance planimetry measurements can predict clinical response and reflux following peroral endoscopic myotomy (POEM).MethodsA multicenter cohort study of patients with achalasia undergoing POEM was established from prospective databases and retrospective chart reviews. Patients who underwent impedance planimetry before and after POEM were included. Clinical response was defined as an Eckardt score of ≤ 3. Tenfold cross-validated area under curve (AUC) values were established for the different impedance planimetry measurements associated with clinical response and reflux development.ResultsOf the 290 patients included, 91.7 % (266/290) had a clinical response and 39.4 % (108/274) developed reflux following POEM. The most predictive impedance planimetry measurements for a clinical response were: percent change in cross-sectional area (%ΔCSA) and percent change in distensibility index (%ΔDI), with AUCs of 0.75 and 0.73, respectively. Optimal cutoff values for %ΔCSA and %ΔDI to determine a clinical response were a change of 360 % and 272 %, respectively. Impedance planimetry values were much poorer at predicting post-POEM reflux, with AUCs ranging from 0.40 to 0.62.ConclusionPercent change in CSA and distensibility index were the most predictive measures of a clinical response, with a moderate predictive ability. Impedance planimetry values for predicting reflux following POEM showed weak predictive capacity.

Data on individual tree crowns from remote sensing have the potential to advance forest ecology by providing information about forest composition and structure with a continuous spatial coverage over large spatial extents. Classifying individual trees to their taxonomic species over large regions from remote sensing data is challenging. Methods to classify individual species are often accurate for common species, but perform poorly for less common species and when applied to new sites. We ran a data science competition to help identify effective methods for the task of classification of individual crowns to species identity. The competition included data from three sites to assess each methods’ ability to generalize patterns across two sites simultaneously and apply methods to an untrained site. Three different metrics were used to assess and compare model performance. Six teams participated, representing four countries and nine individuals. The highest performing method from a previous competition in 2017 was applied and used as a baseline to understand advancements and changes in successful methods. The best species classification method was based on a two-stage fully connected neural network that significantly outperformed the baseline random forest and gradient boosting ensemble methods. All methods generalized well by showing relatively strong performance on the trained sites (accuracy = 0.46–0.55, macro F1 = 0.09–0.32, cross entropy loss = 2.4–9.2), but generally failed to transfer effectively to the untrained site (accuracy = 0.07–0.32, macro F1 = 0.02–0.18, cross entropy loss = 2.8–16.3). Classification performance was influenced by the number of samples with species labels available for training, with most methods predicting common species at the training sites well (maximum F1 score of 0.86) relative to the uncommon species where none were predicted. Classification errors were most common between species in the same genus and different species that occur in the same habitat. Most methods performed better than the baseline in detecting if a species was not in the training data by predicting an untrained mixed-species class, especially in the untrained site. This work has highlighted that data science competitions can encourage advancement of methods, particularly by bringing in new people from outside the focal discipline, and by providing an open dataset and evaluation criteria from which participants can learn.

Abstract Background To assess the compound effects of BMI and sustained depressive symptoms on changes in knee structure, cartilage composition, and knee pain over 4 years using statistical interaction analyses. Methods One thousand eight hundred forty-four individuals from the Osteoarthritis Initiative Database were analyzed at baseline and 4-year follow-up. Individuals were categorized according to their BMI and presence of depressive symptoms (based on the Center for Epidemiological Studies Depression Scale (threshold≥16)) at baseline and 4-year follow-up. 3 T MRI was used to quantify knee cartilage T2 over 4 years, while radiographs were used to assess joint space narrowing (JSN). Mixed effects models examined the effect of BMI-depressive symptoms interactions on outcomes of cartilage T2, JSN, and knee pain over 4-years. Results The BMI-depressive symptoms interaction was significantly associated with knee pain (p

The impact of diffusion thermo on transient natural convection flow of a chemically reactive fluid with heat source/sink in a tube is investigated. The Laplace transform technique enables the governing equations to be solved analytically with the solutions inverted by the Riemann-sum approximation method. Constant values of Prandtl number and Schmidt number of 0.71 and 0.75 are used for the study. A time variable ranging from 0.2 to a steady-state, chemical reaction, and heat source/sink parameters ranging from −0.6–0.6, and the Dufour number ranging from 0–0.8 are used for the study. This study reveals that the Dufour number elevates the Nusselt number and the skin friction. Furthermore, it posits that when the Dufour number is small, the temperature heightens with time, and then switches over to decreasing with time when the Dufour number is large. The present model finds application in the pharmaceutical, petroleum, and paint-making industries, etc.

Brain microglia (MG) may serve as a human immunodeficiency virus 1 (HIV) reservoir and ignite rebound viremia following cessation of antiretroviral therapy (ART), but they have yet to be proven to harbor replication-competent HIV. Here, we isolated brain myeloid cells (BrMCs) from nonhuman primates and rapid autopsy of people with HIV (PWH) on ART and sought evidence of persistent viral infection. BrMCs predominantly displayed microglial markers, in which up to 99.9% of the BrMCs were TMEM119+ MG. Total and integrated SIV or HIV DNA was detectable in the MG, with low levels of cell-associated viral RNA. Provirus in MG was highly sensitive to epigenetic inhibition. Outgrowth virus from parietal cortex MG in an individual with HIV productively infected both MG and PBMCs. This inducible, replication-competent virus and virus from basal ganglia proviral DNA were closely related but highly divergent from variants in peripheral compartments. Phenotyping studies characterized brain-derived virus as macrophage tropic based on the ability of the virus to infect cells expressing low levels of CD4. The lack of genetic diversity in virus from the brain suggests that this macrophage-tropic lineage quickly colonized brain regions. These data demonstrate that MG harbor replication-competent HIV and serve as a persistent reservoir in the brain.

Human NIMA-related kinases have primarily been studied for their roles in cell cycle progression (NEK1/2/6/7/9), checkpoint-DNA-damage control (NEK1/2/4/5/10/11), and ciliogenesis (NEK1/4/8). We previously showed that Caenorhabditis elegans NEKL-2 (NEK8/9 homolog) and NEKL-3 (NEK6/7 homolog) regulate apical clathrin-mediated endocytosis (CME) in the worm epidermis and are essential for molting. Here we show that NEKL-2 and NEKL-3 also have distinct roles in controlling endosome function and morphology. Specifically, loss of NEKL-2 led to enlarged early endosomes with long tubular extensions but showed minimal effects on other compartments. In contrast, NEKL-3 depletion caused pronounced defects in early, late, and recycling endosomes. Consistently, NEKL-2 was strongly localized to early endosomes, whereas NEKL-3 was localized to multiple endosomal compartments. Loss of NEKLs also led to variable defects in the recycling of two resident cargoes of the trans-Golgi network (TGN), MIG-14/Wntless and TGN-38/TGN38, which were missorted to lysosomes after NEKL depletion. In addition, defects were observed in the uptake of clathrin-dependent (SMA-6/Type I BMP receptor) and independent cargoes (DAF-4/Type II BMP receptor) from the basolateral surface of epidermal cells after NEKL-2 or NEKL-3 depletion. Complementary studies in human cell lines further showed that siRNA knockdown of the NEKL-3 orthologs NEK6 and NEK7 led to missorting of the mannose 6-phosphate receptor from endosomes. Moreover, in multiple human cell types, depletion of NEK6 or NEK7 disrupted both early and recycling endosomal compartments, including the presence of excess tubulation within recycling endosomes, a defect also observed after NEKL-3 depletion in worms. Thus, NIMA family kinases carry out multiple functions during endocytosis in both worms and humans, consistent with our previous observation that human NEKL-3 orthologs can rescue molting and trafficking defects in C. elegans nekl-3 mutants. Our findings suggest that trafficking defects could underlie some of the proposed roles for NEK kinases in human disease.

In this study we report the synthesis of single crystals of burbankite, Na3Ca2La(CO3)5, at 5 GPa and 1073 K. The structural evolution, bulk modulus and thermal expansion of burbankite were studied and determined by two separate high-pressure (0–7.07(5) GPa) and high-temperature (298–746 K) in situ single-crystal X-ray diffraction experiments. The refined parameters of a second-order Birch–Murnaghan equation of state (EoS) are V0= 593.22(3) Å3 and KT0= 69.8(4) GPa. The thermal expansion coefficients of a Berman-type EoS are α0= 6.0(2) ×10-5 K−1, α1= 5.7(7) ×10-8 K−2 and V0= 591.95(8) Å3. The thermoelastic parameters determined in this study allow us to estimate the larger density of burbankite in the pressure-temperature range of 5.5–6 GPa and 1173–1273 K, with respect to the density of carbonatitic magmas at the same conditions. For this reason, we suggest that burbankite might fractionate from the magma and play a key role as an upper-mantle reservoir of light trivalent rare earth elements (REE3+).