The acquired immunodeficiency syndrome (AIDS)-causing lentiviruses human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) effectively evade host immunity and, once established, ...infections with these viruses are only rarely controlled by immunological mechanisms. However, the initial establishment of infection in the first few days after mucosal exposure, before viral dissemination and massive replication, may be more vulnerable to immune control. Here we report that SIV vaccines that include rhesus cytomegalovirus (RhCMV) vectors establish indefinitely persistent, high-frequency, SIV-specific effector memory T-cell (T(EM)) responses at potential sites of SIV replication in rhesus macaques and stringently control highly pathogenic SIV(MAC239) infection early after mucosal challenge. Thirteen of twenty-four rhesus macaques receiving either RhCMV vectors alone or RhCMV vectors followed by adenovirus 5 (Ad5) vectors (versus 0 of 9 DNA/Ad5-vaccinated rhesus macaques) manifested early complete control of SIV (undetectable plasma virus), and in twelve of these thirteen animals we observed long-term (≥1 year) protection. This was characterized by: occasional blips of plasma viraemia that ultimately waned; predominantly undetectable cell-associated viral load in blood and lymph node mononuclear cells; no depletion of effector-site CD4(+) memory T cells; no induction or boosting of SIV Env-specific antibodies; and induction and then loss of T-cell responses to an SIV protein (Vif) not included in the RhCMV vectors. Protection correlated with the magnitude of the peak SIV-specific CD8(+) T-cell responses in the vaccine phase, and occurred without anamnestic T-cell responses. Remarkably, long-term RhCMV vector-associated SIV control was insensitive to either CD8(+) or CD4(+) lymphocyte depletion and, at necropsy, cell-associated SIV was only occasionally measurable at the limit of detection with ultrasensitive assays, observations that indicate the possibility of eventual viral clearance. Thus, persistent vectors such as CMV and their associated T(EM) responses might significantly contribute to an efficacious HIV/AIDS vaccine.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
By current estimates, at any given time, approximately 11% to 20% of children in the United States have a behavioral or emotional disorder, as defined in the Diagnostic and Statistical Manual of ...Mental Disorders, Fifth Edition. Between 37% and 39% of children will have a behavioral or emotional disorder diagnosed by 16 years of age, regardless of geographic location in the United States. Behavioral and emotional problems and concerns in children and adolescents are not being reliably identified or treated in the US health system. This clinical report focuses on the need to increase behavioral screening and offers potential changes in practice and the health system, as well as the research needed to accomplish this. This report also (1) reviews the prevalence of behavioral and emotional disorders, (2) describes factors affecting the emergence of behavioral and emotional problems, (3) articulates the current state of detection of these problems in pediatric primary care, (4) describes barriers to screening and means to overcome those barriers, and (5) discusses potential changes at a practice and systems level that are needed to facilitate successful behavioral and emotional screening. Highlighted and discussed are the many factors at the level of the pediatric practice, health system, and society contributing to these behavioral and emotional problems.
At sites of vascular damage, factor VIII (fVIII) is proteolytically activated by thrombin and binds to activated platelet surfaces with activated factor IX (fIXa) to form the intrinsic "tenase" ...complex. Previous structural and mutational studies of fVIII have identified the C1 and C2 domains in binding to negatively charged membrane surfaces through β-hairpin loops with solvent-exposed hydrophobic residues and a ring of positively charged basic residues. Several hemophilia A-associated mutations within the C domains are suggested to disrupt lipid binding, preventing formation of the intrinsic tenase complex. In this study, we devised a novel platform for generating recombinant C1, C2, and C1C2 domain constructs and performed mutagenesis of several charged residues proximal to the putative membrane binding region of each C domain. Binding measurements between phosphatidylserine (PS)-containing lipid membrane surfaces and fVIII C domains demonstrated an ionic strength dependence on membrane binding affinity. Mutations to basic residues adjacent to the surface-exposed hydrophobic regions of C1 and C2 differentially disrupted membrane binding, with abrogation of binding occurring for mutations to conserved arginine residues in the C1 (R2163) and C2 (R2320) domains. Lastly, we determined the X-ray crystal structure of the porcine fVIII C2 domain bound to
-phospho-L-serine, the polar headgroup of PS, which binds to a basic cleft and makes charge-charge contact with R2320. We conclude that basic clefts in the fVIII C domains bind to PS-containing membranes through conserved arginine residues
a C domain modularity, where each C domain possesses modest electrostatic-dependent affinity and tandem C domains are required for high affinity binding.
To investigate whether NICU discharge summaries documented neonatal AKI and estimate if nephrology consultation mediated this association.
Secondary analysis of AWAKEN multicenter retrospective ...cohort.
AKI severity and diagnostic criteria.
AKI documentation on NICU discharge summaries using multivariable logistic regression to estimate associations and test for causal mediation.
Among 605 neonates with AKI, 13% had documented AKI. Those with documented AKI were more likely to have severe AKI (70.5% vs. 51%, p < 0.001) and SCr-only AKI (76.9% vs. 50.1%, p = 0.04). Nephrology consultation mediated 78.0% (95% CL 46.5-109.4%) of the total effect of AKI severity and 82.8% (95% CL 70.3-95.3%) of the total effect of AKI diagnostic criteria on documentation.
We report a low prevalence of AKI documentation at NICU discharge. AKI severity and SCr-only AKI increased odds of AKI documentation. Nephrology consultation mediated the associations of AKI severity and diagnostic criteria with documentation.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Murine cells exhibit a profound block to HIV-1 virion production that was recently mapped to a species-specific structural attribute of the murine version of the chromosomal region maintenance 1 ...(mCRM1) nuclear export receptor and rescued by the expression of human CRM1 (hCRM1). In human cells, the HIV-1 Rev protein recruits hCRM1 to intron-containing viral mRNAs encoding the Rev response element (RRE), thereby facilitating viral late gene expression. Here we exploited murine 3T3 fibroblasts as a gain-of-function system to study hCRM1's species-specific role in regulating Rev's effector functions. We show that Rev is rapidly exported from the nucleus by mCRM1 despite only weak contributions to HIV-1's posttranscriptional stages. Indeed, Rev preferentially accumulates in the cytoplasm of murine 3T3 cells with or without hCRM1 expression, in contrast to human HeLa cells, where Rev exhibits striking en masse transitions between the nuclear and cytoplasmic compartments. Efforts to bias Rev's trafficking either into or out of the nucleus revealed that Rev encoding a second CRM1 binding domain (Rev-2xNES) or Rev-dependent viral gag-pol mRNAs bearing tandem RREs (GP-2xRRE), rescue virus particle production in murine cells even in the absence of hCRM1. Combined, these results suggest a model wherein Rev-associated nuclear export signals cooperate to regulate the number or quality of CRM1's interactions with viral Rev/RRE ribonucleoprotein complexes in the nucleus. This mechanism regulates CRM1-dependent viral gene expression and is a determinant of HIV-1's capacity to produce virions in nonhuman cell types.
Cells derived from mice and other nonhuman species exhibit profound blocks to HIV-1 replication. Here we elucidate a block to HIV-1 gene expression attributable to the murine version of the CRM1 (mCRM1) nuclear export receptor. In human cells, hCRM1 regulates the nuclear export of viral intron-containing mRNAs through the activity of the viral Rev adapter protein that forms a multimeric complex on these mRNAs prior to recruiting hCRM1. We demonstrate that Rev-dependent gene expression is poor in murine cells despite the finding that, surprisingly, the bulk of Rev interacts efficiently with mCRM1 and is rapidly exported from the nucleus. Instead, we map the mCRM1 defect to the apparent inability of this factor to engage Rev multimers in the context of large viral Rev/RNA ribonucleoprotein complexes. These findings shed new light on HIV-1 gene regulation and could inform the development of novel antiviral strategies that target viral gene expression.
National Oceanic and Atmospheric Administration’s Coral Reef Conservation Program supports the National Coral Reef Monitoring Program (NCRMP) in the United States Pacific, Atlantic, Caribbean, and ...Gulf of Mexico. NCRMP conducts standardized observations of biological, climatic, and socioeconomic indicators across American Samoa, Guam, the Main Hawaiian Islands, the Northwestern Hawaiian Islands, the Northern Mariana Islands, the Pacific Remote Islands, Florida, the Flower Garden Banks, Puerto Rico, and the United States Virgin Islands. NCRMP provides periodic, national-level assessments of the status of United States coral reef ecosystems and communities connected to them. In 2014, NCRMP partnered with the University of Maryland Center for Environmental Science on an unprecedented collaboration between federal and jurisdictional/state agencies, academia, and non-governmental organizations to synthesize NCRMP data into a reporting format designed to be accessible and relevant to the public and policy makers. The process involved multi-year data analyses of key benthic, fish, and climate indicators. In populated jurisdictions, socioeconomic data were integrated to assess public support for management actions, participation in pro-environmental behaviors, and awareness of threats to coral reefs. Jurisdictions were scored using a report-card scale (0–100%) by establishing references for each indicator using best-available historical data or expert opinion where historical data did not exist or were not statistically comparable. Despite overall ecosystem scores of Fair for all combined Atlantic (70%) and Pacific (74%) jurisdictions, the current trend is downward with a majority of United States coral reefs declining and vulnerable to further degradation. Remote, uninhabited reefs had an advantage with respect to reef fish population scores, i.e., Flower Garden Banks (85%) and Pacific Remote Islands (93%), when compared to populated location scores, i.e., Puerto Rico (63%) and Main Hawaiian Islands (66%). All coral reefs are highly impacted by climate change, and climate impacts were more pronounced than expected on remote reefs, i.e., the Northwestern Hawaiian Islands (58%). Presenting results in a report-card style facilitates communication to the public and policy makers, and provides a useful mechanism to garner support for management actions such as expanding protected areas; enforcing existing regulations; increasing climate change education; reducing land-based sources of pollution; and other actions to improve the trajectory of coral reef ecosystem conditions.
In glioblastoma (GBM), contrast enhanced (CE)-MRI delineates bulk tumor with contrast-enhancement but poorly characterizes invasive tumor in the nonenhancing T2W abnormality. There is extensive ...literature in both machine-learning (ML) and mechanistic mathematical oncology seeking to accurately predict diffuse tumor invasion from multi-parametric MRI. ML offers strengths of a data-driven iterative approach, while mechanistic (proliferation-invasion, PI) modeling incorporates spatial relationships with expected drop-offs of tumor cell density from central regions of MRI enhancement. In this study, we build and cross-validate a first-of-its-kind hybrid (ML-PI) model. We collected 82 image-guided biopsies from 18 primary GBM patients throughout CE T1W and nonenhancing T2W regions. For each biopsy, we obtained neuropathologist estimates of tumor cell density and spatially matched MRI (CE T1W, T2W) from which we extracted texture features. PI maps of tumor invasion were generated from MRI-based patient-specific estimates of the net rates of invasion and proliferation. Then, the PI maps were incorporated with a ML model that uses texture features to predict cell density to minimize the prediction error on biopsy samples (ML strength) while making sure tumor-wide prediction (biopsied and unbiopsied regions) conformed with glioblastoma biology (PI strength). We optimized this hybrid ML-PI model using leave-one-out-cross-validation, and compared its performance with PI and ML alone. We used Pearson correlation (r) between cross-validated predicted tumor cell density and true tumor cell density. We focused on prediction within the nonenhancing zone (n=32) because accurate estimation of invasive tumor cell density in this zone has important clinical value for radiation and surgical planning. PI-ML showed significantly stronger correlation (r=0.76) compared to PI (r=0.44) and ML (r=0.04) models alone (p value<0.01). We present a first-of-its-kind hybrid model combining mechanistic modeling and machine learning approaches that accurately quantifies tumor cell gradients within the non-enhancing T2W zone of GBM.
Early-onset colorectal cancer has been on the rise in Western populations. Here, we compare patient characteristics between those with early- (<50 years) vs. late-onset (≥50 years) disease in a large ...multinational cohort of colorectal cancer patients (
= 2193). We calculated descriptive statistics and assessed associations of clinicodemographic factors with age of onset using mutually-adjusted logistic regression models. Patients were on average 60 years old, with BMI of 29 kg/m
, 52% colon cancers, 21% early-onset, and presented with stage II or III (60%) disease. Early-onset patients presented with more advanced disease (stages III-IV: 63% vs. 51%, respectively), and received more neo and adjuvant treatment compared to late-onset patients, after controlling for stage (odds ratio (OR) (95% confidence interval (CI)) = 2.30 (1.82-3.83) and 2.00 (1.43-2.81), respectively). Early-onset rectal cancer patients across all stages more commonly received neoadjuvant treatment, even when not indicated as the standard of care, e.g., during stage I disease. The odds of early-onset disease were higher among never smokers and lower among overweight patients (1.55 (1.21-1.98) and 0.56 (0.41-0.76), respectively). Patients with early-onset colorectal cancer were more likely to be diagnosed with advanced stage disease, to have received systemic treatments regardless of stage at diagnosis, and were less likely to be ever smokers or overweight.
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A careful analysis of two maize recombinant inbred lines (RILs) relative to their inbred parents revealed the presence of several hundred apparently de novo copy number variants (CNVs). These changes ...in genome content were validated via both PCR and whole exome‐array capture‐and‐sequencing experiments. One hundred and eighty‐five genomic regions, which overlap with 38 high‐confidence genes, exhibited apparently de novo copy number variation (CNV) in these two RILs and in many instances the same apparently de novo CNV events were observed in multiple RILs. Further analyses revealed that these recurrent apparently de novo CNVs were caused by segregation of single‐copy homologous sequences that are located in non‐allelic positions in the two parental inbred lines. F1 individuals derived from these inbred lines will be hemizygous for each of these non‐allelic homologs but RIL genotypes will contain these sequences at zero, one or two genomic loci. Hence, the segregation of non‐allelic homologs may contribute to transgressive segregation. Indeed, statistical associations between phenotypic quantitative trait loci and genomic losses were observed for two of 14 tested pairs of non‐allelic homologs.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract
One of the most intense air mass transformations on Earth happens when cold air flows from frozen surfaces to much warmer open water in cold-air outbreaks (CAOs), a process captured ...beautifully in satellite imagery. Despite the ubiquity of the CAO cloud regime over high-latitude oceans, we have a rather poor understanding of its properties, its role in energy and water cycles, and its treatment in weather and climate models. The Cold-Air Outbreaks in the Marine Boundary Layer Experiment (COMBLE) was conducted to better understand this regime and its representation in models. COMBLE aimed to examine the relations between surface fluxes, boundary layer structure, aerosol, cloud, and precipitation properties, and mesoscale circulations in marine CAOs. Processes affecting these properties largely fall in a range of scales where boundary layer processes, convection, and precipitation are tightly coupled, which makes accurate representation of the CAO cloud regime in numerical weather prediction and global climate models most challenging. COMBLE deployed an Atmospheric Radiation Measurement Mobile Facility at a coastal site in northern Scandinavia (69°N), with additional instruments on Bear Island (75°N), from December 2019 to May 2020. CAO conditions were experienced 19% (21%) of the time at the main site (on Bear Island). A comprehensive suite of continuous in situ and remote sensing observations of atmospheric conditions, clouds, precipitation, and aerosol were collected. Because of the clouds’ well-defined origin, their shallow depth, and the broad range of observed temperature and aerosol concentrations, the COMBLE dataset provides a powerful modeling testbed for improving the representation of mixed-phase cloud processes in large-eddy simulations and large-scale models.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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