Open population capture‐recapture models are widely used to estimate population demographics and abundance over time. Bayesian methods exist to incorporate open population modeling with spatial ...capture‐recapture (SCR), allowing for estimation of the effective area sampled and population density. Here, open population SCR is formulated as a hidden Markov model (HMM), allowing inference by maximum likelihood for both Cormack‐Jolly‐Seber and Jolly‐Seber models, with and without activity center movement. The method is applied to a 12‐year survey of male jaguars (Panthera onca) in the Cockscomb Basin Wildlife Sanctuary, Belize, to estimate survival probability and population abundance over time. For this application, inference is shown to be biased when assuming activity centers are fixed over time, while including a model for activity center movement provides negligible bias and nominal confidence interval coverage, as demonstrated by a simulation study. The HMM approach is compared with Bayesian data augmentation and closed population models for this application. The method is substantially more computationally efficient than the Bayesian approach and provides a lower root‐mean‐square error in predicting population density compared to closed population models.
Mycobacterium tuberculosis (Mtb) uses the ESX-1 type VII secretion system to export virulence proteins across its lipid-rich cell wall, which helps permeabilize the host’s macrophage phagosomal ...membrane, facilitating the escape and cell-to-cell spread of Mtb. ESX-1 membranolytic activity depends on a set of specialized secreted Esp proteins, the structure and specific roles of which are not currently understood. Here, we report the X-ray and electron microscopic structures of the ESX-1-secreted EspB. We demonstrate that EspB adopts a PE/PPE-like fold that mediates oligomerization with apparent heptameric symmetry, generating a barrel-shaped structure with a central pore that we propose contributes to the macrophage killing functions of EspB. Our structural data also reveal unexpected direct interactions between the EspB bipartite secretion signal sequence elements that form a unified aromatic surface. These findings provide insight into how specialized proteins encoded within the ESX-1 locus are targeted for secretion, and for the first time indicate an oligomerization-dependent role for Esp virulence factors.
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•The crystal structure of EspB reveals a fused PE/PPE homology domain•EspB has a stabilized bipartite secretion signal that targets the EccCb1 ATPase•EspB oligomerizes to form a ring-shaped heptamer•A model of the heptamer was fit to EM density and crosslinking data
Mycobacterium tuberculosis exports virulence factors to its surface using the ESX-1 secretion system, progressing the infection of human macrophages. Solomonson et al. show that one of these factors, EspB, adopts a PE/PPE-like fold and oligomerizes to form a barrel-shaped structure with heptameric symmetry.
Many architects believe that major improvements in cost-energy-performance must now come from domain-specific hardware. This paper evaluates a custom ASIC - called a Tensor Processing Unit (TPU) - ...deployed in datacenters since 2015 that accelerates the inference phase of neural networks (NN). The heart of the TPU is a 65,536 8-bit MAC matrix multiply unit that offers a peak throughput of 92 TeraOps/second (TOPS) and a large (28 MiB) software-managed on-chip memory. The TPU's deterministic execution model is a better match to the 99th-percentile response-time requirement of our NN applications than are the time-varying optimizations of CPUs and GPUs that help average throughput more than guaranteed latency. The lack of such features helps explain why, despite having myriad MACs and a big memory, the TPU is relatively small and low power. We compare the TPU to a server-class Intel Haswell CPU and an Nvidia K80 GPU, which are contemporaries deployed in the same datacenters. Our workload, written in the high-level TensorFlow framework, uses production NN applications (MLPs, CNNs, and LSTMs) that represent 95% of our datacenters' NN inference demand. Despite low utilization for some applications, the TPU is on average about 15X-30X faster than its contemporary GPU or CPU, with TOPS/Watt about 30X-80X higher. Moreover, using the GPU's GDDR5 memory in the TPU would triple achieved TOPS and raise TOPS/Watt to nearly 70X the GPU and 200X the CPU.
Molecular markers scalable for clinical use are critical for the development of effective treatments and the design of clinical trials. Here, we identify proteins in sera of patients and mouse models ...with Charcot-Marie-Tooth disease (CMT) with characteristics that make them suitable as biomarkers in clinical practice and therapeutic trials. We collected serum from mouse models of CMT1A (C61 het), CMT2D (GarsC201R, GarsP278KY), CMT1X (Gjb1-null), CMT2L (Hspb8K141N) and from CMT patients with genotypes including CMT1A (PMP22d), CMT2D (GARS), CMT2N (AARS) and other rare genetic forms of CMT. The severity of neuropathy in the patients was assessed by the CMT Neuropathy Examination Score (CMTES). We performed multitargeted proteomics on both sample sets to identify proteins elevated across multiple mouse models and CMT patients. Selected proteins and additional potential biomarkers, such as growth differentiation factor 15 (GDF15) and cell free mitochondrial DNA, were validated by ELISA and quantitative PCR, respectively. We propose that neural cell adhesion molecule 1 (NCAM1) is a candidate biomarker for CMT, as it was elevated in Gjb1-null, Hspb8K141N, GarsC201R and GarsP278KY mice as well as in patients with both demyelinating (CMT1A) and axonal (CMT2D, CMT2N) forms of CMT. We show that NCAM1 may reflect disease severity, demonstrated by a progressive increase in mouse models with time and a significant positive correlation with CMTES neuropathy severity in patients. The increase in NCAM1 may reflect muscle regeneration triggered by denervation, which could potentially track disease progression or the effect of treatments. We found that member proteins of the complement system were elevated in Gjb1-null and Hspb8K141N mouse models as well as in patients with both demyelinating and axonal CMT, indicating possible complement activation at the impaired nerve terminals. However, complement proteins did not correlate with the severity of neuropathy measured on the CMTES scale. Although the complement system does not seem to be a prognostic biomarker, we do show complement elevation to be a common disease feature of CMT, which may be of interest as a therapeutic target. We also identify serum GDF15 as a highly sensitive diagnostic biomarker, which was elevated in all CMT genotypes as well as in Hspb8K141N, Gjb1-null, GarsC201R and GarsP278KY mouse models. Although we cannot fully explain its origin, it may reflect increased stress response or metabolic disturbances in CMT. Further large and longitudinal patient studies should be performed to establish the value of these proteins as diagnostic and prognostic molecular biomarkers for CMT.
The Australian 2019/2020 bushfires were unprecedented in their extent and intensity, causing a catastrophic loss of habitat, human and animal life across eastern‐Australia. We use a regional air ...quality model to assess the impact of the bushfires on particulate matter with a diameter less than 2.5 μm (PM2.5) concentrations and the associated health impact from short‐term population exposure to bushfire PM2.5. The mean population Air Quality Index (AQI) exposure between September and February in the fires and no fires simulations indicates an additional ∼437,000 people were exposed to “Poor” or worse AQI levels due to the fires. The AQ impact was concentrated in the cities of Sydney, Newcastle‐Maitland, Canberra‐Queanbeyan and Melbourne. Between October and February 171 (95% CI: 66–291) deaths were brought forward due to short‐term exposure to bushfire PM2.5. The health burden was largest in New South Wales (NSW) (109 (95% CI: 41–176) deaths brought forward), Queensland (15 (95% CI: 5–24)), and Victoria (35 (95% CI: 13–56)). This represents 38%, 13% and 30% of the total deaths brought forward by short‐term exposure to all PM2.5. At a city‐level 65 (95% CI: 24–105), 23 (95% CI: 9–38) and 9 (95% CI: 4–14) deaths were brought forward from short‐term exposure to bushfire PM2.5, accounting for 36%, 20%, and 64% of the total deaths brought forward from all PM2.5. Thus, the bushfires caused substantial AQ and health impacts across eastern‐Australia. Climate change is projected to increase bushfire risk, therefore future fire management policies should consider this.
Plain Language Summary
The Australian 2019/2020 bushfires were unprecedented in their size and intensity, resulting in a catastrophic loss of habitat and human and animal life across eastern‐Australia. We use an air pollution model (WRF‐Chem) to quantify the impact of the bushfires on particulate matter with a diameter less than 2.5 μm (PM2.5) concentrations. We run the model with and without emissions from the fires so their impact on PM2.5 can be isolated. We find that between September and February an additional ∼437,000 people were exposed to “Poor” or worse air quality index levels due to the fires across eastern‐Australia. Short‐term exposure to high PM2.5 concentrations has been linked to negative health impacts. Therefore, we estimate the health impact of population exposure to bushfire PM2.5 across eastern‐Australia, regionally and at city level. Our estimate indicates that between October and February 171 deaths were brought forward due to exposure to PM2.5 from the fires. Regionally, most deaths were brought forward in New South Wales (109 deaths brought forward), Queensland (15), and Victoria (35). Within these regions, the most deaths were brought forward in Sydney (65), Melbourne (23), and Canberra‐Queanbeyan (9) as large populations were exposed to high PM2.5 concentrations due to the bushfires.
Key Points
The fires led to widespread exposure to “Poor” or worse Air Quality Index levels across eastern‐Australia
The highest all‐cause, all‐age mortality from short‐term exposure to bushfire particulate matter with a diameter less than 2.5 μm (PM2.5) was seen in the states of New South Wales, Queensland, and Victoria
All‐cause, all‐age mortality from short‐term exposure to bushfire PM2.5 was highest in the cities of Sydney, Melbourne, and Canberra
At low to intermediate inoculum doses of respiratory syncytial virus (RSV), Sendai virus (parainfluenza virus), and influenza A virus (IAV) infections in mice and hamsters, the activities of NK cells ...can reduce viral burden and protect from fatal disease (Cong and Wei, 2019). Exuberant NK-cell activity, including IFN-γ production, contributes to this aggravated lung inflammation during both IAV and RSV infections (Cong and Wei, 2019; Li et al., 2012; Abdul-Careem et al., 2012). ...elevated IL-2 and IL-18 amplify these pathological activities of NK cells during these infections and promote interstitial pneumonia (Okamoto et al., 2002; Harker et al., 2010; McKinstry et al., 2019). ...while hopes remain high that the potent antiviral functionality of these NK cells will provide clinical benefit, the potential for damage to the lungs, liver, and kidneys should be serious concerns and monitored very carefully in these trials.
Many COVID-19 survivors have post-COVID-19 conditions, and females are at a higher risk. We sought to determine (1) how protein levels change from acute to post-COVID-19 conditions, (2) whether ...females have a plasma protein signature different from that of males, and (3) which biological pathways are associated with COVID-19 when compared to restrictive lung disease. We measured protein levels in 74 patients on the day of admission and at 3 and 6 months after diagnosis. We determined protein concentrations by multiple reaction monitoring (MRM) using a panel of 269 heavy-labeled peptides. The predicted forced vital capacity (FVC) and diffusing capacity of the lungs for carbon monoxide (DLCO) were measured by routine pulmonary function testing. Proteins associated with six key lipid-related pathways increased from admission to 3 and 6 months; conversely, proteins related to innate immune responses and vasoconstriction-related proteins decreased. Multiple biological functions were regulated differentially between females and males. Concentrations of eight proteins were associated with FVC, %, and they together had c-statistics of 0.751 (CI:0.732–0.779); similarly, concentrations of five proteins had c-statistics of 0.707 (CI:0.676–0.737) for DLCO, %. Lipid biology may drive evolution from acute to post-COVID-19 conditions, while activation of innate immunity and vascular regulation pathways decreased over that period. (ProteomeXchange identifiers: PXD041762, PXD029437)
The purpose of this study was to evaluate injury characteristics by position groups.
Prospective, observational study.
A single, major Division I collegiate football program.
All players on a ...collegiate football program each fall regular season.
Exposure to Division I collegiate football and position groups.
Injury rates (IRs) per 1000 athlete exposures (AEs) and injury rate ratios (IRRs) were calculated and analyzed for all monitored injury variables, which included time in the season, body part, type of injury, game and practice injuries, mechanism of injury, and type of exposure.
During the 2012 to 2016 fall regular seasons, there were 200 reported injuries sustained from 48 615 AE. The overall 5-year IR was 4.11 per 1000 AEs (3.57-4.72 95% confidence intervals). Skill players sustained the highest IR in the preseason (IR, 7.56) compared with line (IR, 4.26) and other (IR, 4.10) position groups. In addition, skill players demonstrated a significantly higher IRR compared with the line (IRR, 1.75, P < 0.05) and other (IRR, 1.85, P < 0.05) position groups.
Skill players sustained most of their injuries in the preseason, whereas the linemen and other position groups suffered most of their injuries in the first half of the regular season. Skill players demonstrated a significantly higher IR in preseason, noncontact mechanism injuries, and injuries to the upper leg and thigh compared with line and other position groups. Efforts to reduce soft-tissue muscle strains in skill players targeting the preseason may provide one of the best opportunities to significantly decrease current football IRs, whereas efforts to reduce contact exposures may have the greatest effect on concussions and contact mechanism injuries for the other position group. There were no significant differences in IRs between position groups and type of exposure.
OBJECTIVE:The purpose of this study was to evaluate injury characteristics by position groups.
DESIGN:Prospective, observational study.
SETTING:A single, major Division I collegiate football program.
...PARTICIPANTS:All players on a collegiate football program each fall regular season.
INDEPENDENT VARIABLES:Exposure to Division I collegiate football and position groups.
MAIN OUTCOME MEASURES:Injury rates (IRs) per 1000 athlete exposures (AEs) and injury rate ratios (IRRs) were calculated and analyzed for all monitored injury variables, which included time in the season, body part, type of injury, game and practice injuries, mechanism of injury, and type of exposure.
RESULTS:During the 2012 to 2016 fall regular seasons, there were 200 reported injuries sustained from 48 615 AE. The overall 5-year IR was 4.11 per 1000 AEs (3.57-4.72 95% confidence intervals). Skill players sustained the highest IR in the preseason (IR, 7.56) compared with line (IR, 4.26) and other (IR, 4.10) position groups. In addition, skill players demonstrated a significantly higher IRR compared with the line (IRR, 1.75, P < 0.05) and other (IRR, 1.85, P < 0.05) position groups.
CONCLUSIONS:Skill players sustained most of their injuries in the preseason, whereas the linemen and other position groups suffered most of their injuries in the first half of the regular season. Skill players demonstrated a significantly higher IR in preseason, noncontact mechanism injuries, and injuries to the upper leg and thigh compared with line and other position groups. Efforts to reduce soft-tissue muscle strains in skill players targeting the preseason may provide one of the best opportunities to significantly decrease current football IRs, whereas efforts to reduce contact exposures may have the greatest effect on concussions and contact mechanism injuries for the other position group. There were no significant differences in IRs between position groups and type of exposure.
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