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Tuberculosis (TB), caused by Mycobacterium tuberculosis, is one of the leading causes of death due to an infectious agent. Coinfection with HIV exacerbates M. tuberculosis infection outcomes in people living with HIV. Bacillus Calmette-Guérin (BCG), the only approved TB vaccine, is effective in infants, but its efficacy in adolescents and adults is limited. In this study, we investigated the immune responses elicited by BCG administered via i.v. or intradermal (i.d.) routes in SIV-infected Mauritian cynomolgus macaques (MCM) without the confounding effects of M. tuberculosis challenge. We assessed the impact of vaccination on T cell responses in the airway, blood, and tissues (lung, thoracic lymph nodes, and spleen), as well as the expression of cytokines, cytotoxic effectors, and key transcription factors. Our results showed that i.v. BCG induces a robust and sustained immune response, including tissue-resident memory T cells in lungs, polyfunctional CD4+ and CD8αβ+ T cells expressing multiple cytokines, and CD8αβ+ T cells and NK cells expressing cytotoxic effectors in airways. We also detected higher levels of mycobacteria-specific IgG and IgM in the airways of i.v. BCG-vaccinated MCM. Although i.v. BCG vaccination resulted in an influx of tissue-resident memory T cells in lungs of MCM with controlled SIV replication, MCM with high plasma SIV RNA (>105 copies/ml) typically displayed reduced T cell responses, suggesting that uncontrolled SIV or HIV replication would have a detrimental effect on i.v. BCG-induced protection against M. tuberculosis., (Copyright © 2024 by The American Association of Immunologists, Inc.)

Children living with HIV have a higher risk of developing tuberculosis (TB), a disease caused by the bacterium Mycobacterium tuberculosis (Mtb). Gamma delta (γδ) T cells in the context of HIV/Mtb coinfection have been understudied in children despite in vitro evidence suggesting γδ T cells assist with Mtb control. We investigated whether boosting a specific subset of γδ T cells, phosphoantigen-reactive Vγ9+Vδ2+ cells, could improve TB outcome using a nonhuman primate model of pediatric HIV/Mtb coinfection. Juvenile Mauritian cynomolgus macaques (MCM), equivalent to 4- to 8-year-old children, were infected intravenously (i.v.) with SIV. After 6 months, MCM were coinfected with a low dose of Mtb and then randomized to receive zoledronate (ZOL), a drug that increases phosphoantigen levels, ( n = 5; i.v.) at 3 and 17 days after Mtb accompanied by recombinant human IL-2 (s.c.) for 5 days following each ZOL injection. A similarly coinfected MCM group ( n = 5) was injected with saline as a control. Vγ9+Vδ2+ γδ T cell frequencies spiked in the blood, but not airways, of ZOL+IL-2-treated MCM following the first dose, however, were refractory to the second dose. At necropsy 8 weeks after Mtb, ZOL+IL-2 treatment did not reduce pathology or bacterial burden. γδ T cell subset frequencies in granulomas did not differ between treatment groups. These data show that transiently boosting peripheral γδ T cells with ZOL+IL-2 soon after Mtb coinfection of SIV-infected MCM did not improve Mtb host defense.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is one of the leading causes of death due to an infectious agent. Coinfection with HIV exacerbates Mtb infection outcomes in people living with HIV (PLWH). Bacillus Calmette-Guérin (BCG), the only approved TB vaccine, is effective in infants, but its efficacy in adolescents and adults is limited. Here, we investigated the immune responses elicited by BCG administered via intravenous (IV) or intradermal (ID) routes in Simian Immunodeficiency Virus (SIV)-infected Mauritian cynomolgus macaques (MCM) without the confounding effects of Mtb challenge. We assessed the impact of vaccination on T cell responses in the airway, blood, and tissues (lung, thoracic lymph nodes, and spleen), as well as the expression of cytokines, cytotoxic molecules, and key transcription factors. Our results showed that IV BCG induces a robust and sustained immune response, including tissue-resident memory T (T RM ) cells in lungs, polyfunctional CD4+ and CD8αβ+ T cells expressing multiple cytokines, and CD8αβ+ T cells and NK cells expressing cytotoxic effectors in airways. We also detected higher levels of mycobacteria-specific IgG and IgM in the airways of IV BCG-vaccinated MCM. Although IV BCG vaccination resulted in an influx of T RM cells in lungs of MCM with controlled SIV replication, MCM with high plasma SIV RNA (>10 5 copies/mL) typically displayed reduced T cell responses, suggesting that uncontrolled SIV or HIV replication would have a detrimental effect on IV BCG-induced protection against Mtb.

Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), is the most common cause of death in people living with human immunodeficiency virus (HIV). Intra-dermal Bacille Calmette-Guérin (BCG) delivery is the only licensed vaccine against tuberculosis; however, it offers little protection from pulmonary tuberculosis in adults and is contraindicated in people living with HIV. Intravenous BCG confers protection against Mtb infection in rhesus macaques; we hypothesized that it might prevent tuberculosis in simian immunodeficiency virus (SIV)-infected macaques, a model for HIV infection. Here intravenous BCG-elicited robust airway T cell influx and elevated plasma and airway antibody titres in both SIV-infected and naive animals. Following Mtb challenge, all 7 vaccinated SIV-naive and 9 out of 12 vaccinated SIV-infected animals were protected, without any culturable bacteria detected from tissues. Peripheral blood mononuclear cell responses post-challenge indicated early clearance of Mtb in vaccinated animals, regardless of SIV infection. These data support that intravenous BCG is immunogenic and efficacious in SIV-infected animals., (© 2023. The Author(s).)

We use machine learning to evaluate surgical skill from videos during the tumor resection and renography steps of a robotic assisted partial nephrectomy (RAPN). This expands previous work using synthetic tissue to include actual surgeries. We investigate cascaded neural networks for predicting surgical proficiency scores (OSATS and GEARS) from RAPN videos recorded from the DaVinci system. The semantic segmentation task generates a mask and tracks the various surgical instruments. The movements from the instruments found via semantic segmentation are processed by a scoring network that regresses (predicts) GEARS and OSATS scoring for each subcategory. Overall, the model performs well for many subcategories such as force sensitivity and knowledge of instruments of GEARS and OSATS scoring, but can suffer from false positives and negatives that would not be expected of human raters. This is mainly attributed to limited training data variability and sparsity., (© 2023. The Author(s).)

Retinoic acid (RA) is a fundamental vitamin A metabolite involved in regulating immune responses through the nuclear RA receptor (RAR) and retinoid X receptor. While performing experiments using THP-1 cells as a model for Mycobacterium tuberculosis infection, we observed that serum-supplemented cultures displayed high levels of baseline RAR activation in the presence of live, but not heat-killed, bacteria, suggesting that M. tuberculosis robustly induces the endogenous RAR pathway. Using in vitro and in vivo models, we have further explored the role of endogenous RAR activity in M. tuberculosis infection through pharmacological inhibition of RARs. We found that M. tuberculosis induces classical RA response element genes such as CD38 and DHRS3 in both THP-1 cells and human primary CD14+ monocytes via a RAR-dependent pathway. M. tuberculosis-stimulated RAR activation was observed with conditioned media and required nonproteinaceous factor(s) present in FBS. Importantly, RAR blockade by (4-[(E)-2-[5,5-dimethyl-8-(2-phenylethynyl)-6H-naphthalen-2-yl]ethenyl]benzoic acid), a specific pan-RAR inverse agonist, in a low-dose murine model of tuberculosis significantly reduced SIGLEC-F+CD64+CD11c+high alveolar macrophages in the lungs, which correlated with 2× reduction in tissue mycobacterial burden. These results suggest that the endogenous RAR activation axis contributes to M. tuberculosis infection both in vitro and in vivo and reveal an opportunity for further investigation of new antituberculosis therapies., (Copyright © 2023 by The American Association of Immunologists, Inc.)

The use of CMOS sensors for rotational spectroscopy is a promising, but challenging avenue for low-cost gas sensing and molecular identification. A main challenge in this approach is that practical CMOS spectroscopy samples contain various different noise sources that reduce the effectiveness of matching techniques for molecular identification with rotational spectroscopy. To help solve this challenge, we develop a software application tool that can demonstrate the feasibility and reliability of detection with CMOS sensor samples. Specifically, the tool characterizes the types of noise in CMOS sample collection and synthesizes spectroscopy files based upon existing databases of rotational spectroscopy samples gathered from other sensors. We use the software to create a large database of plausible CMOS-generated sample files of gases. This dataset is used to help evaluate spectral matching algorithms used in gas sensing and molecular identification applications. We evaluate these traditional methods on the synthesized dataset and discuss how peak finding and spectral matching algorithms can be altered to accommodate the noise sources present in CMOS sample collection., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Pre-existing HIV infection increases tuberculosis (TB) risk in children. Antiretroviral therapy (ART) reduces, but does not abolish, this risk in children with HIV. The immunologic mechanisms involved in TB progression in both HIV-naive and HIV-infected children have not been explored. Much of our current understanding is based on human studies in adults and adult animal models. In this study, we sought to model childhood HIV/Mycobacterium tuberculosis (Mtb) coinfection in the setting of ART and characterize T cells during TB progression. Macaques equivalent to 4 to 8 year-old children were intravenously infected with SIVmac239M, treated with ART 3 months later, and coinfected with Mtb 3 months after initiating ART. SIV-naive macaques were similarly infected with Mtb alone. TB pathology and total Mtb burden did not differ between SIV-infected, ART-treated and SIV-naive macaques, although lung Mtb burden was lower in SIV-infected, ART-treated macaques. No major differences in frequencies of CD4 + and CD8 + T cells and unconventional T cell subsets (Vγ9+ γδ T cells, MAIT cells, and NKT cells) in airways were observed between SIV-infected, ART-treated and SIV-naive macaques over the course of Mtb infection, with the exception of CCR5+ CD4 + and CD8 + T cells which were slightly lower. CD4 + and CD8 + T cell frequencies did not differ in the lung granulomas. Immune checkpoint marker levels were similar, although ki-67 levels in CD8 + T cells were elevated. Thus, ART treatment of juvenile macaques, 3 months after SIV infection, resulted in similar progression of Mtb and T cell responses compared to Mtb in SIV-naive macaques., Competing Interests: The authors declare no conflict of interest.

This paper explores whether a diversity and inclusion strategy focused on using modern intelligence tests can assist public safety organizations in hiring a talented diverse workforce. Doing so may offer strategies for mitigating the issues of systematic racism with which these occupations have historically struggled. Past meta-analytic research shows that traditional forms of intelligence tests, which are often used in this sector, have not consistently demonstrated predictive validity but have negatively impacted Black candidates. As an alternative, we examine a modern intelligence test that consists of novel unfamiliar cognitive problems that test takers must solve without relying on their prior experience. Across six studies of varying public safety jobs (e.g., police, firefighter) in different organizations, we found a pattern of results that supports the criterion-related validity of the modern intelligence test. In addition to consistently predicting job performance and training success, the modern intelligence test also substantially mitigated the observed Black-White group differences. The implications of these findings are discussed in terms of how to alter the legacy of I/O psychology and human resource fields when it comes to our impact on facilitating employment opportunities for Black citizens, particularly in public safety positions.

Molecular dynamics (MD) simulation is widely used to study protein conformations and dynamics. However, conventional simulation suffers from being trapped in some local energy minima that are hard to escape. Thus, most of the computational time is spent sampling in the already visited regions. This leads to an inefficient sampling process and further hinders the exploration of protein movements in affordable simulation time. The advancement of deep learning provides new opportunities for protein sampling. Variational autoencoders are a class of deep learning models to learn a low-dimensional representation (referred to as the latent space) that can capture the key features of the input data. Based on this characteristic, we proposed a new adaptive sampling method, latent space-assisted adaptive sampling for protein trajectories (LAST), to accelerate the exploration of protein conformational space. This method comprises cycles of (i) variational autoencoder training, (ii) seed structure selection on the latent space, and (iii) conformational sampling through additional MD simulations. The proposed approach is validated through the sampling of four structures of two protein systems: two metastable states of Escherichia coli adenosine kinase (ADK) and two native states of Vivid (VVD). In all four conformations, seed structures were shown to lie on the boundary of conformation distributions. Moreover, large conformational changes were observed in a shorter simulation time when compared with structural dissimilarity sampling (SDS) and conventional MD (cMD) simulations in both systems. In metastable ADK simulations, LAST explored two transition paths toward two stable states, while SDS explored only one and cMD neither. In VVD light state simulations, LAST was three times faster than cMD simulation with a similar conformational space. Overall, LAST is comparable to SDS and is a promising tool in adaptive sampling. The LAST method is publicly available at https://github.com/smu-tao-group/LAST to facilitate related research.

HIV-1 cDNA pre-integration complexes persist for weeks in macrophages and remain transcriptionally active. While previous work has focused on the transcription of HIV-1 genes; our understanding of the cellular milieu that accompanies viral production is incomplete. We have used an in vitro system to model HIV-1 infection of macrophages, and single-cell RNA sequencing (scRNA-seq) to compare the transcriptomes of uninfected cells, cells harboring pre-integration complexes (PIC), and those containing integrated provirus and making late HIV proteins. scRNA-seq can distinguish between provirus and PIC cells because their background transcriptomes vary dramatically. PIC cell transcriptomes are characterized by NFkB and AP-1 promoted transcription, while transcriptomes of cells transcribing from provirus are characterized by E2F family transcription products. We also find that the transcriptomes of PIC cells and Bystander cells (defined as cells not producing any HIV transcript and thus presumably not infected) are indistinguishable except for the presence of HIV-1 transcripts. Furthermore, the presence of pathogen alters the transcriptome of the uninfected Bystander cells, so that they are distinguishable from true control cells (cells not exposed to any pathogen). Therefore, a single cell comparison of transcriptomes from provirus and PIC cells provides a new understanding of the transcriptional changes that accompany HIV-1 integration.

Hypoxemia, a medical condition that occurs when the blood is not carrying enough oxygen to adequately supply the tissues, is a leading indicator for dangerous complications of respiratory diseases like asthma, COPD, and COVID-19. While purpose-built pulse oximeters can provide accurate blood-oxygen saturation (SpO 2 ) readings that allow for diagnosis of hypoxemia, enabling this capability in unmodified smartphone cameras via a software update could give more people access to important information about their health. Towards this goal, we performed the first clinical development validation on a smartphone camera-based SpO 2 sensing system using a varied fraction of inspired oxygen (FiO 2 ) protocol, creating a clinically relevant validation dataset for solely smartphone-based contact PPG methods on a wider range of SpO 2 values (70-100%) than prior studies (85-100%). We built a deep learning model using this data to demonstrate an overall MAE = 5.00% SpO 2 while identifying positive cases of low SpO 2  < 90% with 81% sensitivity and 79% specificity. We also provide the data in open-source format, so that others may build on this work., (© 2022. The Author(s).)

We seek to understand if an automated algorithm can replace human scoring of surgical trainees performing the urethrovesical anastomosis in radical prostatectomy with synthetic tissue. Specifically, we investigate neural networks for predicting the surgical proficiency score (GEARS score) from video clips. We evaluate videos of surgeons performing the urethral anastomosis using synthetic tissue. The algorithm tracks surgical instrument locations from video, saving the positions of key points on the instruments over time. These positional features are used to train a multi-task convolutional network to infer each sub-category of the GEARS score to determine the proficiency level of trainees. Experimental results demonstrate that the proposed method achieves good performance with scores matching manual inspection in 86.1% of all GEARS sub-categories. Furthermore, the model can detect the difference between proficiency (novice to expert) in 83.3% of videos. Evaluation of GEARS sub-categories with artificial neural networks is possible for novice and intermediate surgeons, but additional research is needed to understand if expert surgeons can be evaluated with a similar automated system., (© 2021. The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.)

Individuals co-infected with HIV and Mycobacterium tuberculosis (Mtb) are more likely to develop severe tuberculosis (TB) disease than HIV-naive individuals. To understand how a chronic pre-existing Simian immunodeficiency virus (SIV) infection impairs the early immune response to Mtb, we used the Mauritian cynomolgus macaque (MCM) model of SIV/Mtb co-infection. We examined the relationship between peripheral viral control and Mtb burden, Mtb dissemination, and T cell function between SIV+ spontaneous controllers, SIV+ non-controllers, and SIV-naive MCM who were challenged with a barcoded Mtb Erdman strain 6 months post-SIV infection and necropsied 6 weeks post-Mtb infection. Mycobacterial burden was highest in the SIV+ non-controllers in all assessed tissues. In lung granulomas, the frequency of TNF-α-producing CD4 + T cells was reduced in all SIV+ MCM, but IFNγ-producing CD4 + T cells were only lower in the SIV+ non-controllers. Further, while all SIV+ MCM had more PD1+ and TIGIT+ T cells in the lung granulomas relative to SIV-naive MCM, SIV+ controllers exhibited the highest frequency of cells expressing these markers. To measure the effect of SIV infection on within-host bacterial dissemination, we sequenced the molecular barcodes of Mtb present in each tissue and characterized the Mtb population complexity. While Mtb population complexity was not associated with SIV infection group, lymph nodes had increased complexity when compared with lung granulomas across all groups. These results provide evidence that SIV+ animals, independent of viral control, exhibit a dysregulated T cell immune response and enhanced dissemination of Mtb, likely contributing to the poor TB disease course across all SIV/Mtb co-infected animals. IMPORTANCE HIV and TB remain significant global health issues, despite the availability of treatments. Individuals with HIV, including those who are virally suppressed, are at an increased risk to develop and succumb to severe TB disease when compared with HIV-naive individuals. Our study aims to understand the relationship between the extent of SIV replication, mycobacterial growth, and T cell function in the tissues of co-infected Mauritian cynomolgus macaques during the first 6 weeks of Mtb infection. Here we demonstrate that increased viral replication is associated with increased bacterial burden in the tissues and impaired T cell responses, and that the immunological damage attributed to virus infection is not fully eliminated when animals spontaneously control virus replication.

Molecular dynamics (MD) simulations have been actively used in the study of protein structure and function. However, extensive sampling in the protein conformational space requires large computational resources and takes a prohibitive amount of time. In this study, we demonstrated that variational autoencoders (VAEs), a type of deep learning model, can be employed to explore the conformational space of a protein through MD simulations. VAEs are shown to be superior to autoencoders (AEs) through a benchmark study, with low deviation between the training and decoded conformations. Moreover, we show that the learned latent space in the VAE can be used to generate unsampled protein conformations. Additional simulations starting from these generated conformations accelerated the sampling process and explored hidden spaces in the conformational landscape., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Tian, Jiang, Trozzi, Xiao, Larson and Tao.)

This work introduces a novel application of generative adversarial networks (GANs) for the prediction of starting geometries in transition state (TS) searches based on the geometries of reactants and products. The multi-dimensional potential energy space of a chemical reaction often complicates the location of a starting TS geometry, leading to the correct TS combining reactants and products in question. The proposed TS-GAN efficiently maps the space between reactants and products and generates reliable TS guess geometries, and it can be easily combined with any quantum chemical software package performing geometry optimizations. The TS-GAN was trained and applied to generate TS guess structures for typical chemical reactions, such as hydrogen migration, isomerization, and transition metal-catalyzed reactions. The performance of the TS-GAN was directly compared to that of classical approaches, proving its high accuracy and efficiency. The current TS-GAN can be extended to any dataset that contains sufficient chemical reactions for training. The software is freely available for training, experimentation, and prediction at https://github.com/ekraka/TS-GAN.

Tuberculosis (TB) is the leading infectious cause of death among people living with HIV. People living with HIV are more susceptible to contracting Mycobacterium tuberculosis and often have worsened TB disease. Understanding the immunologic defects caused by HIV and the consequences it has on M. tuberculosis coinfection is critical in combating this global health epidemic. We previously showed in a model of SIV and M. tuberculosis coinfection in Mauritian cynomolgus macaques (MCM) that SIV/ M. tuberculosis -coinfected MCM had rapidly progressive TB. We hypothesized that pre-existing SIV infection impairs early T cell responses to M. tuberculosis infection. We infected MCM with SIVmac239, followed by coinfection with M. tuberculosis Erdman 6 mo later. Although similar, TB progression was observed in both SIV + and SIV-naive animals at 6 wk post- M. tuberculosis infection; longitudinal sampling of the blood (PBMC) and airways (bronchoalveolar lavage) revealed a significant reduction in circulating CD4 + T cells and an influx of CD8 + T cells in airways of SIV + animals. At sites of M. tuberculosis infection (i.e., granulomas), SIV/ M. tuberculosis -coinfected animals had a higher proportion of CD4 + and CD8 + T cells expressing PD-1 and TIGIT. In addition, there were fewer TNF-producing CD4 + T cells in granulomas of SIV/ M. tuberculosis -coinfected animals. Taken together, we show that concurrent SIV infection alters T cell phenotypes in granulomas during the early stages of TB disease. As it is critical to establish control of M. tuberculosis replication soon postinfection, these phenotypic changes may distinguish the immune dysfunction that arises from pre-existing SIV infection, which promotes TB progression., (Copyright © 2021 by The American Association of Immunologists, Inc.)

In their previous work, Srinivas et al. [ J. Cheminf. 2018, 10, 56] have shown that implicit fingerprints capture ligands and proteins in a shared latent space, typically for the purposes of virtual screening with collaborative filtering models applied on known bioactivity data. In this work, we extend these implicit fingerprints/descriptors using deep learning techniques to translate latent descriptors into discrete representations of molecules (SMILES), without explicitly optimizing for chemical properties. This allows the design of new compounds based upon the latent representation of nearby proteins, thereby encoding druglike properties including binding affinities to known proteins. The implicit descriptor method does not require any fingerprint similarity search, which makes the method free of any bias arising from the empirical nature of the fingerprint models [Srinivas, R.; J. Cheminf. 2018, 10, 56]. We evaluate the properties of the potentially novel drugs generated by our approach using physical properties of druglike molecules and chemical complexity. Additionally, we analyze the reliability of the biological activity of the new compounds generated using this method by employing models of protein-ligand interaction, which assists in assessing the potential binding affinity of the designed compounds. We find that the generated compounds exhibit properties of chemically feasible compounds and are predicted to be excellent binders to known proteins. Furthermore, we also analyze the diversity of compounds created using the Tanimoto distance and conclude that there is a wide diversity in the generated compounds.

Computational prediction of Protein-Ligand Interaction (PLI) is an important step in the modern drug discovery pipeline as it mitigates the cost, time, and resources required to screen novel therapeutics. Deep Neural Networks (DNN) have recently shown excellent performance in PLI prediction. However, the performance is highly dependent on protein and ligand features utilized for the DNN model. Moreover, in current models, the deciphering of how protein features determine the underlying principles that govern PLI is not trivial. In this work, we developed a DNN framework named SSnet that utilizes secondary structure information of proteins extracted as the curvature and torsion of the protein backbone to predict PLI. We demonstrate the performance of SSnet by comparing against a variety of currently popular machine and non-Machine Learning (ML) models using various metrics. We visualize the intermediate layers of SSnet to show a potential latent space for proteins, in particular to extract structural elements in a protein that the model finds influential for ligand binding, which is one of the key features of SSnet. We observed in our study that SSnet learns information about locations in a protein where a ligand can bind, including binding sites, allosteric sites and cryptic sites, regardless of the conformation used. We further observed that SSnet is not biased to any specific molecular interaction and extracts the protein fold information critical for PLI prediction. Our work forms an important gateway to the general exploration of secondary structure-based Deep Learning (DL), which is not just confined to protein-ligand interactions, and as such will have a large impact on protein research, while being readily accessible for de novo drug designers as a standalone package.

Antimicrobial resistance is a growing global health and economic concern. Current antimicrobial agents are becoming less effective against common bacterial infections. We previously identified pyrrolocins A and C, which showed activity against a variety of Gram-positive bacteria. Structurally similar compounds, known as pyrrolidinediones (e.g., TA-289, equisetin), also display antibacterial activity. However, the mechanism of action of these compounds against bacteria was undetermined. Here, we show that pyrrolocin C and equisetin inhibit bacterial acetyl-CoA carboxylase (ACC), the first step in fatty acid synthesis. We used transcriptomic data, metabolomic analysis, fatty acid rescue and acetate incorporation experiments to show that a major mechanism of action of the pyrrolidinediones is inhibition of fatty acid biosynthesis, identifying ACC as the probable molecular target. This hypothesis was further supported using purified proteins, demonstrating that biotin carboxylase is the inhibited component of ACC. There are few known antibiotics that target this pathway and, therefore, we believe that these compounds may provide the basis for alternatives to current antimicrobial therapy., Competing Interests: The authors have declared that no competing interests exist.

Mucosal-associated invariant T (MAIT) cells can recognize and respond to some bacterially infected cells. Several in vitro and in vivo models of Mycobacterium tuberculosis (Mtb) infection suggest that MAIT cells can contribute to control of Mtb, but these studies are often cross-sectional and use peripheral blood cells. Whether MAIT cells are recruited to Mtb-affected granulomas and lymph nodes (LNs) during early Mtb infection and what purpose they might serve there is less well understood. Furthermore, whether HIV/SIV infection impairs MAIT cell frequency or function at the sites of Mtb replication has not been determined. Using Mauritian cynomolgus macaques (MCM), we phenotyped MAIT cells in the peripheral blood and bronchoalveolar lavage (BAL) before and during infection with SIVmac239. To test the hypothesis that SIV co-infection impairs MAIT cell frequency and function within granulomas, SIV+ and -naïve MCM were infected with a low dose of Mtb Erdman, and necropsied at 6 weeks post Mtb-challenge. MAIT cell frequency and function were examined within the peripheral blood, BAL, and Mtb-affected lymph nodes (LN) and granulomas. MAIT cells did not express markers indicative of T cell activation in response to Mtb in vivo within granulomas in animals infected with Mtb alone. SIV and Mtb co-infection led to increased expression of the activation/exhaustion markers PD-1 and TIGIT, and decreased ability to secrete TNFα when compared to SIV-naïve MCM. Our study provides evidence that SIV infection does not prohibit the recruitment of MAIT cells to sites of Mtb infection, but does functionally impair those MAIT cells. Their impaired function could have impacts, either direct or indirect, on the long-term containment of TB disease., Competing Interests: The authors have declared that no competing interests exist.

Arterial oxygen saturation ([Formula: see text]) is an indicator of how much oxygen is carried by hemoglobin in the blood. Having enough oxygen is vital for the functioning of cells in the human body. Measurement of [Formula: see text] is typically estimated with a pulse oximeter, but recent works have investigated how smartphone cameras can be used to infer [Formula: see text]. In this paper, we propose methods for the measurement of [Formula: see text] with a smartphone using convolutional neural networks and preprocessing steps to better guard against motion artifacts. To evaluate this methodology, we conducted a breath-holding study involving 39 participants. We compare the results using two different mobile phones. We compare our model with the ratio-of-ratios model that is widely used in pulse oximeter applications, showing that our system has significantly lower mean absolute error (2.02%) than a medical pulse oximeter.

Current ligand-based machine learning methods in virtual screening rely heavily on molecular fingerprinting for preprocessing, i.e., explicit description of ligands' structural and physicochemical properties in a vectorized form. Of particular importance to current methods are the extent to which molecular fingerprints describe a particular ligand and what metric sufficiently captures similarity among ligands. In this work, we propose and evaluate methods that do not require explicit feature vectorization through fingerprinting, but, instead, provide implicit descriptors based only on other known assays. Our methods are based upon well known collaborative filtering algorithms used in recommendation systems. Our implicit descriptor method does not require any fingerprint similarity search, which makes the method free of the bias arising from the empirical nature of the fingerprint models. We show that implicit methods significantly outperform traditional machine learning methods, and the main strengths of implicit methods are their resilience to target-ligand sparsity and high potential for spotting promiscuous ligands.

Following proviral integration into the host cell genome and establishment of a latent state, the human immunodeficiency virus type 1 (HIV-1) can reenter a productive life cycle in response to various stimuli. HIV-1 reactivation occurs when transcription factors, such as nuclear factor-κB (NF-κB), nuclear factor of activated T cells (NFAT), and activator protein -1 (AP-1), bind cognate sites within the long terminal repeat (LTR) region of the HIV-1 provirus to promote transcription. Interestingly, pattern recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs) can reactivate latent HIV-1 through activation of the transcription factor NF-κB. Some PRRs are expressed on central memory CD4+ T cells (TCM), which in HIV-1 patients constitute the main reservoir of latent HIV-1. Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), interacts with PRRs through membrane components. However, the ability of Mtb to reactivate latent HIV-1 has not been extensively studied. Here we show that phosphatidylinositol mannoside 6 (PIM6), a component of the Mtb membrane, in addition to whole bacteria in co-culture, can reactivate HIV-1 in a primary TCM cell model of latency. Using a JLAT model of HIV-1 latency, we found this interaction to be mediated through Toll-like receptor-2 (TLR-2). Thus, we describe a mechanism by which Mtb can exacerbate HIV-1 infection. We hypothesize that chronic Mtb infection can drive HIV-1 reactivation. The phenomenon described here could explain, in part, the poor prognosis that characterizes HIV-1/Mtb co-infection.

Background: The assessment of jaundice in outpatient neonates is problematic. Visual assessment is inaccurate, and more exact methodologies are cumbersome and/or expensive. Our goal in this study was to assess the accuracy of a technology based on the analysis of digital images of newborns obtained using a smartphone application called BiliCam., Methods: Paired BiliCam images and total serum bilirubin (TSB) levels were obtained in a diverse sample of newborns (<7 days old) at 7 sites across the United States. By using specialized software, data on color values in the images ("features") were extracted. Machine learning and regression analysis techniques were used to identify features for inclusion in models to predict an estimated bilirubin level for each newborn. The correlation between estimated bilirubin levels and TSB levels was calculated. In addition, the sensitivity and specificity of the estimated bilirubin levels in identifying newborns with high TSB levels were calculated by using 2 recommended decision rules for jaundice screening., Results: Estimated bilirubin levels were calculated and compared with TSB levels in a diverse sample of 530 newborns (20.8% African American, 26.3% Hispanic, and 21.2% Asian American). The overall correlation was 0.91, and correlations among white, African American, Hispanic, and Asian American newborns were 0.92, 0.90, 0.91, and 0.88, respectively. The sensitivities of BiliCam in identifying newborns with high TSB levels were 84.6% and 100%, respectively, by using 2 decision rules; specificities were 75.1% and 76.4%, respectively., Conclusions: BiliCam provided accurate estimates of TSB values, demonstrating that an inexpensive technology that uses commodity smartphones could be used to effectively screen newborns for jaundice., Competing Interests: POTENTIAL CONFLICT OF INTEREST: Drs Taylor, Stout, and Patel are cofounders of BiliCam, LLC, a company developing the technology described in this study for commercial use; the other authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2017 by the American Academy of Pediatrics.)

Competing Interests: Author Disclosure Statement No competing financial interests exist.

The epithelial tissues of the skin, lungs, reproductive tract, and intestines are the largest physical barriers the body has to protect against infection. Epithelial tissues are woven with a matrix of immune cells programed to mobilize the host innate and adaptive immune responses. Included among these immune cells are gamma delta T lymphocytes (γδ T cells) that are unique in their T cell receptor usage, location, and functions in the body. Stress reception by γδ T cells as a result of traumatic epithelial injury, malignancy, and/or infection induces γδ T cell activation. Once activated, γδ T cells function to repair tissue, induce inflammation, recruit leukocytes, and lyse cells. Many of these functions are mediated via the production of cytokines and growth factors upon γδ T cell activation. Pathogenesis of many chronic inflammatory diseases involves γδ T cells; some of which are exacerbated by their presence, while others are improved. γδ T cells require a delicate balance between their need for acute inflammatory mediators to function normally and the detrimental impact imparted by chronic inflammation. This review will focus on the recent progress made in understanding how epithelial γδ T cells influence the pathogenesis of chronic inflammatory diseases and how a balance between acute and chronic inflammation impacts γδ T cell function. Future studies will be important to understand how this balance is achieved.

The hypothesis underlying this current work is that fresh juice expressed from Papua New Guinea (PNG) medicinal plants (succus) will inhibit human Cytochrome P450s (CYPs). The CYP inhibitory activity identified in fresh material was compared with inhibition in methanol extracts of dried material. Succus is the most common method of traditional medicine (TM) preparation for consumption in PNG. There is increasing concern that TMs might antagonize or complicate drug therapy. We have previously shown that methanol extracts of commonly consumed PNG medicinal plants are able to induce and/or inhibit human CYPs in vitro. In this current work plant succus was prepared from fresh plant leaves. Inhibition of three major CYPs was determined using human liver microsomes and enzyme-selective model substrates. Of 15 species tested, succus from 6/15 was found to inhibit CYP1A2, 7/15 inhibited CYP3A4, and 4/15 inhibited CYP2D6. Chi-squared tests determined differences in inhibitory activity between succus and methanol preparations. Over 80% agreement was found. Thus, fresh juice from PNG medicinal plants does exhibit the potential to complicate drug therapy in at risk populations. Further, the general reproducibility of these findings suggests that methanol extraction of dried material is a reasonable surrogate preparation method for fresh plant samples.

Three new decalin-type tetramic acid analogues, pyrrolocins A (1), B (2), and C (3), were defined as products of a metabolic pathway from a fern endophyte, NRRL 50135, from Papua New Guinea. NRRL 50135 initially produced 1 but ceased its production before chemical or biological evaluation could be completed. Upon transfer of the biosynthetic pathway to a model host, 1-3 were produced. All three compounds are structurally related to equisetin-type compounds, with 1 and 3 having a trans-decalin ring system, while 2 has a cis-fused decalin. All were active against Mycobacterium tuberculosis, with the trans-decalin analogues 1 and 3 exhibiting lower MICs than the cis-decalin analogue 2. Here we report the isolation, structure elucidation, and antimycobacterial activities of 1-3 from the recombinant expression as well as the isolation of 1 from the wild-type fungus NRRL 50135.

Ethnopharmacological Relevance: A substantial proportion of the population in Papua New Guinea (PNG) lives with human immunodeficiency virus (HIV). Treatment requires lifelong use of antiretroviral therapy (ART). The majority of people in PNG use traditional medicines (TM) derived from plants for all types of health promotions. Consequently, there is a concern that herb-drug interactions may impact the efficacy of ART. Herb-drug, or drug-drug, interactions occur at the level of metabolism through two major mechanisms: enzyme induction or enzyme inhibition. In this study, extracts of commonly-used medicinal plants from PNG were screened for herb-drug interactions related to cytochrome P450s (CYPs)., Materials and Methods: Sixty nine methanol extracts of TM plants were screened for their ability to induce CYPs by human aryl hydrocarbon receptor- (hAhR-) and human pregnane X receptor- (hPXR-) dependent mechanisms, utilizing a commercially available cell-based luciferase reporter system. Inhibition of three major CYPs, CYP1A2, CYP3A4, and CYP2D6, was determined using human liver microsomes and enzyme-selective model substrates., Results: Almost one third of the TM plant extracts induced the hAhR-dependent expression of CYP1A2, the hPXR-dependent expression of CYP3A4, or both. Almost two thirds inhibited CYP1A2, CYP3A4, or CYP2D6, or combinations thereof. Many plant extracts exhibited both induction and inhibition properties., Conclusions: We demonstrated that the potent and selective ability of extracts from PNG medicinal plants to affect drug metabolizing enzymes through induction and/or inhibition is a common phenomenon. Use of traditional medicines concomitantly with ART could dramatically alter the concentrations of antiretroviral drugs in the body; and their efficacy. PNG healthcare providers should counsel HIV patients because of this consequence., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Many blood tests used in the evaluation of rheumatic diseases are non-specific and should not be ordered and interpreted in isolation. False positive results can lead to inappropriate therapies with serious adverse events while false negatives may steer the provider to incorrect diagnoses. Relying on blood tests alone without considering the clinical context should be avoided.