Disruption of LEDGF/p75-directed integration derepresses antisense transcription of the HIV-1 genome.

Disruption of HIV-1 Integrase (IN) interactions with the host-factor Lens Epithelium-Derived Growth Factor (LEDGF)/p75 leads to decreased, random integration, increased latent infection, and described here, accumulation of HIV-1 antisense RNA (asRNA). asRNA increase was observed following interruptions of IN-LEDGF/p75 interactions either through pharmacologic perturbations of IN-LEDGF/p75 by treatment with allosteric HIV-1 integrase inhibitors (ALLINIs) or in cell lines with LEDGF genetic knockout. Additionally, by impairing Tat-dependent HIV transcription, asRNA abundance markedly increases.

Potent broadly neutralizing antibodies mediate efficient antibody-dependent phagocytosis of HIV-infected cells.

Antibody-dependent cellular phagocytosis (ADCP) has been implicated in protection against HIV-1. However, methods for measuring ADCP currently rely on the phagocytosis of gp120- or gp41-coated beads that do not reflect physiologically relevant conformations of the viral envelope glycoprotein or the size of a virus-infected cell. We therefore developed a novel approach for measuring ADCP of HIV-infected cells expressing natural conformations of Env.

Self-Reported Financial Difficulties Among Patients with Multiple Myeloma and Chronic Lymphocytic Leukemia Treated at U.S. Community Oncology Clinics (Alliance A231602CD).

Objectives: To estimate the proportion and correlates of self-reported financial difficulty among patients with multiple myeloma (MM) or chronic lymphocytic leukemia (CLL).

Setting: 23 U.S.

Sub-optimal therapy of patients with primary biliary cholangitis (PBC) in the real-life stetting of the German PBC cohort.

Real-world data on the management of patients with primary biliary cholangitis (PBC) are so far scarce in Germany. Therefore, we aimed to establish a nationwide registry and describe the clinical characteristics and therapy of PBC patients.Three different cohorts defined as ursodeoxycholic acid (UDCA) responders, as inadequate responders according to Paris II criteria, and as newly diagnosed patients were prospectively recruited.

Evaluation of force pain thresholds to ensure collision safety in worker-robot collaborative operations.

With the growing demand for robots in the industrial field, robot-related technologies with various functions have been introduced. One notable development is the implementation of robots that operate in collaboration with human workers to share tasks, without the need of any physical barriers such as safety fences. The realization of such collaborative operations in practice necessitates the assurance of safety if humans and robots collide.

Investigation of vagal sensory neurons in mice using optical vagal stimulation and tracheal neuroanatomy.

In rats and guinea pigs, sensory innervation of the airways is derived largely from the vagus nerve, with the extrapulmonary airways innervated by Wnt1+ jugular neurons and the intrapulmonary airways and lungs by Phox2b+ nodose neurons; however, our knowledge of airway innervation in mice is limited. We used genetically targeted expression of enhanced yellow fluorescent protein-channelrhodopsin-2 (EYFP-ChR2) in Wnt1+ or Phox2b+ tissues to characterize jugular and nodose-mediated physiological responses and airway innervation in mice. With optical stimulation, Phox2b+ vagal fibers modulated cardiorespiratory function in a frequency-dependent manner while right Wnt1+ vagal fibers induced a small increase in respiratory rate.

Development of Biomechanical Response Curves for the Calibration of Biofidelic Measuring Devices Used in Robot Collision Testing.

Collaborative robots (cobots) can be employed in close proximity to human workers without safety fences. The operation mode Power and Force Limiting requires that cobots not exceed the biomechanical limits of ISO/TS 15066 to ensure protection against injuries caused by collisions with them. Collision tests must be performed to prove that cobots cannot exceed the biomechanical limits.

Human lysyl-tRNA synthetase phosphorylation promotes HIV-1 proviral DNA transcription.

Human lysyl-tRNA synthetase (LysRS) was previously shown to be re-localized from its normal cytoplasmic location in a multi-aminoacyl-tRNA synthetase complex (MSC) to the nucleus of HIV-1 infected cells. Nuclear localization depends on S207 phosphorylation but the nuclear function of pS207-LysRS in the HIV-1 lifecycle is unknown. Here, we show that HIV-1 replication was severely reduced in a S207A-LysRS knock-in cell line generated by CRISPR/Cas9; this effect was rescued by S207D-LysRS.

Retroviral hijacking of host transport pathways for genome nuclear export.

Recent advances in the study of virus-cell interactions have improved our understanding of how viruses that replicate their genomes in the nucleus (e.g., retroviruses, hepadnaviruses, herpesviruses, and a subset of RNA viruses) hijack cellular pathways to export these genomes to the cytoplasm where they access virion egress pathways.

EURADOS project on the impact of the proposed ICRU operational dose quantities.

Following the publication of the joint The International Commissions on Radiation Units and Measurements (ICRU) and on Radiological Protection (ICRP) report on new operational quantities for radiation protection, the European Dosimetry Group (EURADOS) have carried out an initial evaluation. The EURADOS report analyses the impact that the new quantities will have on: radiation protection practice; calibration and reference fields; European and national regulation; international standards and, especially, dosemeter and instrument design. The task group included experienced scientists drawn from across the various EURADOS working groups.

Exploiting a rodent cell block for intrinsic resistance to HIV-1 gene expression in human T cells.

Unlike humans, mice are unable to support HIV-1 infection. This is due, in part, to a constellation of defined minor, species-specific differences in conserved host proteins needed for viral gene expression. Here, we used precision CRISPR/Cas9 gene editing to engineer a "mousified" version of one such host protein, cyclin T1 (CCNT1), in human T cells.

Regulation of vagally-evoked respiratory responses by the lateral parabrachial nucleus in the mouse.

Vagal sensory inputs to the brainstem can alter breathing through the modulation of pontomedullary respiratory circuits. In this study, we set out to investigate the localised effects of modulating lateral parabrachial nucleus (LPB) activity on vagally-evoked changes in breathing pattern. In isoflurane-anaesthetised and instrumented mice, electrical stimulation of the vagus nerve (eVNS) produced stimulation frequency-dependent changes in diaphragm electromyograph (dEMG) activity with an evoked tachypnoea and apnoea at low and high stimulation frequencies, respectively.

Prevalence and Persistence of Antibiotic Resistance Determinants in the Gut of Travelers Returning to the United Kingdom is Associated with Colonization by Pathogenic Escherichia coli.

The gut microbiota constitutes an ideal environment for the selection, exchange, and carriage of antibiotic resistance determinants (ARDs), and international travel has been identified as a risk factor for acquisition of resistant organisms. Here, we present a longitudinal metagenomic analysis of the gut resistome in travellers to "high-risk" countries (Gutback). Fifty volunteers, recruited at a travel clinic in London, United Kingdom, provided stool samples before (pre-travel), immediately after (post-travel), and 6 months after their return (follow-up) from a high-risk destination.

Trametinib in Patients With , , or -Mutant Tumors: Results From the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocols S1 and S2.

Purpose: NCI-MATCH is a precision medicine trial using genomic testing to allocate patients with advanced malignancies to targeted treatment subprotocols. This report combines two subprotocols evaluating trametinib, a MEK1/2 inhibitor, in patients with ([S1] or [S2]) altered tumors.

Methods: Eligible patients had tumors with deleterious inactivating or mutations by the customized Oncomine AmpliSeq panel.

A statistical model to predict the occurrence of blunt impact injuries on the human hand-arm system.

Biomechanical limits based on pain thresholds ensure safety in workplaces where humans and cobots (collaborative robots) work together. Standardization bodies' decision to rely on pain thresholds stems from the assumption that such limits inherently protect humans from injury. This assumption has never been verified, though.

Effects of a Guideline-Informed Clinical Decision Support System Intervention to Improve Colony-Stimulating Factor Prescribing: A Cluster Randomized Clinical Trial.

Importance: Colony-stimulating factors are prescribed to patients undergoing chemotherapy to reduce the risk of febrile neutropenia. Research suggests that 55% to 95% of colony-stimulating factor prescribing is inconsistent with national guidelines.

Objective: To examine whether a guideline-based standing order for primary prophylactic colony-stimulating factors improves use and reduces the incidence of febrile neutropenia.

A Pragmatic Cluster-Randomized Trial of a Standing Order Entry Intervention for Colony-Stimulating Factor Use Among Patients at Intermediate Risk for Febrile Neutropenia.

Purpose: Primary prophylactic colony-stimulating factors (PP-CSFs) are prescribed to reduce febrile neutropenia (FN) but their benefit for intermediate FN risk regimens is uncertain. Within a pragmatic, randomized trial of a standing order entry (SOE) PP-CSF intervention, we conducted a substudy to evaluate the effectiveness of SOE for patients receiving intermediate-risk regimens.

Methods: TrACER was a cluster randomized trial where practices were randomized to usual care or a guideline-based SOE intervention.

Nanolattice-Forming Hybrid Collagens in Protective Shark Egg Cases.

Nanoscopic structural control with long-range ordering remains a profound challenge in nanomaterial fabrication. The nanoarchitectured egg cases of elasmobranchs rely on a hierarchically ordered latticework for their protective function─serving as an exemplary system for nanoscale self-assembly. Although the proteinaceous precursors are known to undergo intermediate liquid crystalline phase transitions before being structurally arrested in the final nanolattice architecture, their sequences have so far remained unknown.

HIV RGB: Automated Single-Cell Analysis of HIV-1 Rev-Dependent RNA Nuclear Export and Translation Using Image Processing in KNIME.

Single-cell imaging has emerged as a powerful means to study viral replication dynamics and identify sites of virus−host interactions. Multivariate aspects of viral replication cycles yield challenges inherent to handling large, complex imaging datasets. Herein, we describe the design and implementation of an automated, imaging-based strategy, “Human Immunodeficiency Virus Red-Green-Blue” (HIV RGB), for deriving comprehensive single-cell measurements of HIV-1 unspliced (US) RNA nuclear export, translation, and bulk changes to viral RNA and protein (HIV-1 Rev and Gag) subcellular distribution over time.

Substitutions in Nef That Uncouple Tetherin and SERINC5 Antagonism Impair Simian Immunodeficiency Virus Replication in Primary Rhesus Macaque Lymphocytes.

Most simian immunodeficiency viruses (SIVs) use Nef to counteract restriction by the tetherin proteins of their nonhuman primate hosts. In addition to counteracting tetherin, SIV Nef has a number of other functions, including the downmodulation of CD3, CD4, and major histocompatibility complex class I (MHC I) molecules from the surface of SIV-infected cells and the enhancement of viral infectivity by preventing the incorporation of SERINC5 into virions. Although these activities require different surfaces of Nef, they can be difficult to separate because of their dependence on similar interactions with AP-1 or AP-2 for clathrin-mediated endocytosis.

Robust engraftment of fetal nonhuman primate CD34-positive cells in immune-deficient mice.

Nonhuman primates (NHPs) represent one of the most important models for preclinical studies of novel biomedical interventions. In contrast with small animal models, however, widespread utilization of NHPs is restricted by cost, logistics, and availability. Therefore, we sought to develop a translational primatized mouse model, akin to a humanized mouse, to allow for high-throughput in vivo experimentation leveraged to inform large animal immunology-based studies.

N064A (Alliance): Phase II Study of Panitumumab, Chemotherapy, and External Beam Radiation in Patients with Locally Advanced Pancreatic Adenocarcinoma.

Background: This North Central Cancer Treatment Group (NCCTG) N064A (Alliance) phase II trial evaluated upfront chemoradiotherapy incorporating the EGFR inhibitor panitumumab, followed by gemcitabine and panitumumab for unresectable, non-metastatic pancreatic cancer.

Methods: The treatment consisted of fluoropyrimidine and panitumumab given concurrently with radiotherapy followed by gemcitabine and panitumumab for 3 cycles followed by maintenance panitumumab. The primary endpoint was the 12-month overall survival (OS) rate and secondary endpoints included confirmed response rate (RR), OS, progression-free survival (PFS), and adverse events.

Green Tea Extract to Prevent Colorectal Adenomas, Results of a Randomized, Placebo-Controlled Clinical Trial.

Introduction: Preclinical, epidemiological, and small clinical studies suggest that green tea extract (GTE) and its major active component epigallocatechingallate (EGCG) exhibit antineoplastic effects in the colorectum.

Methods: A randomized, double-blind trial of GTE standardized to 150 mg of EGCG b.i.

A Statistical Model to Determine Biomechanical Limits for Physically Safe Interactions With Collaborative Robots.

Collaborative robots (cobots) provide a wide range of opportunities to improve the ergonomics and efficiency of manual work stations. ISO/TS 15066 defines power and force limiting (PFL) as one of four safeguarding modes for these robots. PFL specifies biomechanical limits for hazardous impacts and pinching contacts that a cobot must not exceed to protect humans from serious injuries.