Testosterone therapy over 60 months improves aging male symptoms scores in all men with adult-onset testosterone deficiency.

Objective: We evaluated change (Δ) in AMSS in men with adult-onset testosterone deficiency (TD) on/not on testosterone undecanoate (TU) by analysing a registry of men with adult-onset TD.

Methods: Analyses were performed using non-parametric statistics to determine ΔAMSS at 6-12 monthly intervals in men on/not on TU and movement in AMSS. Factors predicting ΔAMSS were established linear/multiple regression.

Testosterone Replacement Therapy: Effects on Blood Pressure in Hypogonadal Men.

Purpose: While testosterone therapy can improve the various pathologies associated with adult-onset testosterone deficiency (TD), Summary of Product Characteristics (SPC) of five testosterone preparations caution that treatment may be associated with hypertension. This paper evaluates the impact of testosterone undecanoate (TU) on blood pressure (BP) in men with adult-onset TD.

Materials And Methods: Of 737 men with adult-onset TD in an on-going, observational, prospective, cumulative registry, we studied changes in BP using non-parametric sign-rank tests at final assessment and fixed time points.

Testosterone therapy reduces insulin resistance in men with adult-onset testosterone deficiency and metabolic syndrome. Results from the Moscow Study, a randomized controlled trial with an open-label phase.

Aims: To describe changes in homeostasis model assessment of insulin resistance index (HOMA-IR) following testosterone therapy in men with hypogonadism and metabolic syndrome (MetS).

Materials And Methods: A randomized, placebo-controlled, double-blind randomized controlled trial (RCT) comprising 184 men with MetS and hypogonadism (testosterone undecanoate [TU]: 113 men, placebo: 71 men) was conducted. This was followed by an open-label phase in which all men were given TU.

Testosterone replacement therapy: association with mortality in high-risk patient subgroups.

Objectives: We describe studies determining the association between testosterone therapy (TTh) and mortality.

Materials & Methods: We used a registry database of 737 men with adult-onset testosterone deficiency defined as presenting with low serum total testosterone (TT) levels ≤12.1 nmol/L and associated symptoms over a near 10-year follow-up.

HIV-1 Remission: Accelerating the Path to Permanent HIV-1 Silencing.

Despite remarkable progress, a cure for HIV-1 infection remains elusive. Rebound competent latent and transcriptionally active reservoir cells persevere despite antiretroviral therapy and rekindle infection due to inefficient proviral silencing. We propose a novel "block-lock-stop" approach, entailing long term durable silencing of viral expression towards an irreversible transcriptionally inactive latent provirus to achieve long term antiretroviral free control of the virus.

Assessment of diaper dermatitis using a novel electronic health record-embedded scale.

Objective: Quantify the evolution and severity of neonatal skin injury, specifically diaper skin compromise, by embedding a validated skin integrity evaluation into the electronic health record (EHR).

Methods: Retrospective longitudinal cohort analysis of 747 patients stratified by gestation: 22-27, 28-31, 32-24, and 35-37 weeks, from birth to discharge. Primary outcomes were time to first perineal erythema, duration as percent days with erythema, and severity as maximum score.

Bacteroides fragilis expresses three proteins similar to Porphyromonas gingivalis HmuY: Hemophore-like proteins differentially evolved to participate in heme acquisition in oral and gut microbiomes.

Oral and gut microbiomes are important for the maintenance of homeostasis in the human body. Altered or disturbed mutualism between their members results in dysbiosis with local injury and subsequent systemic diseases. The high bacterial density causes intense competition among microbiome residents to acquire nutrients, including iron and heme, the latter of high importance for heme auxotrophic members of the Bacteroidetes phylum.

Computational infrared and Raman spectra by hybrid QM/MM techniques: a study on molecular and catalytic material systems.

Vibrational spectroscopy is one of the most well-established and important techniques for characterizing chemical systems. To aid the interpretation of experimental infrared and Raman spectra, we report on recent theoretical developments in the ChemShell computational chemistry environment for modelling vibrational signatures. The hybrid quantum mechanical and molecular mechanical approach is employed, using density functional theory for the electronic structure calculations and classical forcefields for the environment.

A heme pocket aromatic quadrupole modulates gas binding to cytochrome c'-β: Implications for NO sensors.

The structural basis by which gas-binding heme proteins control their interactions with NO, CO, and O is fundamental to enzymology, biotechnology, and human health. Cytochromes c' (cyts c') are a group of putative NO-binding heme proteins that fall into two families: the well-characterized four alpha helix bundle fold (cyts c'-α) and an unrelated family with a large beta-sheet fold (cyts c'-β) resembling that of cytochromes P460. A recent structure of cyt c'-β from Methylococcus capsulatus Bath revealed two heme pocket phenylalanine residues (Phe 32 and Phe 61) positioned near the distal gas-binding site.

Skin Care for the Extremely Low-Birthweight Infant.

Extremely low-birthweight (ELBW) infants are at increased risk for infection because the innate immune function of their skin is underdeveloped as they lack a competent epidermal barrier. Thus, neonatal clinicians need to pay careful attention to skin care practices, particularly for periviable infants. In this review, we describe the challenges of skin care in ELBW infants and summarize strategies to prevent skin injury, minimize damage when it occurs, and enhance cutaneous innate immunity.

Myokines derived from contracting skeletal muscle suppress anabolism in MCF7 breast cancer cells by inhibiting mTOR.

There is strong evidence that physical activity has a profound protective effect against multiple types of cancer. Here, we show that this effect may be mediated by factors released from skeletal muscle during simulated exercise, , which suppress canonical anabolic signaling in breast cancer. We report attenuated growth of MCF7 breast cancer cells in the presence of a rodent-derived exercise conditioned perfusate, independent of prior exercise training.

Complementarity of neutron, XFEL and synchrotron crystallography for defining the structures of metalloenzymes at room temperature.

Room-temperature macromolecular crystallography allows protein structures to be determined under close-to-physiological conditions, permits dynamic freedom in protein motions and enables time-resolved studies. In the case of metalloenzymes that are highly sensitive to radiation damage, such room-temperature experiments can present challenges, including increased rates of X-ray reduction of metal centres and site-specific radiation-damage artefacts, as well as in devising appropriate sample-delivery and data-collection methods. It can also be problematic to compare structures measured using different crystal sizes and light sources.

QM/MM Simulations of Protein Crystal Reactivity Guided by MSOX Crystallography: A Copper Nitrite Reductase Case Study.

The recently developed multiple structures from one crystal (MSOX) serial crystallography method can be used to provide multiple snapshots of the progress of enzymatic reactions taking place within a protein crystal. Such MSOX snapshots can be used as a reference for combined quantum mechanical/molecular mechanical (QM/MM) simulations of enzyme reactivity within the crystal. QM/MM calculations are used to identify details of reference states that cannot be directly observed by X-ray diffraction experiments, such as protonation and oxidation states.

Nature of the copper-nitrosyl intermediates of copper nitrite reductases during catalysis.

The design and synthesis of copper complexes that can reduce nitrite to NO has attracted considerable interest. They have been guided by the structural information on the catalytic Cu centre of the widespread enzymes Cu nitrite reductases but the chemically novel side-on binding of NO observed in all crystallographic studies of these enzymes has been questioned in terms of its functional relevance. We show conversion of NO to NO in the crystal maintained at 170 K and present 'molecular movies' defining events during enzyme turnover including the formation of side-on Cu-NO intermediate.

Airway Management of COVID-19 Positive Patients Aboard USNS COMFORT Mission to New York City.

During the USNS Comfort mobilization to New York City in response to the pandemic, the ship's medical team cared for over 35 mechanically ventilated corona virus disease 2019 (COVID-19) infected patients. Due to the better than expected mortality rates of these patients, tracheotomy for prolonged intubation or other indicated interventional bronchoscopies were performed on 7 COVID positive patients, as well as 2 with negative screening tests. No member of the health care team subsequently became symptomatic or tested positive for COVID-19.

Testosterone replacement therapy: Pre-treatment sex hormone-binding globulin levels and age may identify clinical subgroups.

Background: Testosterone replacement therapy (TRT) improves health in some but not all men with type 2 diabetes (T2DM) and adult-onset testosterone deficiency (TD). Such heterogeneity is compatible with the concept of patient subgroups that respond differently to therapy.

Objectives: Use baseline SHBG and age to identify putative subgroups that demonstrate different responses in variables such as waist circumference and HbA1c following TRT.

Th17 cells increase in RRMS as well as in SPMS, whereas various other phenotypes of Th17 increase in RRMS only.

Background: The nature and extent of inflammation seen in multiple sclerosis (MS) varies throughout the course of the disease. Changes seen in CD4+ T-helper cells in relapsing-remitting (RR) MS and secondary progressive (SP) MS might differ qualitatively and/or quantitatively.

Objective: The objective of this paper is to study the frequencies of all major CD4+ T-helper subtypes - Th17, Th22 and Th1 lineage cells - in relapse, remission and secondary progression alongside CCR6 status, a chemokine receptor involved in migration of these cells into the central nervous system.

Prevotella intermedia produces two proteins homologous to Porphyromonas gingivalis HmuY but with different heme coordination mode.

As part of the infective process, Porphyromonas gingivalis must acquire heme which is indispensable for life and enables the microorganism to survive and multiply at the infection site. This oral pathogenic bacterium uses a newly discovered novel hmu heme uptake system with a leading role played by the HmuY hemophore-like protein, responsible for acquiring heme and increasing virulence of this periodontopathogen. We demonstrated that Prevotella intermedia produces two HmuY homologs, termed PinO and PinA.

High-throughput structures of protein-ligand complexes at room temperature using serial femtosecond crystallography.

High-throughput X-ray crystal structures of protein-ligand complexes are critical to pharmaceutical drug development. However, cryocooling of crystals and X-ray radiation damage may distort the observed ligand binding. Serial femtosecond crystallography (SFX) using X-ray free-electron lasers (XFELs) can produce radiation-damage-free room-temperature structures.

Characterization and Evolution of Germ1, an Element that Undergoes Diminution in Lampreys (Cyclostomata: Petromyzontidae).

The sea lamprey (Petromyzon marinus) undergoes substantial genomic alterations during embryogenesis in which specific sequences are deleted from the genome of somatic cells yet retained in cells of the germ line. One element that undergoes diminution in P. marinus is Germ1, which consists of a somatically rare (SR) region and a fragment of 28S rDNA.

Sex Hormone Binding Globulin: A Review of its Interactions With Testosterone and Age, and its Impact on Mortality in Men With Type 2 Diabetes.

Introduction: The age-related fall in male testosterone levels can have clinical consequences. The concentration of serum-free testosterone, the putative bioactive moiety, is mediated by carrier proteins, especially SHBG.

Aim: The aim of this study was to consider the nature of hormone binding to carriers with new insights into determining calculated free testosterone levels and review how SHBG and testosterone influence age-related mortality.

Dose-resolved serial synchrotron and XFEL structures of radiation-sensitive metalloproteins.

An approach is demonstrated to obtain, in a sample- and time-efficient manner, multiple dose-resolved crystal structures from room-temperature protein microcrystals using identical fixed-target supports at both synchrotrons and X-ray free-electron lasers (XFELs). This approach allows direct comparison of dose-resolved serial synchrotron and damage-free XFEL serial femtosecond crystallography structures of radiation-sensitive proteins. Specifically, serial synchrotron structures of a heme peroxidase enzyme reveal that X-ray induced changes occur at far lower doses than those at which diffraction quality is compromised (the Garman limit), consistent with previous studies on the reduction of heme proteins by low X-ray doses.

Testosterone Therapy: An Assessment of the Clinical Consequences of Changes in Hematocrit and Blood Flow Characteristics.

Introduction: Clinical guidelines indicate that hematocrit should be monitored during testosterone replacement therapy (TTh), with action taken if a level of 0.54 is exceeded.

Aim: To consider the extent of changes in hematocrit and putative effects on viscosity, blood flow, and mortality rates after TTh.

Resolving polymorphs and radiation-driven effects in microcrystals using fixed-target serial synchrotron crystallography.

The ability to determine high-quality, artefact-free structures is a challenge in micro-crystallography, and the rapid onset of radiation damage and requirement for a high-brilliance X-ray beam mean that a multi-crystal approach is essential. However, the combination of crystal-to-crystal variation and X-ray-induced changes can make the formation of a final complete data set challenging; this is particularly true in the case of metalloproteins, where X-ray-induced changes occur rapidly and at the active site. An approach is described that allows the resolution, separation and structure determination of crystal polymorphs, and the tracking of radiation damage in microcrystals.

A QM/MM Study of Nitrite Binding Modes in a Three-Domain Heme-Cu Nitrite Reductase.

Copper-containing nitrite reductases (CuNiRs) play a key role in the global nitrogen cycle by reducing nitrite (NO₂) to nitric oxide, a reaction that involves one electron and two protons. In typical two-domain CuNiRs, the electron is acquired from an external electron-donating partner. The recently characterised (NiR) system is a three-domain CuNiR, where the cupredoxin domain is tethered to a heme domain that can function as the electron donor.