Optimization of Potent and Selective Cyclohexyl Acid ERAP1 Inhibitors Using Structure- and Property-Based Drug Design.

Endoplasmic reticulum aminopeptidase 1 (ERAP1) cleaves the -terminal amino acids of peptides, which can then bind onto major histocompatibility class I (MHC-I) molecules for presentation onto the cell surface, driving the activation of adaptive immune responses. In cancer, overtrimming of mature antigenic peptides can reduce cytotoxic T-cell responses, and ERAP1 can generate self-antigenic peptides which contribute to autoimmune cellular responses. Therefore, modulation of ERAP1 activity has potential therapeutic indications for cancer immunotherapy and in autoimmune disease.

An eight-founder wheat MAGIC population allows fine-mapping of flowering time loci and provides novel insights into the genetic control of flowering time.

Flowering time synchronizes reproductive development with favorable environmental conditions to optimize yield. Improved understanding of the genetic control of flowering will help optimize varietal adaptation to future agricultural systems under climate change. Here, we investigate the genetic basis of flowering time in winter wheat (Triticum aestivum L.

Are seven amino acid substitutions sufficient to explain the evolution of high l-DOPA 4,5-dioxygenase activity leading to betalain pigmentation? Revisiting the gain-of-function mutants of Bean et al. (2018).

This work revisits a publication by Bean et al. (2018) that reports seven amino acid substitutions are essential for the evolution of l-DOPA 4,5-dioxygenase (DODA) activity in Caryophyllales. In this study, we explore several concerns which led us to replicate the analyses of Bean et al.

Assaying Mitochondrial Function by Multiparametric Flow Cytometry.

Flow cytometry has been a vital tool in cell biology for decades based on its versatile ability to detect and quantifiably measure both physical and chemical attributes of individual cells within a larger population. More recently, advances in flow cytometry have enabled nanoparticle detection. This is particularly applicable to mitochondria, which, as intracellular organelles have distinct subpopulations that can be evaluated based on differences in functional, physical, and chemical attributes, in a manner analogous to cells.

Characterization of Oogonial Stem Cells in Adult Mouse Ovaries with Age and Comparison to In Silico Data on Human Ovarian Aging.

Many adult somatic stem cell lineages are comprised of subpopulations that differ in gene expression, mitotic activity, and differentiation status. In this study, we explored if cellular heterogeneity also exists within oogonial stem cells (OSCs), and how chronological aging impacts OSCs. In OSCs isolated from mouse ovaries by flow cytometry and established in culture, we identified subpopulations of OSCs that could be separated based on differential expression of stage-specific embryonic antigen 1 (SSEA1) and cluster of differentiation 61 (CD61).

Evaluation of Telehealth Visit Attendance After Implementation of a Patient Navigator Program.

Importance: The dramatic rise in use of telehealth accelerated by COVID-19 created new telehealth-specific challenges as patients and clinicians adapted to technical aspects of video visits.

Objective: To evaluate a telehealth patient navigator pilot program to assist patients in overcoming barriers to video visit access.

Design, Setting, And Participants: This quality improvement study investigated visit attendance outcomes among those who received navigator outreach (intervention group) compared with those who did not (comparator group) at 2 US academic primary care clinics during a 12-week study period from April to July 2021.

A comparison of in-house and shared RapidPlan models for prostate radiation therapy planning.

Knowledge-based planning (KBP) can increase plan quality, consistency and efficiency. In this study, we assess the success of a using a publicly available KBP model compared with developing an in-house model for prostate cancer radiotherapy using a single, commercially available treatment planning system based on the ability of the model to achieve the centre's planning goals. Two radiation oncology centres each created a prostate cancer KBP model using the Eclipse RapidPlan software.

Associations between specific sleep and circadian characteristics and alcohol use disorder criteria and problems.

Given the significant heterogeneity of alcohol use disorder (AUD) and the increasing priority to understand individual profiles of AUD, pursuing symptom-level examinations of AUD is important. Disturbances in sleep and circadian rhythms have demonstrated robust associations with alcohol consumption and AUD, yet little research has examined these associations at the symptom- or problem-levels and research to date has focused on one or two sleep/circadian characteristics. We sought to investigate the associations between (a) specific AUD symptoms and (b) domains of alcohol-related problems, and multiple sleep characteristics, collected at a daily level in the naturalistic environment.

Selinexor, daratumumab, and dexamethasone in patients with relapsed or refractory multiple myeloma.

We assessed the safety, efficacy, maximum tolerated dose (MTD), and the recommended phase 2 dose (RP2D) of selinexor, a first in class oral selective inhibitor of nuclear export (100 mg once weekly [QW] or 60 mg twice weekly), in combination with daratumumab (16 mg/kg per label) and dexamethasone (40 mg QW) (SDd) in patients with relapsed refractory multiple myeloma (RRMM). Thirty-four patients (median prior therapies, 3 [range, 2-10]) were enrolled; MM was refractory to proteasome inhibitor (PI) in 85%, immunomodulatory agent (IMiD) in 76%, both in 74%, and daratumumab in 6% of patients. Two dose-limiting toxicities (DLTs) were reported in the selinexor 60 mg twice-weekly cohort with no DLTs in the 100 mg QW cohort, making 100 mg QW the MTD and RP2D.

Targeting the Regulatory Site of ER Aminopeptidase 1 Leads to the Discovery of a Natural Product Modulator of Antigen Presentation.

ER aminopeptidase 1 (ERAP1) is an intracellular enzyme that generates antigenic peptides and is an emerging target for cancer immunotherapy and the control of autoimmunity. ERAP1 inhibitors described previously target the active site and are limited in selectivity, minimizing their clinical potential. To address this, we targeted the regulatory site of ERAP1 using a high-throughput screen and discovered a small molecule hit that is highly selective for ERAP1.

Evolution of l-DOPA 4,5-dioxygenase activity allows for recurrent specialisation to betalain pigmentation in Caryophyllales.

The evolution of l-DOPA 4,5-dioxygenase activity, encoded by the gene DODA, was a key step in the origin of betalain biosynthesis in Caryophyllales. We previously proposed that l-DOPA 4,5-dioxygenase activity evolved via a single Caryophyllales-specific neofunctionalisation event within the DODA gene lineage. However, this neofunctionalisation event has not been confirmed and the DODA gene lineage exhibits numerous gene duplication events, whose evolutionary significance is unclear.

A nanoscale, multi-parametric flow cytometry-based platform to study mitochondrial heterogeneity and mitochondrial DNA dynamics.

Mitochondria are well-characterized regarding their function in both energy production and regulation of cell death; however, the heterogeneity that exists within mitochondrial populations is poorly understood. Typically analyzed as pooled samples comprised of millions of individual mitochondria, there is little information regarding potentially different functionality across subpopulations of mitochondria. Herein we present a new methodology to analyze mitochondria as individual components of a complex and heterogeneous network, using a nanoscale and multi-parametric flow cytometry-based platform.

The evolution of betalain biosynthesis in Caryophyllales.

Within the angiosperm order Caryophyllales, an unusual class of pigments known as betalains can replace the otherwise ubiquitous anthocyanins. In contrast to the phenylalanine-derived anthocyanins, betalains are tyrosine-derived pigments which contain the chromophore betalamic acid. The origin of betalain pigments within Caryophyllales and their mutual exclusion with anthocyanin pigments have been the subject of considerable research.

Redirecting Primary Metabolism to Boost Production of Tyrosine-Derived Specialised Metabolites in Planta.

L-Tyrosine-derived specialized metabolites perform many important functions in plants, and have valuable applications in human health and nutrition. A necessary step in the overproduction of specialised tyrosine-derived metabolites in planta is the manipulation of primary metabolism to enhance the availability of tyrosine. Here, we utilise a naturally occurring de-regulated isoform of the key enzyme, arogenate dehydrogenase, to re-engineer the interface of primary and specialised metabolism, to boost the production of tyrosine-derived pigments in a heterologous plant host.

The potential value of surrogate performance markers at caesarean section for the assessment of surgical competence.

Objectives: We hypothsised that surrogate markers of competence (procedure time and estimated surgical blood loss) could be of value when assessing competence for trainees learning to undertake lower segment caesarean section (LSCS). The study aim was to investigate differences in surrogate markers of surgical competence at LSCS between different training grades of primary surgeon and for different grades of surgical assistant; to assess the potential value of using these surrogate markers in overall assessments of surgical competence.

Study Design: Operating records for elective LSCS were reviewed from January 2007 to January 2015.

Proteomic responses to elevated ocean temperature in ovaries of the ascidian .

, a common sea squirt, exhibits lower reproductive success at the upper extreme of the water temperatures it experiences in coastal New England. In order to understand the changes in protein expression associated with elevated temperatures, and possible response to global temperature change, we reared from embryos to adults at 18°C (a temperature at which they reproduce normally at our collection site in Rhode Island) and 22°C (the upper end of the local temperature range). We then dissected ovaries from animals at each temperature, extracted protein, and measured proteomic levels using shotgun mass spectrometry (LC-MS/MS).

Optimization of visual training for full recovery from severe amblyopia in adults.

The severe amblyopia induced by chronic monocular deprivation is highly resistant to reversal in adulthood. Here we use a rodent model to show that recovery from deprivation amblyopia can be achieved in adults by a two-step sequence, involving enhancement of synaptic plasticity in the visual cortex by dark exposure followed immediately by visual training. The perceptual learning induced by visual training contributes to the recovery of vision and can be optimized to drive full recovery of visual acuity in severely amblyopic adults.

Cholesterol Levels in HIV- and/or HCV-Infected Drug Users Living in Argentina.

Improved understanding of cholesterol levels in HIV- and hepatitis C virus (HCV)-infected persons in Argentina will guide optimal antiretroviral therapy. The authors conducted a cross-sectional study in Argentina to describe associations between HIV, HCV, and cholesterol. Of the 202 participants, 21 were HIV infected, 15 were HCV infected, 46 were HIV/HCV coinfected, and 120 were HIV/HCV uninfected.

Population-based surveillance of HIV drug resistance emerging on treatment and associated factors at sentinel antiretroviral therapy sites in Namibia.

Objective: The World Health Organization (WHO) prospective surveys of acquired HIV drug resistance (HIVDR) evaluate HIVDR emerging after the first year of antiretroviral therapy (ART) and associated factors.

Methods: Consecutive ART starters in 2009 were enrolled at 3 sentinel sites in Namibia. Genotyping was performed at start and after 12 months in patients with HIV viral load (VL) >1000 copies per mL.

Genetic characterization of strains of Saccharomyces uvarum from New Zealand wineries.

We present a genetic characterization of 65 isolates of Saccharomyces uvarum isolated from wineries in New Zealand, along with the complete nucleotide sequence of a single sulfite-tolerant isolate. The genome of the New Zealand isolate averaged 99.85% nucleotide identity to CBS7001, the previously sequenced strain of S.

Household food insecurity associated with antiretroviral therapy adherence among HIV-infected patients in Windhoek, Namibia.

Objective: Food insecurity is emerging as an important barrier to antiretroviral therapy (ART) adherence. The objective of this study was to determine if food insecurity is associated with poor ART adherence among HIV-positive adults in a resource-limited setting that uses the public health model of delivery.

Design: A cross-sectional study using a 1-time questionnaire and routinely collected pharmacy data.

Short communication: effects of omega-3 fatty acids on triglycerides and high-density lipoprotein subprofiles in HIV-infected persons with hypertriglyceridemia.

Hypertriglyceridemia and low high-density lipoprotein (HDL)-cholesterol (HDL-C) may contribute to a presumed accelerated risk for cardiovascular disease in HIV-infected individuals. We evaluated the effect of omega-3 fatty acid treatment on triglycerides, low-density lipoprotein (LDL)-C, HDL-C, and HDL subpopulations. Forty-one HIV-seropositive subjects with hypertriglyceridemia (≥150 mg/dl) on active antiretroviral therapy were enrolled in this placebo-controlled, double-blind, randomized, crossover trial comparing the effects of omega-3 fatty acid treatment (1.

Correlates of non-adherence to antiretroviral therapy in a cohort of HIV-positive drug users receiving antiretroviral therapy in Hanoi, Vietnam.

The HIV epidemic in Vietnam is concentrated, with high prevalence estimates among injection drug users and commercial sex workers. Socio-demographics, substance use and clinical correlates of antiretroviral therapy non-adherence were studied in 100 HIV-1 infected drug users receiving antiretroviral therapy for at least 6 months in Hanoi, Vietnam. All study participants were men with a mean age of 29.