Substrate translocation and inhibition in human dicarboxylate transporter NaDC3.

The human high-affinity sodium-dicarboxylate cotransporter (NaDC3) imports various substrates into the cell as tricarboxylate acid cycle intermediates, lipid biosynthesis precursors and signaling molecules. Understanding the cellular signaling process and developing inhibitors require knowledge of the structural basis of the dicarboxylate specificity and inhibition mechanism of NaDC3. To this end, we determined the cryo-electron microscopy structures of NaDC3 in various dimers, revealing the protomer in three conformations: outward-open C, outward-occluded C and inward-open C.

The Potential Utility of (2S,4R)-4-[F]fluoroglutamine as a Novel Metabolic Imaging Marker for Inflammation Explored by Rat Models of Arthritis and Paw Edema.

Purpose: (2S,4R)-4-[F]fluoroglutamine ([F]FGln) is a promising metabolic imaging marker in cancer. Based on the fact that major inflammatory cells are heavily dependent on glutamine metabolism like cancer cells, we explored the potential utility of [F]FGln as a metabolic imaging marker for inflammation in two rat models: carrageenan-induced paw edema (CIPE) and collagen-induced arthritis (CIA).

Procedures: The CIPE model (n = 4) was generated by injecting 200 µL of 3% carrageenan solution into the left hind paw three hours before the PET.

Biological Evaluation of d-[F]Fluoroalanine and d-[F]Fluoroalanine- as Positron Emission Tomography Imaging Tracers for Bacterial Infection.

d-Amino acids such as d-alanine are substrates for bacterial peptidoglycan biosynthesis and are selectively taken up by bacteria and not mammalian cells. Consequently, d-amino acid metabolism is an attractive target for antibiotic discovery and the development of bacteria-specific imaging agents. d-Fluoroalanine and the deuterium-labeled analogue fludalanine (MK641) were originally explored as antibiotics by Merck but failed in clinical trials due to unaccepted toxicity.

Insect Flight: State of the Field and Future Directions.

The evolution of flight in an early winged insect ancestral lineage is recognized as a key adaptation explaining the unparalleled success and diversification of insects. Subsequent transitions and modifications to flight machinery, including secondary reductions and losses, also play a central role in shaping the impacts of insects on broadscale geographic and ecological processes and patterns in the present and future. Given the importance of insect flight, there has been a centuries-long history of research and debate on the evolutionary origins and biological mechanisms of flight.

The potential utility of (2S,4R)-4-[18F] fluoroglutamine as a novel metabolic imaging marker for inflammation explored by rat models of arthritis and paw edema.

Purpose: ()-4-[F]fluoroglutamine ([F]FGln) is a promising metabolic imaging marker in cancer. Based on the fact that major inflammatory cells are heavily dependent on glutamine metabolism like cancer cells, we explored the potential utility of [F]FGln as a metabolic imaging marker for inflammation in two rat models: carrageenan-induced paw edema (CIPE) and collagen-induced arthritis (CIA).

Procedures: The CIPE model (n = 4) was generated by injecting 200 μL of 3% carrageenan solution into the left hind paw three hours before the PET.

Synthesis and Biological Evaluation of Fluorine-18 and Deuterium Labeled l-Fluoroalanines as Positron Emission Tomography Imaging Agents for Cancer Detection.

To fully explore the potential of F-labeled l-fluoroalanine for imaging cancer and other chronic diseases, a simple and mild radiosynthesis method has been established to produce optically pure l-3-[F]fluoroalanine (l-[F]FAla), using a serine-derivatized, five-membered-ring sulfamidate as the radiofluorination precursor. A deuterated analogue, l-3-[F]fluoroalanine-d (l-[F]FAla-d), was also prepared to improve metabolic stability. Both l-[F]FAla and l-[F]FAla-d were rapidly taken up by 9L/lacZ, MIA PaCa-2, and U87MG cells and were shown to be substrates for the alanine-serine-cysteine (ASC) amino acid transporter.

ABCG2 transporter reduces protein aggregation in cigarette smoke condensate-exposed A549 lung cancer cells.

Cigarette smoke-induced protein aggregation damages the lung cells in emphysema and COPD; however, lung cancer cells continue to thrive, evolving to persist in the toxic environment. Here, we showed that upon the cigarette smoke condensate exposure, A549 lung cancer cells exhibit better survival and reduced level of protein aggregation when compared to non-cancerous Beas-2B and H-6053 cells. Our data suggests that upregulation of efflux pumps in cancer cells assists in reducing smoke toxicity.

A combination of conserved and diverged responses underlies Theobroma cacao's defense response to Phytophthora palmivora.

Background: Plants have complex and dynamic immune systems that have evolved to resist pathogens. Humans have worked to enhance these defenses in crops through breeding. However, many crops harbor only a fraction of the genetic diversity present in wild relatives.

Implications of Delayed Testosterone Recovery in Patients with Prostate Cancer.

Unlabelled: To assess the clinical impact of delayed testosterone recovery (TR) following the discontinuation of medical androgen deprivation therapy (ADT), a retrospective, longitudinal analysis was conducted in adult males with prostate cancer using the Optum® de-identified Electronic Health Record data set and Optum® Enriched Oncology Data (2010-2021). Of 3875 patients who initiated and discontinued ADT, 1553 received one or more testosterone-level tests within the 12 mo following discontinuation and were included in this study. These 1553 patients were categorized into two cohorts: 25% as TR (testosterone levels >280 ng/dl at any test within 12 mo following ADT discontinuation) and 75% as non-TR.

Burden of Illness and Treatment Patterns Among Patients With von Willebrand Disease in US Clinical Practice.

In this retrospective cohort study, data from an integrated US healthcare system containing both electronic medical record data and linked claims data (from 01/2004 to 12/2020) were used to evaluate the clinical burden, treatment patterns, and healthcare resource use (HRU) in patients with von Willebrand disease (VWD). Two patient cohorts were analyzed: the overall VWD population (n  =  396) and a subset of these patients (n  =  75) who were considered potentially eligible for prophylaxis treatment with von Willebrand factor (VWF) based on a history of severe and frequent bleeding. HRU (hospitalizations, outpatient visits, and emergency department visits) were measured in patients with linked claims data (n  =  110, overall VWD patients; n  =  23 potentially VWF-prophylaxis-eligible VWD patients).

Costs of pediatric liver transplantation among commercially insured and Medicaid-insured patients with cholestasis in the US.

Children with rare cholestatic liver diseases, such as Alagille syndrome, progressive familial intrahepatic cholestasis, and biliary atresia typically require liver transplantation (LT). The objective of this analysis was to assess the economic burden of LT on these patients. Health care resource utilization and costs associated with pediatric LT were retrospectively assessed using insurance claims data from the US IBM MarketScan Commercial and Medicaid databases collected between October 2015 and December 2019.

Functional and Clinical Outcomes Associated with Steroid Treatment among Non-ambulatory Patients with Duchenne Muscular Dystrophy1.

Background: Evidence on the long-term efficacy of steroids in Duchenne muscular dystrophy (DMD) after loss of ambulation is limited.

Objective: Characterize and compare disease progression by steroid treatment (prednisone, deflazacort, or no steroids) among non-ambulatory boys with DMD.

Methods: Disease progression was measured by functional status (Performance of Upper Limb Module for DMD 1.

The Economic Burden of Schizophrenia in the United States.

The economic burden of schizophrenia in the United States (US) was estimated at $155.7 billion in 2013. Since 2013, the US experienced significant health care reforms and treatment advances.

Health Care Resource Utilization by Patients with Alagille Syndrome.

Objective: To assess and characterize health care resource utilization (HRU) in children with the rare, genetic, multisystem disorder, Alagille syndrome.

Study Design: This retrospective analysis reviewed commercially insured and Medicaid-insured claims from October 1, 2015 to December 31, 2019 to assess HRU in patients with Alagille syndrome. As there is no specific International Classification ofDiseases-10 code for Alagille syndrome, patients were identified using the following algorithm: ≥1 claim with diagnosis code Q44.

Maralixibat Treatment Response in Alagille Syndrome is Associated with Improved Health-Related Quality of Life.

Objective: The objective of this study was to assess the impact of treatment response to the ileal bile acid transporter inhibitor maralixibat on health-related quality of life (HRQoL) in children with Alagille syndrome.

Study Design: This analysis used data from the ICONIC trial, a phase 2 study with a 4-week double-blind, placebo-controlled, randomized drug withdrawal period in children with Alagille syndrome with moderate-to-severe pruritus. Clinically meaningful treatment response to maralixibat was defined a priori as a ≥1-point reduction in the Itch-Reported Outcome (Observer) score, from baseline to week 48.

Global Regulatory Pathways Converge To Control Expression of Pseudomonas aeruginosa Type IV Pili.

The opportunistic pathogen Pseudomonas aeruginosa relies upon type IV pili (Tfp) for host colonization and virulence. Tfp are retractile surface appendages that promote adherence to host tissue and mediate twitching motility, a form of surface-associated translocation. Tfp are composed of a major structural pilin protein (PilA), several less abundant, fiber-associated pilin-like proteins (FimU, PilV, PilW, PilX, and PilE), and a pilus-associated tip adhesin and surface sensor (PilY1).

PmtA Regulates Pyocyanin Expression and Biofilm Formation in .

The opportunistic pathogen expresses a small molecular weight, cysteine-rich protein (PmtA), identified as a metallothionein (MT) protein family member. The MT family proteins have been well-characterized in eukaryotes as essential for zinc and copper homeostasis, protection against oxidative stress, and the ability to modify a variety of immune activities. Bacterial MTs share sequence homology, antioxidant chemistry, and heavy metal-binding capacity with eukaryotic MTs, however, the impact of bacterial MTs on virulence and infection have not been well-studied.

Impact of the COVID-19 pandemic on adolescent vaccinations: projected time to reverse deficits in routine adolescent vaccination in the United States.

Objective: The COVID-19 pandemic has led to significant reductions in the administration of routinely recommended vaccines among adolescents in the US including tetanus, diphtheria, and acellular pertussis (Tdap); meningococcal (ACWY); and human papillomavirus (HPV) vaccines. The extent to which these deficits could persist in 2021 and beyond is unclear. To address this knowledge gap, this study estimated the cumulative deficits of routine vaccine doses among US adolescents during the COVID-19 pandemic and estimated the time and effort needed to recover from those deficits.

The ups and downs of elevator-type di-/tricarboxylate membrane transporters.

The divalent anion sodium symporter (DASS) family contains both sodium-driven anion cotransporters and anion/anion exchangers. The family belongs to a broader ion transporter superfamily (ITS), which comprises 24 families of transporters, including those of AbgT antibiotic efflux transporters. The human proteins in the DASS family play major physiological roles and are drug targets.

Steroid switching in dystrophinopathy treatment: a US chart review of patient characteristics and clinical outcomes.

To describe reasons for switching from prednisone/prednisolone to deflazacort and associated clinical outcomes among patients with Duchenne and Becker muscular dystrophy (DMD and BMD, respectively) in the USA. A chart review of patients with DMD (n = 62) or BMD (n = 30) who switched from prednisone to deflazacort (02/2017-12/2018) collected demographic/clinical characteristics, reasons for switching, outcomes and common adverse events. The mean ages at switch were 20.

Cautionary Notes on the Use of Arabinose- and Rhamnose-Inducible Expression Vectors in Pseudomonas aeruginosa.

The Pseudomonas aeruginosa virulence factor regulator (Vfr) is a cyclic AMP (cAMP)-responsive transcription factor homologous to the Escherichia coli cAMP receptor protein (CRP). Unlike CRP, which plays a central role in E. coli energy metabolism and catabolite repression, Vfr is primarily involved in the control of P.

Resistance Genes Affect How Pathogens Maintain Plant Abundance and Diversity.

AbstractSpecialized pathogens are thought to maintain plant community diversity; however, most ecological studies treat pathogens as a black box. Here we develop a theoretical model to test how the impact of specialized pathogens changes when plant resistance genes (R-genes) mediate susceptibility. This work synthesizes two major hypotheses: the gene-for-gene model of pathogen resistance and the Janzen-Connell hypothesis of pathogen-mediated coexistence.

Alleles in metabolic and oxygen-sensing genes are associated with antagonistic pleiotropic effects on life history traits and population fitness in an ecological model insect.

Genes with opposing effects on fitness at different life stages are the mechanistic basis for evolutionary theories of aging and life history. Examples come from studies of mutations in model organisms, but there is little knowledge of genetic bases of life history tradeoffs in natural populations. Here, we test the hypothesis that alleles affecting oxygen sensing in Glanville fritillary butterflies have opposing effects on larval versus adult fitness-related traits.