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Anemia due to micronutrient deficiencies has received little attention in public health and modern-day clinical practice. Increasing numbers of persons, mainly in low- and middle-income nations, are faced with malnutrition and malabsorption syndromes, giving rise to various micronutrient deficiencies that can lead to anemias refractory to treatment with iron, folate or vitamin B12. Though relatively uncommon, such underlying nutrient deficiencies may be difficult to recognize as they can coexist with more common causes and there may be few or no specific clinical characteristics pinpointing a particular micronutrient. The main examples of these micronutrients contributing to a small but important burden of anemia are other B-group vitamins, pyridoxine and thiamine, ascorbic acid, the fat-soluble vitamins, A and E and other trace elements such as copper, zinc and selenium. The following review highlights the current state of knowledge and the relevance of these micronutrient deficiencies in the broader context of nutritional anemia.

GABA, the principal inhibitory neurotransmitter in the adult brain, has a parallel inhibitory role in the immune system. We demonstrate that immune cells synthesize GABA and have the machinery for GABA catabolism. Antigen-presenting cells (APCs) express functional GABA receptors and respond electrophysiologically to GABA. Thus, the immune system harbors all of the necessary constituents for GABA signaling, and GABA itself may function as a paracrine or autocrine factor. These observations led us to ask further whether manipulation of the GABA pathway influences an animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). Increasing GABAergic activity ameliorates ongoing paralysis in EAE via inhibition of inflammation. GABAergic agents act directly on APCs, decreasing MAPK signals and diminishing subsequent adaptive inflammatory responses to myelin proteins.

Cancer biomarker testing is a critical element in precision oncology, guiding treatment decisions and improving patient outcomes. However, the complexity and variability of biomarker testing processes present significant challenges for cancer centers, often leading to delays and inefficiencies that can compromise care quality. The American Society for Clinical Pathology explored the concept of a novel laboratory professional role: the cancer biomarker testing navigator (BTN). This study explored the feasibility and impact of the BTN role on laboratory operations and workflows through a 3-phase project consisting of a quantitative needs assessment, qualitative focus group discussions, and a short-term feasibility pilot conducted at 2 cancer centers. The needs assessment revealed that many laboratories lack dedicated staff for coordinating biomarker testing, leading to operational inefficiencies. The roundtable discussions highlighted common challenges in biomarker testing and identified potential benefits of the BTN role, such as improved communication, better tracking of send-out tests, and enhanced task efficiency. The feasibility pilot demonstrated that BTNs could coordinate multigene next-generation sequencing panels and expedite key steps to ensure optimal preanalytical processes, reduce delays in testing, and smooth operations. The BTN role represents a feasible and beneficial addition to pathology laboratories that addresses key operational challenges in cancer biomarker testing and offers a promising solution to streamline laboratory operations, improve multidisciplinary communication, and enhance patient care coordination. Further exploration is warranted to refine the BTN role and assess its long-term sustainability in and impact on diverse laboratory settings.

Background Heterozygous loss-of-function mutations in the progranulin (PGRN) gene ( GRN ) cause a reduction in PGRN and lead to the development of frontotemporal dementia (FTD- GRN ). PGRN is a secreted lysosomal chaperone, immune regulator, and neuronal survival factor that is shuttled to the lysosome through multiple receptors, including sortilin. Here, we report the characterization of latozinemab, a human monoclonal antibody that decreases the levels of sortilin, which is expressed on myeloid and neuronal cells and shuttles PGRN to the lysosome for degradation, and blocks its interaction with PGRN. Methods In vitro characterization studies were first performed to assess the mechanism of action of latozinemab. After the in vitro studies, a series of in vivo studies were performed to assess the efficacy of a mouse-cross reactive anti-sortilin antibody and the pharmacokinetics, pharmacodynamics, and safety of latozinemab in nonhuman primates and humans. Results In a mouse model of FTD- GRN , the rodent cross-reactive anti-sortilin antibody, S15JG, decreased total sortilin levels in white blood cell (WBC) lysates, restored PGRN to normal levels in plasma, and rescued a behavioral deficit. In cynomolgus monkeys, latozinemab decreased sortilin levels in WBCs and concomitantly increased plasma and cerebrospinal fluid (CSF) PGRN by 2- to threefold. Finally, in a first-in-human phase 1 clinical trial, a single infusion of latozinemab caused a reduction in WBC sortilin, tripled plasma PGRN and doubled CSF PGRN in healthy volunteers, and restored PGRN to physiological levels in asymptomatic GRN mutation carriers. Conclusions These findings support the development of latozinemab for the treatment of FTD- GRN and other neurodegenerative diseases where elevation of PGRN may be beneficial. Trial registration ClinicalTrials.gov, NCT03636204. Registered on 17 August 2018, https://clinicaltrials.gov/ct2/show/NCT03636204 .

Tricuspid valve regurgitation (TR) is a common complication of end-stage heart failure. Increased pulmonary venous pressures caused by left ventricular (LV) dysfunction can result in a progressive dilation of the right ventricle and tricuspid valve annulus, resulting in functional TR. Here, we review what is known about TR in the setting of severe LV dysfunction necessitating long-term mechanical support with left ventricular assist devices (LVADs), including the occurrence of significant TR, its pathophysiology, and natural history. We examine the impact of uncorrected TR on LVAD outcomes and the impact of tricuspid valve interventions at the time of LVAD placement, revealing that TR frequently improves after LVAD placement with or without concomitant tricuspid valve intervention such that the benefit of concomitant intervention remains controversial. We summarize the current evidence on which to base medical decisions and provide recommendations for future directions of study to address outstanding questions in the field.

Muscle contraction is triggered by the opening of acetylcholine receptors at the vertebrate nerve–muscle synapse 1 , 2 , 3 , 4 . The M2 helix of this allosteric membrane protein lines the channel, and contains a ‘gate’ that regulates the flow of ions through the pore. We used single-molecule kinetic analysis to probe the transition state of the gating conformational change and estimate the relative timing of M2 motions in the α-subunit of the murine acetylcholine receptor 5 . This analysis produces a ‘ Φ -value’ for a given residue that reflects its open-like versus closed-like character at the transition state. Here we show that most of the residues throughout the length of M2 have a Φ -value of ∼0.64 but that some near the middle have lower Φ -values of 0.52 or 0.31, suggesting that αM2 moves in three discrete steps. The core of the channel serves both as a gate that regulates ion flow and as a hub that directs the propagation of the gating isomerization through the membrane domain of the acetylcholine receptor.

Background Alzheimer’s disease (AD) is characterized by amyloid plaques, tau tangles, and neuronal loss. Progranulin (PGRN) is a secreted immune regulator, lysosomal chaperone, and neuronal survival factor. Genetic polymorphisms that reduce PGRN levels are associated with an increased risk for AD and other neurodegenerative disorders. The receptor sortilin binds and targets PGRN for lysosomal degradation, resulting in a reduction of extracellular PGRN. AL101 (GSK4527226) is a monoclonal antibody that binds to the sortilin receptor and is being developed as a potential PGRN-elevating therapy for AD. Methods Cell-based in vitro studies examined the interaction of AL101 with sortilin and its effect on PGRN levels. In vivo studies evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of AL101 in rats and nonhuman primates. A phase 1 study in healthy volunteers assessed PK, safety, tolerability, and PD biomarkers after intravenous or subcutaneous dosing of AL101. Results Cell-based assays showed that AL101 increased PGRN levels by decreasing cell surface sortilin levels and partially blocking the sortilin-PGRN interaction. Preclinical studies in rats and monkeys demonstrated that AL101 decreased cell surface sortilin levels on white blood cells and increased PGRN levels by up to 2-fold in cerebrospinal fluid (CSF) and up to 4-fold in blood. In the phase 1 study in healthy volunteers, both single and multiple doses of AL101 led to significant increases in plasma and CSF PGRN levels, providing additional support for its potential as a PGRN-elevating therapy. Limitations The first-in-human dose-finding study was aimed at investigating the safety and tolerability of AL101 and was not sufficiently powered to detect changes in exploratory outcomes, such as neurodegeneration biomarkers. Clinical studies are needed to evaluate AL101 in AD patients. Conclusions AL101 was shown to bind sortilin and decrease cell surface sortilin levels, leading to consistent elevations of PGRN across in vitro, preclinical, and human studies. These results support continued development of AL101 and its investigation as a potential treatment for AD and other neurodegenerative conditions where PGRN could play a role. Trial registration Clinicaltrials.gov, NCT04111666. Registered on October 1, 2019. https://clinicaltrials.gov/ct2/show/NCT04111666 .

Three-dimensional (3D) bioimaging, visualization and data analysis are in strong need of powerful 3D exploration techniques. We develop virtual finger (VF) to generate 3D curves, points and regions-of-interest in the 3D space of a volumetric image with a single finger operation, such as a computer mouse stroke, or click or zoom from the 2D-projection plane of an image as visualized with a computer. VF provides efficient methods for acquisition, visualization and analysis of 3D images for roundworm, fruitfly, dragonfly, mouse, rat and human. Specifically, VF enables instant 3D optical zoom-in imaging, 3D free-form optical microsurgery, and 3D visualization and annotation of terabytes of whole-brain image volumes. VF also leads to orders of magnitude better efficiency of automated 3D reconstruction of neurons and similar biostructures over our previous systems. We use VF to generate from images of 1,107 Drosophila GAL4 lines a projectome of a Drosophila brain. Large three-dimensional images are commonly generated through biological experimentation. Here the authors report software tools for exploration of three-dimensional images along with applications to assist in imaging, microsurgery, visualization and annotation of large image data sets.

Immunogenetic as well as environmental and occupational exposures have been linked to the development of rheumatoid arthritis (RA), RA-associated lung disease, and other primary lung disorders. Importantly, various inhalants can trigger post-translational protein modifications, resulting in lung autoantigen expression capable of stimulating pro-inflammatory and/or pro-fibrotic immune responses. To further elucidate gene-environment interactions contributing to pathologic lung inflammation, we exploited an established model of organic dust extract (ODE) exposure with and without collagen-induced arthritis (CIA) in C57BL/6 wild type (WT) versus HLA-DR4 transgenic mice. ODE-induced airway infiltration driven by neutrophils was significantly increased in DR4 versus WT mice, with corresponding increases in bronchoalveolar lavage fluid (BALF) levels of TNF-⍺, IL-6, and IL-33. Lung histopathology demonstrated increased number of ectopic lymphoid aggregates comprised of T and B cells following ODE exposure in DR4 mice. ODE also induced citrullination, malondialdehyde acetaldehyde (MAA) modification, and vimentin expression that co-localized with MAA and was enhanced in DR4 mice. Serum and BALF anti-MAA antibodies were strikingly increased in ODE-treated DR4 mice. Coupling ODE exposure with Type II collagen immunization (CIA) resulted in similarly augmented pro-inflammatory lung profiles in DR4 mice (relative to WT mice) that was accompanied by a profound increase in infiltrating lung CD4 + and CD8 + T cells as well as CD19 + CD11b + autoimmune B cells. Neither modeling strategy induced significant arthritis. These findings support a model in which environmental insults trigger enhanced post-translational protein modification and lung inflammation sharing immunopathological features with RA-associated lung disease in the selected immunogenetic background of HLA-DR4 mice.

The efficacy of 1 alpha ,25-dihydroxyvitamin D3 (Vit-D) limits its topical use despite its profound effects on cellular differentiation, proliferation, and immunomodulation. Therefore, in search for a more effective analog of Vit-D, in this study we have evaluated the antiproliferative and proapoptotic effects of 1 alpha ,25-dihydroxyvitamin D3-3-bromoacetate (BE). Proliferation and apoptosis studies in normal human epidermal keratinocytes (NHEKs) were conducted by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), CFSE (carboxy fluorescein succinimidyl ester) dilution, and Annexin V assays. Western blot analysis and real-time PCR were performed to determine its effect on signal transduction. A reconstructed human epidermis (RHE) model was used to further validate the therapeutic role of BE in psoriasis. BE was significantly more potent than an equivalent concentration of Vit-D in inhibiting growth and survival of human keratinocytes. The antimitotic effect was found to be due to the inhibition of phosphorylation of serine/threonine protein kinase (AKT) and its downstream target, mammalian target of rapamycin (mTOR). In the RHE model, BE reversed IL-22-induced psoriasiform changes more effectively than Vit-D. Interestingly, BE inhibited the IL-22-induced gene expression of AKT1, MTOR, chemokines [IL-8 and RANTES (regulated upon activation, normal T-cell expressed and secreted)], and psoriasin (S100A7) more significantly than Vit-D. These results suggest the potential of BE as a prospective therapeutic agent for psoriasis.