PICALM Alzheimer's risk allele causes aberrant lipid droplets in microglia.

Despite genome-wide association studies (GWAS) of late-onset Alzheimer's disease (LOAD) having identified many genetic risk loci, the underlying disease mechanisms remain largely unclear. Determining causal disease variants and their LOAD-relevant cellular phenotypes has been a challenge. Here, using our approach for identifying functional GWAS risk variants showing allele-specific open chromatin, we systematically identified putative causal LOAD-risk variants in human induced pluripotent stem (iPS)-cell-derived neurons, astrocytes and microglia, and linked a PICALM LOAD-risk allele to a microglial-specific role of PICALM in lipid droplet (LD) accumulation.

Proteomic profile at the time of surgery correlates with disease stage and surgical outcome in periprosthetic joint infection.

Periprosthetic joint infection (PJI) is the most common and difficult to treat form of arthroplasty failure. While treatment with debridement, antibiotics, and implant retention (DAIR) is preferable to one- or two-stage implant exchange based on morbidity and cost, outcomes are not successful in all cases selected for this management strategy. DAIR is currently recommended when infection is perceived to be in an "acute" phase, based on symptom duration; despite this selection strategy, DAIR failure rates are high.

Targeted Quantitation of Phosphotyrosine-Containing Proteins in T-Cell Receptor Signaling Using a SureQuant-Based Mass Spectrometry Approach.

T-cell receptor (TCR) signaling plays a crucial role in various biological processes and is usually studied using global mass spectrometry-based phosphoproteomic studies. Despite advancements in targeted mass spectrometry-based assays for protein quantification, their application in studying signaling processes, for example, reproducible measurements of post-translational modifications (PTMs) such as phosphorylation, remains limited. Tyrosine phosphorylation is critical for many signaling pathways but presents challenges due to the low abundance of phosphotyrosine-containing peptides.

Dynamic extracellular interactions with AMPA receptors.

Synaptic plasticity in the central nervous system enables the encoding, storing, and integrating new information. AMPA-type glutamate receptors (AMPARs) are ligand-gated ion channels that mediate most fast excitatory synaptic transmission in the brain, and plasticity of AMPARs signaling underlies the long-lasting changes in synaptic efficacy and strength important for learning and memory. Recent work has indicated that the enigmatic N-terminal domain (NTD) of AMPARs may be a critical regulator of synaptic targeting and plasticity of AMPARs.

ALG13 loss-of-function alters glycosylation, impairs neuronal maturation, and drives network hypoactivity in a cortical organoid model of CDG.

Background: Congenital disorders of glycosylation (CDGs) are a group of rare metabolic diseases recognized for their neurological presentations, including developmental delay and seizures. However, the link between glycosylation defects and cortical brain network pathology remains elusive.

Methods: To address this unmet need, we generated iPSC derived human cortical organoids (hCOs) for ALG13-CDG, which is the second most common CDG that is also X-linked.

Deciphering the Glycoproteomic Landscape of Mood Disorders: Unveiling Molecular Association Between CDG and Depression Resilience.

The lack of a molecular understanding of mood disorders has impeded progress in diagnosis and treatment. Glycosylation may provide insights into the complex mechanisms underlying these conditions. We conducted N-glycoproteomic analysis on dorsolateral prefrontal cortex samples from individuals with major depressive disorder (MDD) and bipolar disorder (BD), in depressive or manic states at death.

PGM1 deficiency disrupts sarcomere and mitochondrial function in a stem-cell cardiomyocyte model.

Background: Phosphoglucomutase-1 (PGM1) plays a pivotal role in glycolysis, glycogen metabolism, and glycosylation. Pathogenic variants in PGM1 cause PGM1-congenital disorder of glycosylation (PGM1-CDG), a multisystem disorder with cardiac involvement. While glycosylation abnormalities in PGM1-CDG are treatable with galactose, cardiomyopathy does not improve suggesting a glycosylation-independent pathomechanism.

Novel mouse model reveals neurodevelopmental origin of PMM2-CDG brain pathology.

Congenital disorders of glycosylation (CDG) are a group of neurogenetic conditions resulting from disruptions in the cellular glycosylation machinery. The majority of CDG patients have compound heterozygous pathogenic variants in the phosphomannomutase 2 ( gene. Individuals with PMM2-CDG exhibit multi-systemic symptoms, prominently featuring neurological deficits with nearly all patients exhibiting cerebellar hypoplasia and ataxia.

Therapeutic Yoga: A feasible complementary approach for glycemic control in individuals with impaired fasting glucose and elevated HbA1c.

Background: Impaired Fasting Glucose (IFG) with elevated glycated hemoglobin (HbA1c) is a key precursor to type 2 diabetes mellitus (T2DM). Although asymptomatic, IFG significantly raises the risk of developing T2DM and cardiovascular complications, emphasizing the need for early intervention. The Therapeutic Yoga Module (TYM) was designed to offer a feasible and effective remedy for improving glycemic control.

A survey on practices of embalming techniques and usage of soft embalming methods in Indian medical institutes.

Background: Soft cadavers are becoming increasingly popular for surgical skills development in competency-based medical education curricula. However, few studies evaluate this strategy's viability, dependability, and validity, particularly in India. This study intends to investigate embalming procedures and procedural skills practices at medical institutions.

Proteomic analysis of exosomes from lymphatic affluents reveals their implications in developing premetastatic niche in melanoma.

Melanoma is an aggressive form of skin cancer that often spreads via lymphatic pathways to regional and distant sites. Melanoma-derived lymphatic exosomes play a crucial role in forming a tumor-supportive environment for metastasis, or premetastatic niche, within the first tumor draining lymph node, also known as the sentinel lymph node (SLN). Therefore, analyzing the proteomic content of tumor-draining lymphatic exosomes that deliver oncogenic molecules to the SLN is important in understanding the premetastatic niche.

Splanchnic and Leg Glucagon Metabolism in Healthy Individuals and Those With Type 1 Diabetes: First-in-Human Study Using [13C9,15N1]Glucagon.

Unlabelled: Circulating glucagon concentrations differ between individuals with no diabetes (ND) and those with type 1 diabetes (T1D). We combined an isotope dilution technique using stable tracers [6,22-13C9,15N1]glucagon and [6,14,19,22-13C9,15N1]glucagon with splanchnic and leg catheterization in participants with ND (n = 8; age 23.1 ± 2.

Establishment of salivary tissue-organoid biorepository: characterizing salivary gland stem/progenitor cells and novel differentiation marker PSMA/FOLH1.

The salivary gland (SG) is vital for oral function and overall health through secretion of saliva. However salivary dysfunction due to aging, medications, autoimmune disorders, and cancer treatments poses significant challenges. We established the first diverse and clinically annotated salivary regenerative biobank at Mayo Clinic to study salivary gland stem/progenitor cells (SGSPCs).

A Selective MAP3K1 Inhibitor Facilitates Discovery of NPM1 as a Member of the Network.

The quinoxaline core is found in several biologically active compounds, with Erdafitinib being the first FDA-approved quinoxaline derivative that targets a kinase and exhibits anti-cancer properties. We previously reported a quinoxaline analog () that displayed anti-cancer effects by inhibiting IKKβ, a key kinase in the NFκB pathway. Here, we present the synthesis of a regioisomer (-) and its characterization as a selective MAP3K1 inhibitor with improved metabolic stability and oral bioavailability.

Further delineation of defects in MRPS2 causing human OXPHOS deficiency and early developmental abnormalities in zebrafish.

Mitochondrial ribosomal protein-small 2 (MRPS2) encodes a vital structural protein essential for assembling mitoribosomal small subunit and thus mitochondrial translation. Any defect in mitochondrial translation impacts OXPHOS activity and cellular respiration. Defects in MRPS2 have been implicated recently in four families with combined oxidative phosphorylation deficiency-36 (MIM# 617950).

Detecting red blood cell protein antigens by tandem mass spectrometry.

Background: Tandem mass spectrometry (MS/MS) has become a common clinical laboratory testing modality has demonstrated success in distinguishing between small protein variations in transthyretin amyloidosis. Since many common clinically significant RBC antigens are also small protein variations, this study aimed to determine if MS/MS could correctly detect common RBC antigens within the Rh, Kell, Duffy, MNS, Kidd, Diego, and Lutheran blood group systems.

Study Design And Methods: Residual samples from serotyped/genotyped blood donors at a hospital-based blood donation center from February to August 2021 were analyzed.

A novel dominant-negative variant of IRF8 in a mother and son: Clinical, phenotypic and biological characteristics.

Background: The few reported patients with pathogenic IRF8 variants have manifested 2 distinct phenotypes: (1) an autosomal recessive severe immunodeficiency with significant neutrophilia and absence of or significant decrease in monocytes and dendritic cells and (2) a dominant-negative form with only a decrease in conventional type 2 dendritic cells (cDC2s) and susceptibility to mycobacterial disease.

Objectives: Genetic testing of a child with persistent EBV viremia identified a novel IRF8 variant: c.1279dupT (p.

A Rare, Atypical Case of Porcupine Quill Shot in the Glenoid Fossa: Case Report and Review of Literature.

Human injury due to porcupine quill attack is quite unusual, as their interaction is very rare owing to their habitat. However encroachment into their wildlife can cause grave injuries due to their quills, which are modified keratin having backward facing sharp barbs. The injuries resulting from porcupine quill may cause pain, infection, foreign body reactions, vascular trauma, gastric perforations and are difficult to retrieve because of their structure.

Proteomic analysis of carotid artery plaques with and without vulnerable features on magnetic resonance angiography with vessel wall imaging: a pilot study.

Objective: Extracranial carotid artery pathology accounts for 15% to 20% of ischemic strokes. Advancements in magnetic resonance angiography (MRA) with vessel wall imaging (VWI) have enabled the identification of vulnerable plaques, aiding in risk stratification for neurovascular events. This pilot study aimed to identify proteins in plaques with and without vulnerable features on MRA with VWI.

Immunogenic cryptic peptides dominate the antigenic landscape of ovarian cancer.

Increased infiltration of CD3 and CD8 T cells into ovarian cancer (OC) is linked to better prognosis, but the specific antigens involved are unclear. Recent reports suggest that HLA class I can present peptides from noncoding genomic regions, known as noncanonical or cryptic peptides, but their immunogenicity is underexplored. To address this, we used immunopeptidomic analysis and RNA sequencing on five metastatic OC samples, which identified 311 cryptic peptides (40 to 83 per patient).

Lysosomal NKG7 restrains mTORC1 activity to promote CD8 T cell durability and tumor control.

During infection and cancer, mTORC1-mediated metabolic regulation impacts CD8 T cell effector expansion and memory development. However, the mechanisms by which CD8 T cells regulate mTORC1 to support their unique metabolic requirements remain unknown. Here we show that NKG7, a lysosomal protein whose expression is restricted to cytotoxic lymphocytes, negatively regulates mTORC1 recruitment and activation by inhibiting assembly and function of the lysosomal proton pump, vacuolar ATPase (v-ATPase).

Single Cell Untargeted Lipidomics Using Liquid Chromatography Ion Mobility-Mass Spectrometry.

Advancements in technology over the years have propelled omics analysis to the level of single cell resolution. Following the breakthroughs in single cell transcriptomics and genomics, single cell proteomics has recently rapidly progressed, aided by highly sensitive mass spectrometry instrumentation. However, there is currently a paucity of studies and methodologies for single cell lipidomics, aside from imaging-based approaches.

Exploring BCL2 regulation and upstream signaling transduction in venetoclax resistance in multiple myeloma: potential avenues for therapeutic intervention.

Investigating venetoclax (VTX) resistance in multiple myeloma (MM) is crucial for the development of novel therapeutic strategies to tackle resistance. We conducted a multi-omic characterization of established VTX-resistant isogenic human myeloma cell lines (HMCL) and primary MM patient samples pre- and post-VTX treatment. Transcriptomic and proteomic analysis revealed that resistance was largely associated with BCL-2 family protein dysregulation, including upregulation of anti-apoptotic proteins such as MCL-1, BCL-XL, BCL-2, and downregulation of pro-apoptotic members.

Quality Assessment of Randomized Controlled Trials Published In Journal of Maxillofacial and Oral Surgery (MAOS) From 2009-2021 Using RoB-2.0 Tool.

Aim: Analyzing quality of Randomized Controlled trials (RCTs) published in the Journal of Maxillofacial and Oral Surgery (MAOS) since inception using Cochrane Risk of Bias tool version 2.0.

Methodology: Three authors independently screened and evaluated the RCTs according to Cochrane Risk of Bias tool version 2.

Lipidomic Expression Analysis in Carotid Atherosclerotic Disease: A Systematic Review.

Background: Lipids are key molecules for atherosclerosis, with tight regulation mechanisms, making them potential biomarkers for disease-specific diagnostics and therapeutics. Therefore, we aim to perform a systematic literature review on lipidomic analysis in serum/plasma and plaque samples of patients with carotid atherosclerosis.

Methods: We performed a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines on the lipidomic profile in serum/plasma and carotid artery plaques from patients with significant carotid disease by degree of stenosis in preoperative imaging and clinical presentation (symptomatic, asymptomatic, and radiation-induced carotid disease).