Immune perturbations in human pancreas lymphatic tissues prior to and after type 1 diabetes onset.

Autoimmune destruction of pancreatic β cells results in type 1 diabetes (T1D), with pancreatic immune infiltrate representing a key feature in this process. Studies of human T1D immunobiology have predominantly focused on circulating immune cells in the blood, while mouse models suggest diabetogenic lymphocytes primarily reside in pancreas-draining lymph nodes (pLN). A comprehensive study of immune cells in human T1D was conducted using pancreas draining lymphatic tissues, including pLN and mesenteric lymph nodes, and the spleen from non-diabetic control, β cell autoantibody positive non-diabetic (AAb+), and T1D organ donors using complementary approaches of high parameter flow cytometry and CITEseq.

Vascular Proteome Responses Precede Organ Dysfunction in a Murine Model of Staphylococcus aureus Bacteremia.

Vascular dysfunction and organ failure are two distinct, albeit highly interconnected, clinical outcomes linked to morbidity and mortality in human sepsis. The mechanisms driving vascular and parenchymal damage are dynamic and display significant molecular cross talk between organs and tissues. Therefore, assessing their individual contribution to disease progression is technically challenging.

Endothelial Heparan Sulfate Mediates Hepatic Neutrophil Trafficking and Injury during Staphylococcus aureus Sepsis.

Hepatic failure is an important risk factor for poor outcome in septic patients. Using a chemical tagging workflow and high-resolution mass spectrometry, we demonstrate that rapid proteome remodeling of the vascular surfaces precedes hepatic damage in a murine model of Staphylococcus aureus sepsis. These early changes include vascular deposition of neutrophil-derived proteins, shedding of vascular receptors, and altered levels of heparin/heparan sulfate-binding factors.

The Prolyl-tRNA Synthetase Inhibitor Halofuginone Inhibits SARS-CoV-2 Infection.

We identify the prolyl-tRNA synthetase (PRS) inhibitor halofuginone , a compound in clinical trials for anti-fibrotic and anti-inflammatory applications , as a potent inhibitor of SARS-CoV-2 infection and replication. The interaction of SARS-CoV-2 spike protein with cell surface heparan sulfate (HS) promotes viral entry . We find that halofuginone reduces HS biosynthesis, thereby reducing spike protein binding, SARS-CoV-2 pseudotyped virus, and authentic SARS-CoV-2 infection.

Elongated neutrophil-derived structures are blood-borne microparticles formed by rolling neutrophils during sepsis.

Rolling neutrophils form tethers with submicron diameters. Here, we report that these tethers detach, forming elongated neutrophil-derived structures (ENDS) in the vessel lumen. We studied ENDS formation in mice and humans in vitro and in vivo.

SARS-CoV-2 Infection Depends on Cellular Heparan Sulfate and ACE2.

We show that SARS-CoV-2 spike protein interacts with both cellular heparan sulfate and angiotensin-converting enzyme 2 (ACE2) through its receptor-binding domain (RBD). Docking studies suggest a heparin/heparan sulfate-binding site adjacent to the ACE2-binding site. Both ACE2 and heparin can bind independently to spike protein in vitro, and a ternary complex can be generated using heparin as a scaffold.

SARS-CoV-2 Infection Depends on Cellular Heparan Sulfate and ACE2.

We show that SARS-CoV-2 spike protein interacts with cell surface heparan sulfate and angiotensin converting enzyme 2 (ACE2) through its Receptor Binding Domain. Docking studies suggest a putative heparin/heparan sulfate-binding site adjacent to the domain that binds to ACE2. In vitro, binding of ACE2 and heparin to spike protein ectodomains occurs independently and a ternary complex can be generated using heparin as a template.

Proteomic atlas of organ vasculopathies triggered by Staphylococcus aureus sepsis.

Sepsis is a life-threatening condition triggered by a dysregulated host response to microbial infection resulting in vascular dysfunction, organ failure and death. Here we provide a semi-quantitative atlas of the murine vascular cell-surface proteome at the organ level, and how it changes during sepsis. Using in vivo chemical labeling and high-resolution mass spectrometry, we demonstrate the presence of a vascular proteome that is perfusable and shared across multiple organs.

ApoC-III ASO promotes tissue LPL activity in the absence of apoE-mediated TRL clearance.

Hypertriglyceridemia results from accumulation of triglyceride (TG)-rich lipoproteins (TRLs) in the circulation and is associated with increased CVD risk. ApoC-III is an apolipoprotein on TRLs and a prominent negative regulator of TG catabolism. We recently established that in vivo apoC-III predominantly inhibits LDL receptor-mediated and LDL receptor-related protein 1-mediated hepatic TRL clearance and that apoC-III-enriched TRLs are preferentially cleared by syndecan-1 (SDC1).

Epidermis and Enamel: Insights Into Gnawing Criticisms of Human Bitemark Evidence.

Critics describe forensic dentists' management of bitemark evidence as junk science with poor sensitivity and specificity and state that linkages to a biter are unfounded. Those vocal critics, supported by certain media, characterize odontologists' previous errors as egregious and petition government agencies to render bitemark evidence inadmissible. Odontologists acknowledge that some practitioners have made past mistakes.

Bite-Mark and Pattern Injury Analysis: A Brief Status Overview.

Bite marks are one component of forensic investigation requiring subjective interpretation for determining unknown source evidence to a putative suspect. Recent scrutiny has lead to questions about the scientific validity of patterned evidence, bite-mark analysis in particular, and its role in judicial proceedings. This article discusses some issues that persist in forensic circles and the difficulties surrounding the field of bite-mark analysis that inherently must employ human subjectivity in its execution of duty.

Vitamin D treatment modulates organic dust-induced cellular and airway inflammatory consequences.

Exposure to organic dusts elicits airway inflammatory diseases. Vitamin D recently has been associated with various airway inflammatory diseases, but its role in agricultural organic dust exposures is unknown. This study investigated whether vitamin D reduces organic dust-induced inflammatory outcomes in cell culture and animal models.

Toll-like receptor 2 regulates organic dust-induced airway inflammation.

Organic dust exposure in agricultural environments results in significant airway inflammatory diseases. Gram-positive cell wall components are present in high concentrations in animal farming dusts, but their role in mediating dust-induced airway inflammation is not clear. This study investigated the role of Toll-like receptor (TLR) 2, a pattern recognition receptor for gram-positive cell wall products, in regulating swine facility organic dust extract (DE)-induced airway inflammation in mice.

The use of full spectrum digital photography for evidence collection and preservation in cases involving forensic odontology.

Photography often represents the best method to collect and preserve evidence in forensic cases. This is especially true in forensic odontology with cases involving dental identification, human abuse and, perhaps most significantly, bitemark cases. Basic visible light photography is adequate in most dental identification cases; however, full spectrum digital photography is best utilized to collect all available evidence in cases of human abuse and bitemarks.

Analysis of a quantitative trait locus for seizure susceptibility in mice using bacterial artificial chromosome-mediated gene transfer.

Purpose: Previous quantitative trait loci (QTL) mapping studies from our laboratory identified a 6.6 Mb segment of distal chromosome 1 that contains a gene (or genes) having a strong influence on the difference in seizure susceptibility between C57BL/6 (B6) and DBA/2 (D2) mice. A gene transfer strategy involving a bacterial artificial chromosome (BAC) DNA construct that contains several candidate genes from the critical interval was used to test the hypothesis that a strain-specific variation in one (or more) of the genes is responsible for the QTL effect.

Acupuncture normalizes the release of accumbal dopamine during the withdrawal period and after the ethanol challenge in chronic ethanol-treated rats.

Many studies have shown that acupuncture can contribute to the biochemical balance in the central nervous system and maintenance or recovery of homeostasis. It is well known that chronic administration of ethanol may produce depletion or sensitization of extracellular dopamine levels in the nucleus accumbens. The present study was designed to investigate the effects of acupuncture on chronic ethanol-induced changes in extracellular dopamine levels in the nucleus accumbens shell (using in vivo microdialysis in unanesthetized rats).

Effect of acupuncture on behavioral hyperactivity and dopamine release in the nucleus accumbens in rats sensitized to morphine.

Acupuncture as a therapeutic intervention has been used for the treatment of many functional disorders including substance abuse. However, there are still many unanswered question about the basic mechanism underlying acupuncture's effectiveness in the treatment of drug addiction. Repeated injection of psycostimulants or morphine can produce behavioral and neurochemical sensitization and have been used as a model for studying drug addiction.

Electroacupuncture reduces stress-induced expression of c-fos in the brain of the rat.

We have previously shown that electroacupuncture (EA) at Shaohai and Neiguan (HT3-PC6) points significantly attenuated stress-induced peripheral responses, including increases in blood pressure, heart rate and plasma catecholamines. In this study, we examined the central effect of EA on the expression of c-fos, one of the immediate-early genes in the brain of rats subjected to immobilization stress. Immobilization stress (180 minutes) preferentially produced a significant increase in Fos-like immunoreactivity (FLI) in stress-relevant regions including the paraventricular hypothalamic nucleus (PVN), arcuate nucleus (ARN), supraoptic nucleus (SON), suprachiasmatic nucleus (SCN), medial amygdaloid nucleus (AMe), bed nucleus of the stria terminalis (BST), hippocampus, lateral septum (LS), nucleus accumbens, and the locus coeruleus (LC).

Confirmation of a major QTL influencing oral morphine intake in C57 and DBA mice using reciprocal congenic strains.

C57BL/6 (B6) and DBA/2 (D2) mice exhibit disparate behavior when tested for voluntary morphine intake in a two-bottle choice drinking paradigm with B6 mice consuming 10 times more drug than D2 mice. Previous genetic mapping studies identified a locus, Mop2, on the proximal part of chromosome 10 that explained over half of the genetic variance in this mouse model of opioid self-administration. We constructed a set of reciprocal congenic strains between B6 and D2 mice in which the proximal portion of chromosome 10 has been introgressed from one strain onto the background of the other.

Lessons learned from the WTC disaster: a first-person account.

Sept. 11, 2001, was a day of learning for the world. We learned oceans do not isolate the United States from acts of terrorism.

Acupuncture-mediated inhibition of ethanol-induced dopamine release in the rat nucleus accumbens through the GABAB receptor.

Clinical trials are currently underway to determine the effectiveness of acupuncture in the treatment of drug abuse. However, there are still many unanswered questions about the basic mechanisms of acupuncture. Studies have shown that the GABA(B) receptor system may play a significant modulatory role in the mesolimbic system in drug abuse, including ethanol.