Piperazine-Fused Cyclic Disulfides Unlock High-Performance Bioreductive Probes of Thioredoxins and Bifunctional Reagents for Thiol Redox Biology.

We report piperazine-fused six-membered-cyclic disulfides as redox substrates that unlock best-in-class bioreduction probes for live cell biology, since their self-immolation after reduction is unprecedentedly rapid. We develop scalable, diastereomerically pure, six-step syntheses that access four key - and -piperazine-fused cyclic dichalcogenides without chromatography. Fluorogenic redox probes using the disulfide piperazines are activated >100-fold faster than the prior art monoamines, allowing us to deconvolute reduction and cyclization rates during activation.

Chemical Proteomic Discovery of Isotype-Selective Covalent Inhibitors of the RNA Methyltransferase NSUN2.

5-Methylcytosine (m C) is an RNA modification prevalent on tRNAs, where it can protect tRNAs from endonucleolytic cleavage to maintain protein synthesis. The NSUN family (NSUN1-7 in humans) of RNA methyltransferases are capable of installing the methyl group onto the C position of cytosines in RNA. NSUNs are implicated in a wide range of (patho)physiological processes, but selective and cell-active inhibitors of these enzymes are lacking.

Correction to "40 Years of Duocarmycins: A Graphical Structure/Function Review of Their Chemical Evolution, from SAR to Prodrugs and ADCs".

[This corrects the article DOI: 10.1021/jacsau.2c00448.

Bacterial pathogens in pediatric appendicitis: a comprehensive retrospective study.

Background: Appendicitis is a frequent condition, with peak incidences in the second decade of life. Its pathogenesis is under debate, but bacterial infections are crucial, and antibiotic treatment remains essential. Rare bacteria are accused of causing complications, and various calculated antibiotics are propagated, yet there is no comprehensive microbiological analysis of pediatric appendicitis.

Cyclic Dichalcogenides Extend the Reach of Bioreductive Prodrugs to Harness Thiol/Disulfide Oxidoreductases: Applications to -Duocarmycins Targeting the Thioredoxin System.

Small-molecule prodrug approaches that can activate cancer therapeutics selectively in tumors are urgently needed. Here, we developed the first antitumor prodrugs designed for activation by thiol-manifold oxidoreductases, targeting the thioredoxin (Trx) system. The Trx system is a critical cellular redox axis that is tightly linked to dysregulated redox/metabolic states in cancer, yet it cannot be addressed by current bioreductive prodrugs, which mainly cluster around oxidized nitrogen species.

40 Years of Duocarmycins: A Graphical Structure/Function Review of Their Chemical Evolution, from SAR to Prodrugs and ADCs.

Synthetic analogues of the DNA-alkylating cytotoxins of the duocarmycin class have been extensively investigated in the past 40 years, driven by their high potency, their unusual mechanism of bioactivity, and the beautiful modularity of their structure-activity relationship (SAR). This Perspective analyzes how the molecular designs of synthetic duocarmycins have evolved: from (1) early SAR studies, through to modern applications for directed cancer therapy as (2) prodrugs and (3) antibody-drug conjugates in late-stage clinical development. Analyzing 583 primary research articles and patents from 1978 to 2022, we distill out a searchable A0-format "Minard map" poster of ca.

Selective cellular probes for mammalian thioredoxin reductase TrxR1: rational design of RX1, a modular 1,2-thiaselenane redox probe.

Quantifying the activity of key cellular redox players is crucial for understanding physiological homeostasis, and for targeting their perturbed states in pathologies including cancer and inflammatory diseases. However, cellularly-selective probes for oxidoreductase turnover are sorely lacking. We rationally developed the first probes that selectively target the mammalian selenoprotein thioredoxin reductase (TrxR), using a cyclic selenenylsulfide oriented to harness TrxR's unique selenolthiol chemistry while resisting the cellular monothiol background.

The Lunchbox Study: A Pilot Examination of Packed Lunches of Children with Autism Spectrum Disorder.

Background: This study examined foods packed and consumed by children with autism spectrum disorder (ASD) and calculated the percentage of packed school lunches meeting National School Lunch Program (NSLP) standards. Fruit and vegetable (FV) consumption was further examined by investigating its association with the number and type of foods packed. Methods: Participants included 59 private school students observed for five school meals.

Cyclic 5-membered disulfides are not selective substrates of thioredoxin reductase, but are opened nonspecifically.

The cyclic five-membered disulfide 1,2-dithiolane has been widely used in chemical biology and in redox probes. Contradictory reports have described it either as nonspecifically reduced in cells, or else as a highly specific substrate for thioredoxin reductase (TrxR). Here we show that 1,2-dithiolane probes, such as "TRFS" probes, are nonspecifically reduced by thiol reductants and redox-active proteins, and their cellular performance is barely affected by TrxR inhibition or knockout.

Selective, Modular Probes for Thioredoxins Enabled by Rational Tuning of a Unique Disulfide Structure Motif.

Specialized cellular networks of oxidoreductases coordinate the dithiol/disulfide-exchange reactions that control metabolism, protein regulation, and redox homeostasis. For probes to be selective for redox enzymes and effector proteins (nM to μM concentrations), they must also be able to resist non-specific triggering by the ca. 50 mM background of non-catalytic cellular monothiols.

KLK4 Induces Anti-Tumor Effects in Human Xenograft Mouse Models of Orthotopic and Metastatic Prostate Cancer.

Recent reports have suggested the role of kallikrein-related peptidase 4 (KLK4) to be that of remodeling the tumor microenvironment in many cancers, including prostate cancer. Notably, these studies have suggested a pro-tumorigenic role for KLK4, especially in prostate cancer. However, these have been primarily in vitro studies, with limited in vivo studies performed to date.

The High-Resolution Three-Dimensional Magnetic Detector System 3D-Magma Accurately Measures Gastric and Small Bowel Motility in People with Type 2 Diabetes with Neuropathy.

Gastroparesis is an important complication of diabetes. Motility disorders are underdiagnosed and can lead to unexplained hypoglycemia. Currently diagnostic options are limited.

Treatment of resistance to change in children with autism.

"Resistance to change" represents a core symptom of autism that we conceptualized and assessed as resulting in part due to factors known to govern free-operant choice. During a free-choice baseline, participants chose between problematic, resistive responses and an appropriate alternative response. During the asymmetrical-choice condition, we delivered their most highly preferred item if the participant chose the alternative response (i.

Kallikrein-related peptidases represent attractive therapeutic targets for ovarian cancer.

Aberrant levels of kallikrein-related peptidases (KLK1-15) have been linked to cancer cell proliferation, invasion and metastasis. In ovarian cancer, the KLK proteolytic network has a crucial role in the tissue and tumor microenvironment. Publically available ovarian cancer genome and expression data from multiple patient cohorts show an upregulation of most KLKs.

Aminomethylation/hydrogenolysis as an alternative to direct methylation of metalated isoquinolines - a novel total synthesis of the alkaloid 7-hydroxy-6-methoxy-1-methylisoquinoline.

Highly-substituted isoquinolines are important scaffolds in syntheses of natural products and in drug development and hence, effective synthetic approaches are required. Here we present a novel method for the introduction of a methyl group at C1 of isoquinolines. This is exemplified by a new total synthesis of the alkaloid 7-hydroxy-6-methoxy-1-methylisoquinoline.

[Controlled evaluation of a high-resolution three-dimensional magnetic detector system (3D-MAGMA) as a proof of concept - examination of healthy volunteers before and after application of Metoclopramide (MCP)].

Background: Changes in gastric and small bowel motility are a common clinical problem. Currently diagnostic options are limited because each method harbors certain disadvantages. It has been shown that the high-resolution three-dimensional magnetic detector system 3D-MAGMA is capable of reliably measuring gastric and small intestine motor activity.

NOROVIRUS OUTBREAK AT A DAYCARE CENTER IN BANGKOK, 2014.

Norovirus is a leading cause of acute non-bacterial gastroenteritis worldwide, affecting developing and developed countries, both children and adults. This study describes an outbreak of acute gastroenteritis at a daycare center of a tertiary level hospital in Bangkok, Thailand during October 2014. Although none of the staff became symptomatic, 8 of 11 children attending the center and 4 of their household contacts developed acute gastroenteritis.

[Jejunal ulcerations - a diagnostic challenge in a patient with coeliac disease].

A subset of patients with coeliac disease (CD) suffers persistent or recurrent complaints despite a strict adherence to a gluten-free diet (GFD) that can be caused by refractory coeliac disease (RCD). We present a patient with weight loss and signs of malassimilation secondary to villous atrophy and jejunal ulcerations complicating known CD. We demonstrate a stepwise approach to the diagnosis and subtyping of RCD and to rule out important alternative causes of jejunal ulcerations.

A spatial assessment of baseline nutrient and water quality values in the Ashepoo-Combahee-Edisto (ACE) Basin, South Carolina, USA.

The Ashepoo-Combahee-Edisto (ACE) Basin (South Carolina, USA) National Estuarine Research Reserve System (NERRS) encompasses some of the least developed USA coastline. Yet, periodic sampling showed that certain regions have higher nutrient, fecal coliform, and chlorophyll a levels, often with lower dissolved oxygen, than other South Carolina estuaries. To evaluate the spatial extent of these issues, a summer (2008) baseline study was conducted.