Matthew S.

The structure of the catalytic subunit of cAMP-dependent protein kinase (PKA-C), a prototype for the protein kinase superfamily, laid the foundatio...

Sepsis causes muscle wasting and cachexia but mechanisms remain unclear. Cachexia in cancer and burn injury is partly attributed to ‘browning’; where white adipose tissue (WAT) develops a catabolic, thermogenic brown adipose tissue-like phenotype. We hypothesised that sepsis-induced muscle wasting is caused by browning. 58 male Wistar rats were randomised to sham (n = 17) or experimental sepsis induced by intraperitoneal zymosan (n = 41). Tibialis anterior mass was measured on Days 3 and 14. Browning was sought using whole body and WAT respirometry, RNA-sequencing, immunoblot, thermal imaging and multi-photon microscopy of WAT. Fourteen-day mortality in rats receiving zymosan was 17%. In survivors, body mass loss peaked at day 3 and persisted to day 14 with associated tibialis anterior muscle mass loss. Zymosan peritonitis caused hypermetabolism during the late recovery phase (Days 11–14), but no difference in epididymal white adipose tissue temperature nor oxygen flux. At Day 14 transcriptomics showed inflammation but no increase in uncoupling protein (UCP)-1 at transcript or protein levels. SERCA2 protein was however increased fourfold in retroperitoneal WAT at day 14 (p = 0.016). Rats recovering from zymosan peritonitis developed muscle wasting and cachexia associated with WAT inflammation and whole-body hypermetabolism. No evidence of browning was seen at functional, transcriptomic or protein levels, therefore our data do not support the hypothesis of classical browning as a driver of sepsis-induced muscle wasting and cachexia. SERCA2 protein expression was however increased in retroperitoneal WAT at day 14.

Reply to Sun: Behavior affects epidemic outcomes

Social distancing can mitigate the spread of diseases in humans and animals. Social distancing allows susceptible individuals to protect themselves...

Millions of people worldwide are living with movement and sensory impairments owing to spinal cord injury, stroke and other neurological conditions.

Cerebral amyloid angiopathy (CAA) commonly co-occurs with Alzheimer’s disease (AD), yet the molecular changes that accompany vascular $$\upbeta $$-amyloid deposition in human tissue remain incompletely defined. Herein, we use a novel imaging approach that combines matrix-assisted laser desorption/ionization imaging mass spectrometry (IMS) with immunofluorescence microscopy on the same sections of postmortem human frontal cortex to map the lipid microenvironment of leptomeningeal vasculature in cases with and without CAA. Autofluorescence-guided regions-of-interest were imaged by IMS in both negative and positive ion modes and registered to post-IMS-acquired microscopy images. Immunofluorescence microscopy using markers for collagen IV, $$\upalpha $$-smooth muscle actin ($$\upalpha $$SMA), and thiazine red enabled automated segmentation of total, amyloid-positive, and amyloid-negative vasculature regions. A CAA index, the ratio of amyloid-positive area to total vasculature area in a region imaged by IMS, was used to define vasculature and classify each case into having CAA, or CAA-present, and not having CAA, or CAA-absent. An interpretable machine learning approach (XGBoost models with Shapley additive explanations for interpretation) was trained on pixel-level spectra and identified lipid signatures of vascular identity shared across groups as well as class-specific marker candidates that distinguished CAA-present from CAA-absent vasculature. CAA-absent vessels were characterized by higher contributions from phosphatidylserines (e.g., long-chain polyunsaturated PS species). Univariate differences were inconsistent between the two groups, but multivariate models in negative mode yielded stable discriminatory features. These results define spatial lipid correlates of vascular amyloid pathology in the human brain and establish a multimodal framework for mechanistically linking lipid metabolism, vascular integrity, and CAA in AD.

DNA methyltransferase 1 (DNMT1) is essential for mammalian development and is frequently dysregulated in cancer. While its recruitment to hemimethylated DNA by UHRF1 is well established, its broader chromatin occupancy and regulation remain unclear. We show that DNMT1 is enriched at unmethylated CpG islands of actively transcribed genes largely by its CXXC domain. Upon selective catalytic inhibition, DNMT1 redistributes to partially methylated, inaccessible regions in a UHRF1-dependent and RFTS-dependent manner. Although coding gene expression is largely unchanged, sustained DNMT1 inhibition and subsequent global DNA hypomethylation trigger reactivation of endogenous viral elements, including an uncharacterized class of double-stranded RNA mega-intergenic transcripts (mintRNAs) driving a cell-intrinsic viral mimicry response. We identify RNF4 as a major regulator of DNMT1 catalytic function that, beyond its canonical role in DNA–protein crosslink resolution, controls the levels of SUMOylated DNMT1, establishing SUMOylation as a rheostat that regulates DNMT1 activity to maintain DNA methylation and safeguard against viral mimicry.

Methicillin-resistant Staphylococcus aureus (MRSA) is an emerging cause of catheter-associated urinary tract infection (CAUTI), which frequently pr...

The structure of the catalytic subunit of cAMP-dependent protein kinase (PKA-C), a prototype for the protein kinase superfamily, laid the foundatio...