Citations

Abstract Brief inhalation of carbon dioxide (CO 2 ) has been proposed to counteract transient hypocapnia by enhancing oxygen unloading, vasodilation, and sympathetic modulation. Despite these potential ergogenic mechanisms, CO 2 has rarely been investigated in the exercise context. The present study investigated whether brief CO 2 inhalation (iCO 2 ) influences performance and recovery during high‐intensity interval exercise. Nine healthy adults completed two randomized, single‐blinded crossover trials of repeated cycling intervals at 85% peak work rate until volitional exhaustion or cadence dropped below 60 rpm, with a minimum 2‐min interval duration required and 3‐min active recovery between bouts. Participants inhaled 5% CO 2 or room air (15 breaths) before and after each exercise bout. Gas exchange, cardiovascular responses, and perceived exertion were assessed. Total exercise time was similar between trials; however, participants completed more intervals with iCO 2 . During the first interval, iCO 2 increased exercise duration and VO 2 . At matched exercise time, perceived exertion and dyspnea were lower with iCO 2 . During recovery, systolic blood pressure was lower and heart rate was higher following iCO 2 . Brief iCO 2 improved first‐interval performance, altered cardiovascular recovery, and reduced perceptual strain but did not extend overall exercise duration. These findings suggest iCO 2 may transiently modulate tolerance and autonomic‐vascular responses during high‐intensity interval exercise.

ABSTRACT Glioblastoma (GBM) is universally lethal despite decades of research to find effective treatments. This highlights the need to identify druggable targets essential for sustaining the malignant phenotype but dispensable for normal tissue. We propose that the enzyme α-tubulin acetyl transferase ( ATAT1 ) meets these criteria. ATAT1 acetylates α-tubulin at lysine 40, which increases microtubule stability and promotes microtubule-based transport. While ATAT1 knockout mice have only a very mild phenotype, ATAT1 suppression in GBM has multiple therapeutic effects by reducing tumor invasion, proliferation, and therapeutic resistance. These translate not only into improved survival with ATAT1 targeting by itself, but also into synergy when ATAT1 deletion is combined with FDA approved therapies. This study strongly supports our conclusion that ATAT1 is a promising therapeutic target in GBM.

Acute hyponatremia is an uncommon complication of percutaneous cholecystostomy drainage with minimal literature to date. We present a case of a patient with necrotizing pancreatitis causing perforated cholecystitis, requiring percutaneous cholecystostomy that was complicated by acute hyponatremia. High biliary solute and volume loss led to the hyponatremia and elucidated downstream biliary obstruction. Fluid resuscitation, biliary stenting, and endoscopic drainage corrected the patient's sodium and symptoms in this multidisciplinary case.

Abstract The success of Chimeric Antigen Receptor (CAR) T cell therapy is heavily dependent on the quality of the final cellular product. Current expansion protocols often rely on reagents that require removal from cell culture media, posing logistical challenges in manufacturing, and can also lead to terminal differentiation. Here, we evaluate the use of a soluble, bead-free T cell activator, T cell expansion protein (T-CEP), as a streamlined alternative for generating potent CAR-T cells. Human T cells were activated with T-CEP or known T cell activators (Dynabeads and TransAct) and transduced with either CD19 or interleukin-13 (IL-13) mutein (tetravariant-13; TV-13)-based CAR lentiviral vectors. Our results demonstrate that T-CEP supports robust CAR-T cell expansion and achieves transduction efficiencies comparable to commercial reagents for both types of CAR-T cells. Notably, T-CEP significantly favored the expansion of CD8 + T cells, yielding an enhanced CD27 + phenotype and a lower CD4:CD8 ratio compared to TransAct. Cytotoxicity assays confirmed that T-CEP-expanded CAR-T cells possess cytolytic function equivalent to commercial reagents for both CARs, while exhibiting lower levels of inflammatory cytokine secretion. In summary, T-CEP represents a competitive alternative to existing expansion agents, as it does not require its removal during CAR-T manufacturing and generates a CD8 + dominant, less-differentiated phenotype without compromising efficacy. Key Points T-CEP is a soluble, bead-free activator that streamlines CAR-T manufacturing by eliminating the need for reagent removal from cultures. T-CEP consistently yields a desirable CD27 + CD8 + phenotype with a moderate inflammatory profile compared to industry-standard expanders.

Background: Hepatic stellate cells (HSCs) play a pivotal role in driving fibrosis during chronic liver injury. HSCs produce vast amounts of fibrotic proteins, causing endoplasmic reticulum (ER) stress and initiating the unfolded protein response (UPR). While the UPR is important for fibrogenesis, how signaling through UPR transducer Protein Kinase R-like ER Kinase (PERK) and its effectors impact HSC activation and fibrogenesis is unclear. Here, we sought to uncover the role of PERK and its effector GADD45A in liver fibrosis. Methods: PERK–GADD45A signaling was assessed in primary and immortalized HSCs treated with TGFβ, and mouse models of fibrosis. Genetic and pharmacological disruption of PERK or GADD45A was used to assess the role of PERK or GADD45A in HSC activation, proliferation, and fibrogenesis. HSC-specific Gadd45a -null mice were utilized to investigate the role of GADD45A on CCl 4 -induced fibrosis. Results: We found that TGFβ-induction of collagen I drives activation of PERK signaling in HSCs. Furthermore, loss or inhibition of PERK limits long-term HSC activation as illustrated by reduced levels of collagen I and fibronectin, impaired collagen I deposition, and reduced cell proliferation in vitro. Next, we show that PERK signaling induces expression of GADD45A during HSC activation, and loss of GADD45A disrupts HSC activation and expression of proliferation and cell-cycle-associated genes in immortalized and primary HSCs. Finally, HSC-specific GADD4Aa loss limits CCl 4 -driven fibrogenesis in vivo. Conclusion: PERK signaling is critical for HSC activation, and loss of the PERK downstream effector GADD45A limits fibrosis progression. Disruption of HSC activation and proliferation, coupled with dysregulation of cell-cycle-associated genes upon PERK or GADD45A loss, suggests that PERK–GADD45A signaling impacts multiple facets of HSC pathophysiology.