ER remodelling is a feature of ageing and depends on ER-phagy.
Donahue EKF, Hepowit NL, Ruark EM, Mulligan AG, Keuchel B, Urban ND, Peng L, Stephens S, Johnson DJ, Wallace NS, Jackson LP, Ellisman MH, Arrojo E Drigo R, Folkmann AW, Truttmann MC, MacGurn JA, Burkewitz K.
Nat Cell Biol. 2026 Feb 2. doi: 10.1038/s41556-025-01860-1. Online ahead of print.
PMID: 41629400
Abstract: The endoplasmic reticulum (ER) comprises an array of subdomains, each defined by a characteristic structure and function. Although altered ER processes are linked to age-onset pathogenesis, it is unclear whether shifts in ER structure or dynamics underlie these functional changes. Here we establish ER structural and functional remodelling as a conserved feature of ageing across yeast, Caenorhabditis elegans and mammals. Focusing on C. elegans as the exemplar of metazoan ageing, we reveal striking age-related reductions in ER volume across diverse tissues and a morphological shift from rough sheets to tubular ER. This morphological transition corresponds with large-scale shifts in ER proteome composition from protein synthesis to lipid metabolism, a phenomenon conserved in mammalian tissues. We show that Atg8 and ULK1-dependent ER-phagy drives age-associated ER remodelling through tissue-specific factors, including the previously uncharacterized ER-phagy regulator TMEM-131 and the IRE-1-XBP-1 branch of the unfolded protein response. Providing support for a model where ER remodelling is adaptive, diverse lifespan-extending paradigms downscale and remodel ER morphology throughout life. Furthermore, mTOR-dependent lifespan extension in yeast and worms requires ER-phagy, indicating that ER remodelling is a proactive and protective response during ageing. These results reveal ER-phagy and ER dynamics as pronounced, underappreciated mechanisms of both normal ageing and age-delaying interventions.
The history and evolution of pediatric ophthalmology training: celebrating 50 years of the American Association for Pediatric Ophthalmology and Strabismus.
Donahue EKF, Baker JD, Donahue SP.
J AAPOS. 2026 Feb 3:104750. doi: 10.1016/j.jaapos.2026.104750. Online ahead of print.
PMID: 41644036 Free article. No abstract available.
Glutamine synthetase deficiency enhances CD8 T cell survival and stress resilience in the tumor microenvironment.
Fisher-Gupta EL, Hathaway ES, Perera JM, Jennings EQ, Chi C, Sewell AE, Stone SH, Muka JE, Sinard RC, DeCorte JA, Chen H, Wilson JT, Meiler J, Rathmell JC.
J Immunol. 2026 Jan 21;215(1):vkaf250. doi: 10.1093/jimmun/vkaf250.
PMID: 41171699 Free PMC article.
Abstract: Cellular immunotherapy has revolutionized the treatment of hematologic malignancies yet has had limited success in the solid tumor microenvironment (TME). While insufficient nutrients can lead to T cell metabolic stress in the TME, the glutamine antagonist DON can paradoxically enhance antitumor immunity. Because DON inhibits both essential and nonessential enzymes whose impairment may contribute to dose-limiting toxicities, mechanisms underlying DON-induced antitumor activity have remained unclear. Here, we aimed to identify specific DON targets that increase T cell antitumor activity and test if more selective inhibition of glutamine metabolism could replicate the effects of DON with reduced toxicity. CRISPR screening in the TME of DON-relevant glutamine metabolizing enzymes identified some targets that were essential in tumor-infiltrating CD8 T cells, but that tumor-infiltrating CD8 T cells lacking the DON target glutamine synthetase (GS) were enriched. Upon adoptive T cell transfers, GS-deficient CD8+ T cells displayed improved survival, a higher proportion TCF-1+ Tox- stem-like cells, and greater antitumor and memory function. GS converts glutamate to glutamine and GS-deficient cells exhibited increased intracellular glutamate and reduced glutathione levels, which correlated with enhanced mitochondrial respiration and resistance to reactive oxygen species. Pharmacological inhibition of GS reduced tumor burden in multiple orthotopic murine tumor models in a manner dependent on adaptive immunity. Our findings establish GS as a key metabolic regulator of CD8+ T cells stress resilience in the TME. By preserving intracellular glutamate, GS inhibition reprograms T cells for improved survival and function, offering a promising therapeutic strategy to enhance immune-based cancer treatments.
Keywords: T cell; antitumor immunity; glutamine; glutamine synthetase; immunometabolism.
Revisiting Hemostasis Strategy: The Impact of Excessive Monopolar Electrocautery on Periosteal-Driven Spinal Fusion.
Okonkwo DD, Kawabata A, Mckee RM, Utagawa K, Reese JC, Oyaizu T, Moore-Lotridge SN, Stephens BF, Louer CR, Yoshii T, Schoenecker JG.
Spine J. 2026 Feb 4:S1529-9430(26)00041-0. doi: 10.1016/j.spinee.2026.01.019. Online ahead of print.
PMID: 41651294 Free article.
Abstract
Background context: The common surgical approach in posterior spinal fusion (PSF) conflicts with basic principles of bone repair and may lead to high failure rates. In recent years, experimental data has shown that the periosteum plays an indispensable role in fracture bone repair both for skeletal stem/progenitor cells (SSPCs) and for angiogenesis promotion. However, the role of the periosteum in spinal fusion remains experimentally poorly defined. Furthermore, current surgical approach often involves electrocautery to achieve subperiosteal dissection. However, the impact of this electrocautery remains not fully defined. We hypothesize that the periosteum is a potent driver of spinal fusion, and that its excessive ablation through electrocautery can be a significant iatrogenic contributor to reduced bone formation.
Purpose: This study investigates the periosteum’s contribution to spinal fusion and how electrocautery, commonly used for subperiosteal dissection, impacts this contribution.
Study design: A non-decorticated murine PSF model compared bone formation after sharp dissection with electrocautery (Caut) versus sharp dissection without electrocautery (Sharp). A non-decorticated model was utilized to isolate the contributions of the periosteum without decortication as a confounding variable.
Methods: Bone formation and integration were evaluated using microCT and histology. Pulse-chase lineage tracing in Aggrecan CreERT2+/Ai9+ mice tracked SSPC source and differentiation pathway. This model identifies mostly cells committed to the chondrogenic lineage during regeneration. Angiogenesis was assessed with Microfil, including 2D and 3D reconstructions.
Results: Bone formation was significantly lower on the cauterized side (p = 0.0002; p < 0.0001) 6 weeks after surgery. Sharp dissection without electrocautery triggered a periosteum-driven regenerative process similar to fracture repair, involving both endochondral and intramembranous ossification. Electrocautery abolished this response and significantly decreased periosteum-derived chondrogenesis (p = 0.0009). Angiogenesis was also reduced on the cauterized side (p = 0.0367). Without surgical decortication, new bone integrated into the native cortex through biological remodeling, indicating that surgical decortication may not be necessary.
Conclusion: The periosteum is a potent driver of PSF bone formation through combined endochondral and intramembranous ossification, achieving integration without surgical decortication.
Clinical significance: Monopolar electrocautery can destroy key regenerative contributions of the periosteum in PSF, cautioning the excessive use of monopolar electrocautery in surgical practices. More research is needed to determine the impact of alternate means of achieving hemostasis such as bipolar on bone formation, as these may better preserve periosteal tissue.
Keywords: Angiogenesis; Bone Formation; Bone Regeneration; Electrocautery; Periosteum; Spinal Fusion.
Temperature performance of a commercially available hybrid power cooler for cardiac allograft preservation.
Petrovic M, Trahanas JM, DeVries S, Lowman J, Wang CC, Ahmad A, Lima B, Keck C, Schwartz C, Shah AS, Bacchetta M, Bommareddi S, Williams AM.
JTCVS Tech. 2025 Nov 26;35:102167. doi: 10.1016/j.xjtc.2025.102167. eCollection 2026 Feb.
PMID: 41658894 Free PMC article. No abstract available.
Glucagon-like peptide-1 receptor signaling deficiency exacerbates hematopoietic stem cell graft rejection in mice.
Rusznak M, Sierra-Hernandez D, Dupuy C, Toki S, Wu AY, Rao U, Abney M, Zhang J, Hu Q, Warren CM, Drucker DJ, Niswender KD, Engelhardt B, Kim TK, Gibson-Corley KN, Cahill KN, Cooke KR, Peebles RS Jr.
J Immunol. 2026 Jan 21;215(1):vkaf251. doi: 10.1093/jimmun/vkaf251.
PMID: 40990163 Free PMC article.
Abstract: Graft failure (GF) following hematopoietic stem cell transplantation (HSCT) remains a major complication particularly in the setting of human leukocyte antigen (HLA)-mismatched grafts where residual host lymphocytes can drive immune-mediated rejection. While strategies to mitigate GF have been explored, such as intensified conditioning or donor T cell supplementation, these approaches carry significant risks, including increased toxicity and graft-versus-host disease (GVHD). Recent studies have highlighted the glucagon-like peptide-1 receptor (GLP1R) as a critical regulator of immune homeostasis, yet its role in HSC engraftment remains unexplored. Here, we demonstrated that GLP1R deficiency in recipient mice leads to a profound increase in GF following MHC-mismatched allogeneic HSCT. Although GLP1R knockout (GLP1RKO) and wild-type (WT) mice exhibited comparable survival and engraftment following syngeneic or minor antigen-mismatched transplants, GLP1RKO mice undergoing MHC-mismatched HSCT experienced significantly greater weight loss, earlier mortality, and reduced donor chimerism. Histologic and cytokine analyses confirmed that this phenotype is not driven by GVHD, but rather by early graft rejection. Depletion of CD90+ recipient T cells prior to transplantation rescued engraftment in GLP1RKO mice, further supporting a model in which GLP1R signaling restrains host lymphocyte-mediated graft rejection. These findings identify GLP1R as a novel regulator of allogeneic HSC engraftment and suggest that GLP1R agonists, widely used for metabolic disorders, may have therapeutic potential in preventing HSC graft rejection. Given the lack of targeted interventions for HSC graft rejection, further studies are warranted to investigate GLP1R-directed therapies in the context of allogeneic HSCT.
Keywords: GF; GLP1R; HSCT; rejection.
Sex‑specific cardiovascular risk in estrogen‑treated androgen‑deprived males: metabolic characterization of glucose, adipose, and lipid pathways.
Thorson AS, Schaefers KP, Litts B, Rein J, Adapa S, Chinnarasu S, Shapiro K, Zhao Y, Yu S, Recupido B, Streng KJ, Ahn IS, Lan R, Pierre-Louis O, Forson D, Bennett M, Luviano H, Saleem M, Zhu L, Yang X, Kirabo A, M Stafford J.
Cardiovasc Diabetol. 2026 Feb 2. doi: 10.1186/s12933-025-03059-y. Online ahead of print.
PMID: 41622197 Free article.
Abstract
Background: Estrogen therapy and androgen‑deprivation were once combined to treat prostate cancer (PrCa). Clinical studies later showed that prolonged estrogen exposure in androgen‑deprived men raises cardiovascular disease (CVD) risk, yet the metabolic pathways responsible remain unclear.
Methods: We generated an androgen‑deprived, 17β‑estradiol (E2)-treated mouse model by gonadectomizing male C57BL/6 J mice and implanting sub‑cutaneous delayed‑release E2 or vehicle pellets. Mice received a Western‑style diet and were housed at thermoneutrality to accelerate CVD‑risk phenotypes. Metabolic profiling included hyperinsulinemic‑euglycemic clamps, oral lipid and pyruvate tolerance tests, flow cytometry of immune cells, and single‑nucleus RNA sequencing of liver tissue.
Results: In hypogonadal males, E2 treatment induced several metabolic disturbances. During clamps, E2‑treated mice showed markedly elevated gluconeogenesis, corroborated by higher glucose peaks and AUC during pyruvate tolerance testing and by up‑regulation of hepatic Pck1 mRNA. Triglyceride (TG) clearance, which improves with E2 in females, was impaired in E2‑treated males: oral lipid‑tolerance testing revealed prolonged TG excursions, reduced maximal lipase activity, lower non‑lipase clearance at 6 h post-OLTT, and decreased free‑fatty‑acid peak levels. Hepatic lipase, VLDL clearance receptors Ldlr and Lrp1, and microsomal triglyceride transfer protein (MTP) transcripts were down‑regulated. SnRNA‑seq showed suppression of lipid‑clearance genes with E2 treatment in males. Subcutaneous adipocytes were hypertrophic, and flow cytometry identified increased TNFα‑positive macrophages, an inflammatory milieu that could promote insulin resistance. Cardiac morphology was modestly altered; E2‑treated males exhibited a larger left‑ventricular end‑diastolic diameter, while ejection fraction and arterial pressure remained unchanged.
Conclusion: Estradiol administration in androgen‑deprived male mice produces a constellation of metabolic derangements-including enhanced hepatic gluconeogenesis, impaired TG clearance, and inflammatory adipocyte hypertrophy-that likely underlie the increased CVD risk observed clinically. The identified molecular nodes (PEPCK, hepatic lipase, LRP1, LDLR, MTP, and adipose‑macrophage TNFα) provide potential targets for mitigating estrogen‑induced CVD risk while preserving its therapeutic benefit for PrCa.
Imaging the past: Dental pathologies and cardiovascular disease in Egyptian mummified remains.
Witt AA, Smith DK, Thompson RC, Thomas GS, Sutherland ML, Sutherland JD, Michalik DE, Rowan CJ, Van Schaik KD.
J Am Dent Assoc. 2026 Jan 30:S0002-8177(25)00691-9. doi: 10.1016/j.adaj.2025.11.013. Online ahead of print.
PMID: 41618943 Free article.
Abstract
Background: Imaging advancements markedly enhance the assessment of skeletal and dental pathologies in clinical and archaeological contexts. Among the most frequently observed dental conditions in bioarcheological studies are periodontal disease and caries, both of which can provide valuable insights into systemic conditions (eg, cardiovascular disease). When identified in mummified remains, dental pathologies offer a unique perspective on the health status and disease burden of past populations and the interplay between oral and systemic health across human history.
Methods: Using a database of computed tomographic scans of Egyptian mummies, the authors investigated the prevalence and extent of dental pathologies, including periapical lucencies and teeth with caries, and the distance from the cementoenamel junction to the alveolar crest. Regression analyses were used to examine the associations between oral health variables and vascular pathology.
Results: Advanced demineralization, indicative of destructive carious processes, and periodontal disease were highly prevalent in this mummified cohort. Furthermore, oral pathologies were determined to be correlated with the number of calcified vascular beds, although these findings were not independent of age- or sex-related effects at large.
Conclusions: The authors established evidence of periodontitis, teeth with caries, and impacted teeth in mummified remains, along with correlations between oral health and cardiovascular disease.
Practical implications: Findings from these ancient remains highlight the long-standing presence of oral disease, reinforcing that oral health problems are not only modern. For contemporary clinicians, this historical perspective underscores the value of culturally sensitive dentistry and how population behaviors contribute to distinct oral health challenges.
Keywords: Egypt; Mummified remains; cardiovascular disease; dental pathology; periodontal health.
Fluid balance is Associated with Differential Effects on Respiratory Failure between Critically Ill and Non-Critically Ill Adults with SARS-CoV-2: a Retrospective Cohort Study.
Kerchberger VE, Lee AX, DeCorte JA, Chada NC, Koyama T, Ware LB.
Shock. 2026 Feb 2. doi: 10.1097/SHK.0000000000002804. Online ahead of print.
PMID: 41670545
PFAS Alter Thyroid Histology and Cellular Signaling In Vitro and In Vivo.
Hartmann HA, Caroland KP, Tumbic GW, Rampy J, Chen HC, Chen SC, Mannes C, Wahoski CC, Loberg MA, Liang C, Diaz D, Tigue ML, Sheng Q, Ye F, Lee E, Weiss VL.
J Endocr Soc. 2025 Dec 18;10(2):bvaf210. doi: 10.1210/jendso/bvaf210. eCollection 2026 Feb.
PMID: 41608197 Free PMC article.
Ovarian Hormones and Obesity Drive Th17-mediated Airway Inflammation through Estrogen Receptor-α Signaling.
Henriquez Pilier E, Cephus JY, Kuehnle SN, Tannous E, Tomasello A, McKernan KE, Peebles RS, Cahill KN, Rathmell JC, Newcomb DC.
Am J Physiol Lung Cell Mol Physiol. 2026 Feb 13. doi: 10.1152/ajplung.00400.2025. Online ahead of print.
PMID: 41686163
Metformin does not significantly alter longitudinal dynamics of clonal hematopoiesis.
Pareek E, Pershad Y, Zhao K, Uddin MM, Xue L, Vlasschaert C, Mack TM, Haessler J, Collins JM, Glick E, Glaser V, Heise R, Ling W, Haring B, Shadyab A, Beydoun H, Wallace R, Jaiswal S, Manson JE, Natarajan P, Honigberg MC, Kooperberg C, Whitsel EA, Kitzman JO, Bick AG, Reiner AR, Desai P.
Clin Cancer Res. 2026 Jan 28. doi: 10.1158/1078-0432.CCR-25-3606. Online ahead of print.
PMID: 41603726
Donation After Circulatory Death Heart Transplant Without Preimplant Reanimation Using Rapid Ultraoxygenated Recovery.
Williams AM, Trahanas J, Bommareddi S, McGann KC, Ahmad A, Lima B, Wang CC, Petrovic M, Devries S, Lowman J, Absi T, Quintana E, Siddiqi H, Amancherla K, Brinkley M, Tsai S, Menachem JN, Pedrotty D, Rali AS, Sacks S, Zalawadiya S, Lepore J, Pretorious M, Schlendorf K, Bacchetta M, Shah AS.
JAMA. 2026 Jan 26:e2525169. doi: 10.1001/jama.2025.25169. Online ahead of print.
PMID: 41587047
Prolonged Pulseless Electrical Activity Warm Ischemia Predicts Mortality and Graft Dysfunction in Donation after Circulatory Death Heart Transplant.
Williams AM, Wang CC, Ahmad A, Trahanas J, Bommareddi S, McGann KC, Petrovic M, Devries S, Lowman J, Absi T, Quintana E, Siddiqi H, Amancherla K, Brinkley M, Tsai S, Menachem JN, Pedrotty D, Rali AS, Sacks S, Punnoose L, Zalawadiya S, Schlendorf K, Bacchetta M, Shah AS, Lima B.
J Thorac Cardiovasc Surg. 2026 Feb 3:S0022-5223(26)00093-0. doi: 10.1016/j.jtcvs.2026.01.026. Online ahead of print.
PMID: 41644042
From ask to action: how sponsorship circles strengthen career pathways for women in radiology.
Averill S, Witt AA, Frederick-Dyer K, Sheppard A, Zamora K, Reddy S, Silver JK, Englander MJ.
Clin Imaging. 2026 Mar;131:110732. doi: 10.1016/j.clinimag.2026.110732. Epub 2026 Jan 22.
PMID: 41579471 Free article.