A role for nuclear lamins in nuclear envelope assembly

The molecular interactions responsible for nuclear envelope assembly after mitosis are not well understood. In this study, we demonstrate that a peptide consisting of the COOH-terminal domain of Xenopus lamin B3 (LB3T) prevents nuclear envelope assembly in Xenopus interphase extracts. Specifically, LB3T inhibits chromatin decondensation and blocks the formation of both the nuclear lamina–pore complex and nuclear membranes. Under these conditions, some vesicles bind to the peripheral regions of the chromatin. These “nonfusogenic” vesicles lack lamin B3 (LB3) and do not bind LB3T; however, “fusogenic” vesicles containing LB3 can bind LB3T, which blocks their association with chromatin and, subsequently, nuclear membrane assembly. LB3T also binds to chromatin in the absence of interphase extract, but only in the presence of purified LB3. Additionally, we show that LB3T inhibits normal lamin polymerization in vitro. These findings suggest that lamin polymerization is required for both chromatin decondensation and the binding of nuclear membrane precursors during the early stages of normal nuclear envelope assembly

Risk Factors for CMV and BK Infections in an Elderly Veteran Population Following Kidney Transplantation: Implications for Immunosuppression Induction and Management

Cytomegalovirus (CMV) and BK Polyomavirus (BKPyV) are the most common opportunistic pathogens following kidney transplantation. We evaluated 102 patients with a median age of 63 at Edward Hines VA Hospital from November 2020 to December 2022. Our primary interest was the incidence of CMV and BKPyV infections, as well as CMV and BKPyV coinfection. Secondary interests included time to infection, rejection, and graft and patient survival. There were no statistically significant differences in patient age, donor age, race, transplant type, incidence of delayed graft function, or induction in both cohorts (any infection (N = 46) vs. those without (N = 56)). There was a 36% (37/102) incidence of CMV, a 17.6% (18/102) of BKPyV and an 8.8% (9/102) incidence of coinfection. There was a decreased incidence of CMV infection in Basiliximab induction versus antithymocyte globulin (21% and 43%). CMV risk status had no effect on the incidence of CMV infection following transplant. African American recipients had a lower incidence of BKPyV infection (12% vs. 39%), yet a higher incidence was observed in those with high cPRA (50% vs. 14%). Most CMV and/or BKPyV infections occurred within the first six months post-transplant (54%). Immunosuppression management of the elderly should continually be evaluated to reduce opportunistic infections post-transplant

Prevalence and feasibility of assessing the frailty phenotype among hemodialysis patients in a dialysis unit

Background: Frailty increases risk of morbidity and mortality in hemodialysis patients. Frailty assessments could trigger risk reduction interventions if broadly adopted in clinical practice. We aimed to assess the clinical feasibility of frailty assessment among Veteran hemodialysis patients. Methods: Hemodialysis patients' ≥50 years were recruited from a single dialysis unit between 9/1/2021 and 3/31/2022.Patients who consented underwent a frailty phenotype assessment by clinical staff. Five criteria were assessed: unintentional weight loss, low grip strength, self-reported exhaustion, slow gait speed, and low physical activity. Participants were classified as frail (3-5 points), pre-frail (1-2 points) or non-frail (0 points). Feasibility was determined by the number of eligible participants completing the assessment. Results: Among 82 unique dialysis patients, 45 (52%) completed the assessment, 13 (16%) refused, 18 (23%) were not offered the assessment due to death, transfers, or switch to transplant or peritoneal dialysis, and 6 patients were excluded because they did not meet mobility criteria. Among assessed patients, 40(88%) patients were identified as pre-frail (46.6%) or frail (42.2%). Low grip strength was most common (90%). Those who refused were more likely to have peripheral vascular disease (p = 0.001), low albumin (p = 0.0187), low sodium (p = 0.0422), and ineligible for kidney transplant (p = 0.005). Conclusions: Just over half of eligible hemodialysis patients completed the frailty assessment suggesting difficulty with broad clinical adoption expectations. Among those assessed, frailty and pre-frailty prevalence was high. Given patients who were not tested were clinically high risk, our reported prevalence likely underestimates true frailty prevalence. Providing frailty reduction interventions to all hemodialysis patients could have high impact for this group.</p

Impact of the new kidney allocation system A2/A2B --\u3e B policy on access to transplantation among minority candidates

Blood group B candidates, many of whom represent ethnic minorities, have historically had diminished access to deceased donor kidney transplantation (DDKT). The new national kidney allocation system (KAS) preferentially allocates blood group A2/A2B deceased donor kidneys to B recipients to address this ethnic and blood group disparity. No study has yet examined the impact of KAS on A2 incompatible (A2i) DDKT for blood group B recipients overall or among minorities. A case-control study of adult blood group B DDKT recipients from 2013 to 2017 was performed, as reported to the Scientific Registry of Transplant Recipients. Cases were defined as recipients of A2/A2B kidneys, whereas controls were all remaining recipients of non-A2/A2B kidneys. A2i DDKT trends were compared from the pre-KAS (1/1/2013-12/3/2014) to the post-KAS period (12/4/2014-2/28/2017) using multivariable logistic regression. Post-KAS, there was a 4.9-fold increase in the likelihood of A2i DDKT, compared to the pre-KAS period (odds ratio [OR] 4.92, 95% confidence interval [CI] 3.67-6.60). However, compared to whites, there was no difference in the likelihood of A2i DDKT among minorities post-KAS. Although KAS resulted in increasing A2/A2B--\u3eB DDKT, the likelihood of A2i DDKT among minorities, relative to whites, was not improved. Further discussion regarding A2/A2B--\u3eB policy revisions aiming to improve DDKT access for minorities is warranted

Regulation of DNA damage and transcriptional output in the vasculature through a cytoglobin-HMGB2 axis

Identifying novel regulators of vascular smooth muscle cell function is necessary to further understand cardiovascular diseases. We previously identified cytoglobin, a hemoglobin homolog, with myogenic and cytoprotective roles in the vasculature. The specific mechanism of action of cytoglobin is unclear but does not seem to be related to oxygen transport or storage like hemoglobin. Herein, transcriptomic profiling of injured carotid arteries in cytoglobin global knockout mice revealed that cytoglobin deletion accelerated the loss of contractile genes and increased DNA damage. Overall, we show that cytoglobin is actively translocated into the nucleus of vascular smooth muscle cells through a redox signal driven by NOX4. We demonstrate that nuclear cytoglobin heterodimerizes with the non-histone chromatin structural protein HMGB2. Our results are consistent with a previously unknown function by which a non-erythrocytic hemoglobin inhibits DNA damage and regulates gene programs in the vasculature by modulating the genome-wide binding of HMGB2