The association of self-reported sleep and circadian measures with glycemic control and diabetes complications among young adults with type 2 diabetes.

We aim to examine the association of sleep duration, sleep quality, late chronotype, and circadian misalignment with glycemic control and risk of complications in young adults with youth-onset type 2 diabetes followed in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study. Self-reported sleep duration, quality, timing, and circadian misalignment were assessed via a modified Pittsburgh Sleep Quality Index (PSQI) questionnaire, and chronotype was assessed via the Morningness-Eveningness Questionnaire (MEQ). We examined diabetes complications including loss of glycemic control (defined as hemoglobin A1c ≥8%), hypertension, dyslipidemia, albuminuria, and diabetic peripheral neuropathy. Multivariable logistic regression models were constructed to assess associations between sleep and circadian measures with outcomes of interest, such as loss of glycemic control and diabetes complications. A total of 421 participants (34.2% male), mean age 23.6 ± 2.5 yr, mean body mass index (BMI) of 36.1 ± 8.3 kg/m2, and mean diabetes duration of 10.0 ± 1.5 yr were evaluated. Self-reported short sleep duration, daytime sleepiness, and sleep quality were not associated with loss of glycemic control or diabetes complications. Late self-reported bedtime (after midnight) on work/school nights, rather than self-expressed chronotype or circadian misalignment, was independently associated with loss of glycemic control. An association was seen between late bedtimes and albuminuria but was attenuated after adjusting for depression. In conclusion, late bedtime on work/school days, rather than short sleep duration, daytime sleepiness, or poor sleep quality, was independently associated with loss of glycemic control in this longitudinal cohort of young adults with youth-onset type 2 diabetes.NEW & NOTEWORTHY The prevalence of type 2 diabetes in youth is increasing at an alarming rate. Identifying potentially modifiable factors modulating glycemic control is critically important to reduce micro and macrovascular complications. In a large cohort of youth-onset type 2 diabetes, self-reported late bedtime on work/school days was independently associated with loss of glycemic control in this longitudinal cohort of young adults with youth-onset type 2 diabetes.

Psychosocial Factors and Glycemic Control in Young Adults With Youth-Onset Type 2 Diabetes.

Importance: Youth-onset type 2 diabetes is associated with poor glycemic control and early onset of complications. Identification of psychosocial factors associated with poor glycemic control is needed to inform efficacious interventions. Objective: To identify psychosocial factors associated with glycated hemoglobin (HbA1c) levels in young adults with youth-onset type 2 diabetes. Design, Setting, and Participants: For the iCount cohort study, HbA1c levels were measured twice (at baseline [T1] and at 1 year [T2]) during the last years (2017-2019) of the observational phase of the multicenter Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY2) study. Participants were young adults who had been diagnosed with type 2 diabetes during childhood or adolescence. Data were analyzed from December 2021 to September 2023. Main Outcomes and Measures: Glycemic control was examined categorically (high [≥8.0%] vs low [<8.0%] HbA1c), continuously (HbA1c level), and over time (change in HbA1c: decreased ≥0.5%, remained stable, or increased ≥0.5%). Psychosocial measures included beliefs about medicines, depression and anxiety symptoms, diabetes distress, diabetes self-efficacy, self-management support, and unmet material needs. Multivariable logistic and linear regression models evaluated the association of each psychosocial factor with the probability of T2 HbA1c of 8.0% or greater, T2 HbA1c level, and change in HbA1c. Results: Of the 411 TODAY2 participants approached, 381 enrolled in the iCount study, and 348 with T1 and T2 HbA1c data comprised the analysis group. The 348 participants had a mean (SD) age of 26.1 (2.5) years and a mean (SD) HbA1c of 9.4% (2.8%). Most participants (229 [65.8%]) were women. In adjusted multivariable regressions, greater beliefs that diabetes medicines are necessary (odds ratio [OR], 1.19 [95% CI, 1.03-1.37]; P = .02), concerns about medicines (OR, 1.20 [95% CI, 1.00-1.45]; P = .049), diabetes distress (OR, 1.08 [95% CI, 1.02-1.15]; P = .006), and high distress (OR, 2.18 [95% CI, 1.15-4.13]; P = .02) increased the odds of high HbA1c at T2. Greater support (OR, 0.67 [95% CI, 0.46-0.97]; P = .04) and diabetes self-efficacy (OR, 0.91 [95% CI, 0.84-0.99]; P = .02) decreased the odds of high HbA1c at T2. Diabetes distress was associated with higher HbA1c level at T2 (coefficient, 0.08 [95% CI, 0.02-0.13]; P = .01). Beliefs that diabetes medicines are necessary (OR, 1.20 [95% CI, 1.03-1.39]; P = .02) and concerns about medicines (OR, 1.22 [95% CI, 1.00-1.47]; P = .048) increased the odds of an HbA1c decrease of at least 0.5% over 1 year. Conclusions and Relevance: In this cohort study of young adults with youth-onset type 2 diabetes, beliefs about medicines, high diabetes distress, low diabetes self-efficacy, and self-management support were associated with high HbA1c over time. Future research should assess whether interventions that address these factors result in improved glycemic control in this at-risk group.

Genetic and pharmacological modulation of lamin A farnesylation determines its function and turnover.

Hutchinson-Gilford Progeria syndrome (HGPS) is a severe premature ageing disorder caused by a 50 amino acid truncated (Δ50AA) and permanently farnesylated lamin A (LA) mutant called progerin. On a cellular level, progerin expression leads to heterochromatin loss, impaired nucleocytoplasmic transport, telomeric DNA damage and a permanent growth arrest called cellular senescence. Although the genetic basis for HGPS has been elucidated 20 years ago, the question whether the Δ50AA or the permanent farnesylation causes cellular defects has not been addressed. Moreover, we currently lack mechanistic insight into how the only FDA-approved progeria drug Lonafarnib, a farnesyltransferase inhibitor (FTI), ameliorates HGPS phenotypes. By expressing a variety of LA mutants using a doxycycline-inducible system, and in conjunction with FTI, we demonstrate that the permanent farnesylation, and not the Δ50AA, is solely responsible for progerin-induced cellular defects, as well as its rapid accumulation and slow clearance. Importantly, FTI does not affect clearance of progerin post-farnesylation and we demonstrate that early, but not late FTI treatment prevents HGPS phenotypes. Collectively, our study unravels the precise contributions of progerin's permanent farnesylation to its turnover and HGPS cellular phenotypes, and how FTI treatment ameliorates these. These findings are applicable to other diseases associated with permanently farnesylated proteins, such as adult-onset autosomal dominant leukodystrophy.

Antihypertensive and Lipid-Lowering Medication Adherence in Young Adults With Youth-Onset Type 2 Diabetes.

Importance: Youth-onset type 2 diabetes is associated with early development of chronic complications. Treatment of elevated blood pressure (BP), nephropathy, and dyslipidemia are critical to reduce morbidity. Data are needed on adherence to BP- and lipid-lowering medications in young adults with youth-onset diabetes. Objective: To assess adherence and factors associated with adherence to BP- and lipid-lowering medications in young adults with youth-onset type 2 diabetes and diagnoses of hypertension, nephropathy, or dyslipidemia. Design, Setting, and Participants: This cohort study measured medication adherence with 3 monthly unannounced pill counts at 2 time points 1 year apart during iCount, conducted during the last years (2017-2019) of the observational phase of the Treatment Options for Type 2 Diabetes in Adolescents and Youth study. Psychosocial factors associated with medication adherence were examined. Participants included individuals with youth-onset type 2 diabetes with hypertension, nephropathy, or dyslipidemia receiving diabetes care in their communities. Data were analyzed from September 2022 to September 2023. Main Outcomes and Measures: The main outcome was BP- and lipid-lowering medication adherence, with low adherence defined as using less than 80% of pills and high adherence, at least 80% of pills. Psychosocial factors were measured using the Beliefs about Medicines Questionnaire and Material Needs Insecurities Survey. Results: Of 381 participants in iCount, 243 participants (mean [SD] age, 26.12 [2.51] years; 159 [65.43%] women) with hypertension, nephropathy, or dyslipidemia were included in analysis. Among 196 participants with hypertension or nephropathy, 157 (80.1%) had low adherence. Participants with low adherence, compared with those with high adherence, were younger (mean [SD] age, 25.99 [2.41] vs 27.26 [2.41] years; P = .005), had higher glycated hemoglobin A1c (mean [SD], 10.33% [2.66 percentage points] vs 8.85% [2.39 percentage points]; P = .001), shorter diabetes duration (mean [SD], 12.32 [1.49] vs 12.90 [1.46] years; P = .03), and less education (eg, 17 participants [10.83%] vs 0 participants with no high school diploma; P = .004). Of 146 participants with dyslipidemia, 137 (93.8%) had low adherence and only 9 participants (6.2%) had high adherence. Of 103 participants with low adherence to BP-lowering medications and using oral hypoglycemic agents, 83 (80.58%) had low adherence to oral hypoglycemic agents. Beliefs that medications are necessary were higher for participants with high adherence to BP-lowering medications than those with low adherence in unadjusted analyses (mean [SD] necessity score, 16.87 [6.78] vs 13.89 [9.15]; P = .03). In adjusted multivariable analyses of participants with hypertension or nephropathy, having at least 1 unmet social need (odds ratio [OR], 0.20; 95% CI, 0.05-0.65; P = .04) and medication concerns (OR, 0.63; 95% CI, 0.40-0.96; P = .01) were associated with worse medication adherence 1 year follow-up. Diabetes distress, self-efficacy, depressive and anxiety symptoms, and self-management support were not associated with 1-year medication adherence. Conclusions and Relevance: These findings suggest that adherence to BP- and lipid-lowering medications was very poor in this cohort. To improve medication adherence and prevent early vascular events, approaches that identify and address medication concerns and unmet social needs are needed.

Subcellular Force Imbalance in Actin Bundles Induces Nuclear Repositioning and Durotaxis.

Durotaxis is a phenomenon in which cells migrate toward substrates of increasing stiffness. However, how cells assimilate substrate stiffness as a directional cue remains poorly understood. In this study, we experimentally show that mouse embryonic fibroblasts can discriminate between different substrate stiffnesses and develop higher traction forces at regions of the cell adhering to the stiffer pillars. In this way, the cells generate a force imbalance between adhesion sites. It is this traction force imbalance that drives durotaxis by providing directionality for cell migration. Significantly, we found that traction forces are transmitted via LINC complexes to the cell nucleus, which serves to maintain the global force imbalance. In this way, LINC complexes play an essential role in anterograde nuclear movement and durotaxis. This conclusion is supported by the fact that LINC complex-deficient cells are incapable of durotaxis and instead migrate randomly on substrates featuring a stiffness gradient.

Implementation of a quadratus lumborum regional block protocol with assessment of effectiveness for patients with appendicitis: a quality improvement project.

PURPOSE: This study analyzes the implementation of the routine use of quadratus lumborum blocks (QLBs) on postoperative pain and opioid consumption among children undergoing laparoscopic appendectomy compared to those not receiving regional anesthesia. METHODS: Children undergoing laparoscopic appendectomy within a multi-hospital children's healthcare system were retrospectively reviewed from 2017 to 2021. Patients were stratified by appendicitis type (uncomplicated vs. complicated). Pain scores and opioid consumption in the post-anesthesia care unit (PACU) and within the first 24 h postoperatively were compared by block status (no block [NB] vs. QLB) and appendicitis type. RESULTS: 2033 patients were reviewed, and 610 received a QLB. The frequency of rescue opioid use was reduced in the PACU (uncomplicated: QLB 46.6% vs. NB 54.6%, p = 0.005; complicated: QLB 28.5% vs. NB 39.9%, p = 0.01) and postoperatively (complicated: QLB 33.7% vs. NB 52.9%, p < 0.001) for those who received a QLB. This resulted in reduced opioid consumption as measured by morphine milligram equivalents per kilogram postoperatively. CONCLUSION: QLBs can be safely administered in children and provide improvements in opioid consumption postoperatively. QLBs should remain a strongly favored regional anesthetic technique because of their wide applicability for abdominal surgeries to minimize rescue opioid analgesic use. TYPE OF STUDY: Retrospective comparative study. LEVEL OF EVIDENCE: Level III.

Local colonisations and extinctions of European birds are poorly explained by changes in climate suitability.

Climate change has been associated with both latitudinal and elevational shifts in species' ranges. The extent, however, to which climate change has driven recent range shifts alongside other putative drivers remains uncertain. Here, we use the changing distributions of 378 European breeding bird species over 30 years to explore the putative drivers of recent range dynamics, considering the effects of climate, land cover, other environmental variables, and species' traits on the probability of local colonisation and extinction. On average, species shifted their ranges by 2.4 km/year. These shifts, however, were significantly different from expectations due to changing climate and land cover. We found that local colonisation and extinction events were influenced primarily by initial climate conditions and by species' range traits. By contrast, changes in climate suitability over the period were less important. This highlights the limitations of using only climate and land cover when projecting future changes in species' ranges and emphasises the need for integrative, multi-predictor approaches for more robust forecasting.

Spinal versus general anesthesia: Comparing outcomes in pediatric patients undergoing urologic procedures.

INTRODUCTION: Available literature comparing spinal anesthesia (SA) to general anesthesia (GA) in the pediatric population describes multiple benefits in appropriately selected patients including cost reduction, lower incidence of complications, and shorter operative times. In patients undergoing urologic procedures, data are sparse. OBJECTIVE: Our goal was to expand on the paucity of existing urologic literature as SA appears to be uniquely suited for a substantial number of its common pediatric procedures. METHODS: Within a single institution, patients who had a urologic procedure performed under SA between May 2019 and July 2021 and were less than 18 months old were compared with a matched cohort of patients who had GA. The SA and GA groups were compared by two-sample t-tests, chi-square test for independence, and Fisher's exact test. RESULTS: There were a total of 184 SA and 202 GA patients. There was no significant difference in the demographics except that SA patients were younger and weighed less than GA patients. The patients in the SA group needed less opioids both during the surgery (0% vs 26.1% p N/A) and in the immediate postoperative period when compared with GA patients (0% vs 18.2% p N/A). The patients who had SA had fewer complications necessitating PICU admission, or cancellation of surgery (0% vs 6.8% p = 0.03). Total anesthesia and emergence time were lower for SA patients (41 vs 50.2 p = 0.001 & 3.4 vs 6.1 p = 0.001). Both surgery and total OR time were not different between the groups (37.6 vs 35.5 p = 0.35 and 56.3 vs 54.4 p = 0.49). Overall, raw material cost was also found to be lower per procedure in the SA group vs the GA group ($8.90 vs $38.8: 77% reduction). Adjusted total mean costs for the surgery were not different between groups. The reduction in opioid use postoperatively also suggests reduced cost in the management of postoperative pain in the SA group. DISCUSSION: Total anesthesia time, opioid use, and serious complications were all significantly lower in the SA group. We did not find significant difference in total surgery cost between two groups. However, patients who had SA had better pain control and needed less rescue analgesics in the immediate postoperative period. No patients in either group were sent home with opioids. CONCLUSION: Spinal anesthesia was found to be an equally effective and appropriate alternative to GA with many proposed benefits for common pediatric urologic procedures. With further research, SA may prove to be a safer alternative in patients at risk for complications related to GA general anesthesia while also offering a cost benefit.

The power of TOPMed imputation for the discovery of Latino-enriched rare variants associated with type 2 diabetes.

AIMS/HYPOTHESIS: The Latino population has been systematically underrepresented in large-scale genetic analyses, and previous studies have relied on the imputation of ungenotyped variants based on the 1000 Genomes (1000G) imputation panel, which results in suboptimal capture of low-frequency or Latino-enriched variants. The National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) released the largest multi-ancestry genotype reference panel representing a unique opportunity to analyse rare genetic variations in the Latino population. We hypothesise that a more comprehensive analysis of low/rare variation using the TOPMed panel would improve our knowledge of the genetics of type 2 diabetes in the Latino population. METHODS: We evaluated the TOPMed imputation performance using genotyping array and whole-exome sequence data in six Latino cohorts. To evaluate the ability of TOPMed imputation to increase the number of identified loci, we performed a Latino type 2 diabetes genome-wide association study (GWAS) meta-analysis in 8150 individuals with type 2 diabetes and 10,735 control individuals and replicated the results in six additional cohorts including whole-genome sequence data from the All of Us cohort. RESULTS: Compared with imputation with 1000G, the TOPMed panel improved the identification of rare and low-frequency variants. We identified 26 genome-wide significant signals including a novel variant (minor allele frequency 1.7%; OR 1.37, p=3.4 × 10-9). A Latino-tailored polygenic score constructed from our data and GWAS data from East Asian and European populations improved the prediction accuracy in a Latino target dataset, explaining up to 7.6% of the type 2 diabetes risk variance. CONCLUSIONS/INTERPRETATION: Our results demonstrate the utility of TOPMed imputation for identifying low-frequency variants in understudied populations, leading to the discovery of novel disease associations and the improvement of polygenic scores. DATA AVAILABILITY: Full summary statistics are available through the Common Metabolic Diseases Knowledge Portal ( https://t2d.hugeamp.org/downloads.html ) and through the GWAS catalog ( https://www.ebi.ac.uk/gwas/ , accession ID: GCST90255648). Polygenic score (PS) weights for each ancestry are available via the PGS catalog ( https://www.pgscatalog.org , publication ID: PGP000445, scores IDs: PGS003443, PGS003444 and PGS003445).

Patient-Reported Outcomes in Pain Management After Ambulatory Pediatric General and Urologic Surgery.

BACKGROUND: Many studies evaluating opioid stewardship interventions' effects on postoperative pain rely on emergency department (ED) visits or readmissions, but patient-reported pain scores represent a more complete picture of the postoperative experience. This study compares patient-reported pain scores after ambulatory pediatric and urologic procedures and the effect of an opioid stewardship intervention that nearly eliminated the use of outpatient narcotics. METHODS: This is a retrospective comparative study including 3173 pediatric patients who underwent ambulatory procedures from 2015 to 2019, during which there was an intervention to reduce narcotic prescriptions. Postoperative day one phone calls assessed pain levels using a four-point scale (no pain, mild pain, moderate pain controlled with medication, or severe pain uncontrolled with medication). We quantified the proportion of patients prescribed opioids pre-versus post-intervention and compared pain scores for patients receiving opioid versus non-opioid regimens. RESULTS: Opioid prescription rates demonstrated a 6.5-fold reduction after opioid stewardship efforts. The majority of patients (2838) received non-opioids, with only 335 patients receiving opioids. Opioid patients reported moderate/severe pain slightly more than non-opioid patients (14.1% vs. 10.4%, p = 0.04). On by-procedure analyses, there were no subgroups in which non-opioid patients reported significantly higher pain scores. CONCLUSIONS: Non-opioid postoperative pain regimens appear to be effective, with only 10.4% of patients reporting moderate/severe pain after ambulatory procedures. Future studies assessing patient-reported outcomes are necessary to optimize pain control for all patients and to determine whether there is ever an indication for opioid prescription after ambulatory general pediatric or urologic surgery. TYPE OF STUDY: Retrospective comparative study. LEVEL OF EVIDENCE: Level III.

The meiotic LINC complex component KASH5 is an activating adaptor for cytoplasmic dynein.

Cytoplasmic dynein-driven movement of chromosomes during prophase I of mammalian meiosis is essential for synapsis and genetic exchange. Dynein connects to chromosome telomeres via KASH5 and SUN1 or SUN2, which together span the nuclear envelope. Here, we show that KASH5 promotes dynein motility in vitro, and cytosolic KASH5 inhibits dynein's interphase functions. KASH5 interacts with a dynein light intermediate chain (DYNC1LI1 or DYNC1LI2) via a conserved helix in the LIC C-terminal, and this region is also needed for dynein's recruitment to other cellular membranes. KASH5's N-terminal EF-hands are essential as the interaction with dynein is disrupted by mutation of key calcium-binding residues, although it is not regulated by cellular calcium levels. Dynein can be recruited to KASH5 at the nuclear envelope independently of dynactin, while LIS1 is essential for dynactin incorporation into the KASH5-dynein complex. Altogether, we show that the transmembrane protein KASH5 is an activating adaptor for dynein and shed light on the hierarchy of assembly of KASH5-dynein-dynactin complexes.

Do Salient Social Norms Moderate Mortality Salience Effects? A (Challenging) Meta-Analysis of Terror Management Studies.

Terror management theory postulates that mortality salience (MS) increases the motivation to defend one's cultural worldviews. How that motivation is expressed may depend on the social norm that is momentarily salient. Meta-analyses were conducted on studies that manipulated MS and social norm salience. Results based on 64 effect sizes for the hypothesized interaction between MS and norm salience revealed a small-to-medium effect of g = 0.34, 95% confidence interval [0.26, 0.41]. Bias-adjustment techniques suggested the presence of publication bias and/or the exploitation of researcher degrees of freedom and arrived at smaller effect size estimates for the hypothesized interaction, in several cases reducing the effect to nonsignificance (range gcorrected = -0.36 to 0.15). To increase confidence in the idea that MS and norm salience interact to influence behavior, preregistered, high-powered experiments using validated norm salience manipulations are necessary. Concomitantly, more specific theorizing is needed to identify reliable boundary conditions of the effect.

Nesprin-1 LINC complexes recruit microtubule cytoskeleton proteins and drive pathology in Lmna-mutant striated muscle.

Mutations in LMNA, the gene encoding A-type lamins, cause laminopathies-diseases of striated muscle and other tissues. The aetiology of laminopathies has been attributed to perturbation of chromatin organization or structural weakening of the nuclear envelope (NE) such that the nucleus becomes more prone to mechanical damage. The latter model requires a conduit for force transmission to the nucleus. NE-associated Linker of Nucleoskeleton and Cytoskeleton (LINC) complexes are one such pathway. Using clustered regularly interspaced short palindromic repeats to disrupt the Nesprin-1 KASH (Klarsicht, ANC-1, Syne Homology) domain, we identified this LINC complex protein as the predominant NE anchor for microtubule cytoskeleton components, including nucleation activities and motor complexes, in mouse cardiomyocytes. Loss of Nesprin-1 LINC complexes resulted in loss of microtubule cytoskeleton proteins at the nucleus and changes in nuclear morphology and positioning in striated muscle cells, but with no overt physiological defects. Disrupting the KASH domain of Nesprin-1 suppresses Lmna-linked cardiac pathology, likely by reducing microtubule cytoskeleton activities at the nucleus. Nesprin-1 LINC complexes thus represent a potential therapeutic target for striated muscle laminopathies.

Breakthrough SARS-CoV-2 Infections after Vaccination in North Carolina.

We characterize the overall incidence and risk factors for breakthrough infection among fully vaccinated participants in the North Carolina COVID-19 Community Research Partnership cohort. Among 15,808 eligible participants, 638 reported a positive SARS-CoV-2 test after vaccination. Factors associated with a lower risk of breakthrough in the time-to-event analysis included older age, prior SARS-CovV-2 infection, higher rates of face mask use, and receipt of a booster vaccination. Higher rates of breakthrough were reported by participants vaccinated with BNT162b2 or Ad26.COV2.S compared to mRNA-1273, in suburban or rural counties compared to urban counties, and during circulation of the Delta and Omicron variants.

Combined alteration of lamin and nuclear morphology influences the localization of the tumor-associated factor AKTIP.

BACKGROUND: Lamins, key nuclear lamina components, have been proposed as candidate risk biomarkers in different types of cancer but their accuracy is still debated. AKTIP is a telomeric protein with the property of being enriched at the nuclear lamina. AKTIP has similarity with the tumor susceptibility gene TSG101. AKTIP deficiency generates genome instability and, in p53-/- mice, the reduction of the mouse counterpart of AKTIP induces the exacerbation of lymphomas. Here, we asked whether the distribution of AKTIP is altered in cancer cells and whether this is associated with alterations of lamins. METHODS: We performed super-resolution imaging, quantification of lamin expression and nuclear morphology on HeLa, MCF7, and A549 tumor cells, and on non-transformed fibroblasts from healthy donor and HGPS (LMNA c.1824C > T p.Gly608Gly) and EDMD2 (LMNA c.775 T > G) patients. As proof of principle model combining a defined lamin alteration with a tumor cell setting, we produced HeLa cells exogenously expressing the HGPS lamin mutant progerin that alters nuclear morphology. RESULTS: In HeLa cells, AKTIP locates at less than 0.5 µm from the nuclear rim and co-localizes with lamin A/C. As compared to HeLa, there is a reduced co-localization of AKTIP with lamin A/C in both MCF7 and A549. Additionally, MCF7 display lower amounts of AKTIP at the rim. The analyses in non-transformed fibroblasts show that AKTIP mislocalizes in HGPS cells but not in EDMD2. The integrated analysis of lamin expression, nuclear morphology, and AKTIP topology shows that positioning of AKTIP is influenced not only by lamin expression, but also by nuclear morphology. This conclusion is validated by progerin-expressing HeLa cells in which nuclei are morphologically altered and AKTIP is mislocalized. CONCLUSIONS: Our data show that the combined alteration of lamin and nuclear morphology influences the localization of the tumor-associated factor AKTIP. The results also point to the fact that lamin alterations per se are not predictive of AKTIP mislocalization, in both non-transformed and tumor cells. In more general terms, this study supports the thesis that a combined analytical approach should be preferred to predict lamin-associated changes in tumor cells. This paves the way of next translational evaluation to validate the use of this combined analytical approach as risk biomarker.

Environmental Change in Southern Appalachia: Local Ecological Knowledge across Residential Groups.

This paper examines how residents of Southern Appalachia observe changes in their natural environment, the values that they assign to plants and animals in that environment, and their understandings and explanations of environmental change. We use semi-structured interviews and participant observation to determine that multigenerational residents and newcomers to the region are observing and noting change in different components of the environment and that they have different determinations of both the causes and likely consequences of that change. While multigenerational residents focus their observation and commentary on staple crops and culturally-important species, newcomers to the area concentrate on species related to recreational pursuits, giving each group insights into different aspects of environmental change. These findings are translated into recommendations for more inclusive and effective environmental and conservation planning.

Genome-wide Association Study of Lipid Traits in Youth With Type 2 Diabetes.

CONTEXT: Dyslipidemia is highly prevalent in youth with type 2 diabetes (T2D), yet the pathogenic components of dyslipidemia in youth with T2D are poorly understood. OBJECTIVE: To evaluate the genetic determinants of lipid traits in youth with T2D through a genome-wide association study. DESIGN PARTICIPANTS AND MAIN OUTCOME MEASURES: We genotyped 206 928 variants and imputed 17 642 824 variants in 1076 youth (mean age 15.0 ± 2.48 years) with T2D from the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) and SEARCH for Diabetes in Youth (SEARCH) studies as part of the Progress in Diabetes Genetics in Youth (ProDiGY) consortium. We performed association testing for triglyceride and low-density lipoprotein cholesterol and high-density lipoprotein cholesterol (HDL-c) concentrations adjusted for the genetic relationship matrix within each substudy followed by meta-analyses for each trait. RESULTS: We identified a novel association between a deletion on chromosome 3 (3:67817380_AT/A_Deletion:RP11-81N13.1) and triglyceride levels at genome-wide level of significance (P = 2.3 × 10-8) with each risk allele increasing triglycerides by 20%. We also identified a genome-wide significant signal at rs247617 (P = 5.1 × 10-9) between HERFUD1 and CETP associated with HDL-c, with carriers of 1 copy of the risk allele having twice higher HDL-c. CONCLUSIONS: Our genetic analyses of lipid traits in youth with T2D have identified 1 novel and 1 previously known locus. Additional studies are needed to further characterize the genetic architecture of dyslipidemia in youth with T2D.

Disrupting the LINC complex by AAV mediated gene transduction prevents progression of Lamin induced cardiomyopathy.

Mutations in the LaminA gene are a common cause of monogenic dilated cardiomyopathy. Here we show that mice with a cardiomyocyte-specific Lmna deletion develop cardiac failure and die within 3-4 weeks after inducing the mutation. When the same Lmna mutations are induced in mice genetically deficient in the LINC complex protein SUN1, life is extended to more than one year. Disruption of SUN1's function is also accomplished by transducing and expressing a dominant-negative SUN1 miniprotein in Lmna deficient cardiomyocytes, using the cardiotrophic Adeno Associated Viral Vector 9. The SUN1 miniprotein disrupts binding between the endogenous LINC complex SUN and KASH domains, displacing the cardiomyocyte KASH complexes from the nuclear periphery, resulting in at least a fivefold extension in lifespan. Cardiomyocyte-specific expression of the SUN1 miniprotein prevents cardiomyopathy progression, potentially avoiding the necessity of developing a specific therapeutic tailored to treating each different LMNA cardiomyopathy-inducing mutation of which there are more than 450.

AKTIP interacts with ESCRT I and is needed for the recruitment of ESCRT III subunits to the midbody.

To complete mitosis, the bridge that links the two daughter cells needs to be cleaved. This step is carried out by the endosomal sorting complex required for transport (ESCRT) machinery. AKTIP, a protein discovered to be associated with telomeres and the nuclear membrane in interphase cells, shares sequence similarities with the ESCRT I component TSG101. Here we present evidence that during mitosis AKTIP is part of the ESCRT machinery at the midbody. AKTIP interacts with the ESCRT I subunit VPS28 and forms a circular supra-structure at the midbody, in close proximity with TSG101 and VPS28 and adjacent to the members of the ESCRT III module CHMP2A, CHMP4B and IST1. Mechanistically, the recruitment of AKTIP is dependent on MKLP1 and independent of CEP55. AKTIP and TSG101 are needed together for the recruitment of the ESCRT III subunit CHMP4B and in parallel for the recruitment of IST1. Alone, the reduction of AKTIP impinges on IST1 and causes multinucleation. Our data altogether reveal that AKTIP is a component of the ESCRT I module and functions in the recruitment of ESCRT III components required for abscission.

A human infertility-associated KASH5 variant promotes mitochondrial localization.

KASH5 is the most recently identified member of the KASH domain family of tail anchored, outer nuclear membrane (ONM) and endoplasmic reticulum (ER) proteins. During meiosis prophase I, KASH5 and SUN1 form a complex that spans the nuclear envelope and which links the telomeres of meiotic chromosomes to cytoplasmic dynein. This connection is essential for homologous chromosome dynamics and pairing. A recent study identified a variant in human KASH5 (L535Q) that correlated with male infertility associated with azoospermia. However, no molecular mechanism was described. Here, we report that this amino acid substitution, within the KASH5 transmembrane domain (TMD) has no predicted effects on secondary structure. However, the overall hydrophobicity of the L535Q TMD, is calculated to be lower than the wild-type KASH5, based on the GES (Goldman-Engelman-Steitz) amino acid hydrophobicity scale. This change in hydrophobicity profoundly affects the subcellular localization of KASH5. Through a series of amino acid substitution studies, we show that the L535Q substitution perturbs KASH5 localization to the ER and ONM and instead results in mistargeting to the mitochondria membrane. We suggest that this mislocalization accounts for the infertility and azoospermia phenotype in patients.