Nevin Manimala

Adv Sci (Weinh). 2025 Aug 11:e04562. doi: 10.1002/advs.202504562. Online ahead of print.

ABSTRACT

Alternative polyadenylation of pre-mRNA generates mRNAs with alternative 3′ ends, thereby increasing the complexity of the transcriptome and proteome. This process is carried out by pre-mRNA 3′ end processing complexes, with the specificity and site selection of polyadenylation primarily defined by the interaction between these complexes and conserved pre-mRNA cis-elements. However, the cis-element recognized by the polyadenylation CFII complex and the downstream cis-element of the poly(A) site remain unknown. Here, FPA, a conserved Spen family RNA-binding protein, is identified to physically interacts with the CFII complex in Arabidopsis. FPA specifically binds to a GA-rich cis-element downstream of the proximal poly(A) site, which is required for the CFII complex to promote proximal poly(A) site usage and prevent 3′ extension. Thus, the CFII complex recognizes the downstream cis-element of the poly(A) site through its interaction with FPA, highlighting the role of RNA-binding proteins as accessory factors in alternative polyadenylation.

PMID:40789077 | DOI:10.1002/advs.202504562

Proc Natl Acad Sci U S A. 2025 Aug 19;122(33):e2514378122. doi: 10.1073/pnas.2514378122. Epub 2025 Aug 11.

ABSTRACT

We use remote sensing observations to document surface deformation caused by the 2025 M_w7.7 Mandalay earthquake. This event is a unique case of an extremely long (~510 km) and sustained supershear rupture probably favored by the rather smooth and continuous geometry of this section of the structurally mature Sagaing Fault. The seismic rupture involved the locked portion of the fault over its entire depth extent (0 to 13 km) with a remarkably uniform slip distribution that averages 3.3 m, and an average stress drop of 4.7 MPa. No shallow-slip deficit is observed. The rupture extent challenges usual scaling laws relating earthquake magnitude, fault length, and slip. The fault ruptured along a known seismic gap that last ruptured in 1839 and tailed off into sections that ruptured during large earthquakes in 1930 and 1946. The amplitude and spatial distribution of fault slip in the 2025 event conform only approximatively to the slip-predictable model and the segmentation inferred from the fault geometry and past ruptures. Plausible sequences of earthquakes with variable magnitude, segmentation, and return periods, including events similar to the 2025 earthquake are produced in quasidynamic simulations using a simplified but nonplanar fault geometry. Based on this simulation, M_w>7.5 events return irregularly with an interevent time of ~141 y on average and a SD of ~40 y. The simulation is consistent with the historical seismicity and with the maximum magnitude ~M_w7.9 and return period (~250 y) derived from moment conservation. Data assimilation into such simulations could provide a way for time-dependent hazard assessment in the future.

PMID:40789035 | DOI:10.1073/pnas.2514378122

Proc Natl Acad Sci U S A. 2025 Aug 19;122(33):e2501224122. doi: 10.1073/pnas.2501224122. Epub 2025 Aug 11.

ABSTRACT

A current tenet in the science of cities is the emergence of power-law relations between population size and a variety of urban indicators, echoing allometric scaling in living organisms akin to Kleiber’s law. However fascinating, existing scaling theories suffer from biases related to the ad-hoc definition of city boundaries and to their neglect of intraurban variability of city properties. Here, to deal rigorously with biases, we explore the hypothesis that the empirical statistics of intracity variations in population counts, road networks, and carbon emissions-across various cities and spatial scales-can be interpreted as resulting from the joint fluctuations of spatially dependent random variables. Rather than relating urban characteristics to overall city size, we focus on how intraurban properties and local population patterns vary together across space. We find that the marginal and joint probability distributions are characterized by finite-size scaling functions which, upon suitable rescaling, collapse onto a set of universal curves. These results are analogous to those relating intraspecies variability in living organisms where the scaling of mean body mass with a characteristic metabolic rate clouds the effects of the variance of both traits. Our findings lay the foundations for a generalized theory of urban metabolism, linking city-scale quantities to the covariation of intraurban characteristics. This also opens up opportunities for a full exploitation of available urban data allowing the integration of biologically inspired theories into the modeling and planning of cities.

PMID:40789025 | DOI:10.1073/pnas.2501224122

Health Rep. 2025 Jul 16;36(7):15-28. doi: 10.25318/82-003-x202500700002-eng.

ABSTRACT

BACKGROUND: Most older Canadians would prefer to stay in their own homes and communities rather than move to long-term care (LTC) facilities. A growing older population, limited LTC capacity, and costs have increased demand for initiatives that enable people to age in their communities for as long as possible.

METHODS: Data from the 2019/2020 Canadian Health Survey on Seniors were used to estimate the prevalence of four types of supports and services (SSs) that assist with living in the community: home adaptations, informal care, home care, and community support services. Separate multivariable logistic regressions for each SS, stratified by age group (65 to 79 years and 80 years or older), examined associations with need-related factors, enabling resources, and predisposing characteristics.

RESULTS: At 25.0% of 65- to 79-year-olds and 51.9% of those aged 80 years or older, home adaptations were the most prevalent SS used in Canada. Use of home care, community support services and informal care was less common, ranging from 5.5% to 11.6% among Canadians aged 65 to 79 and 17.2% to 33.2% among those aged 80 or older. Nonetheless, substantial proportions of the younger (65.4%) and older (31.8%) age groups reported no SS use. In general, having a poor health status, having impairment, not driving, being older, living alone, having a regular health care provider, and being a woman increased the odds of using SSs.

INTERPRETATION: Understanding the factors associated with SS use can help inform policies and programs aimed at assisting older Canadians with aging in the community.

PMID:40789000 | DOI:10.25318/82-003-x202500700002-eng

Health Rep. 2025 Jul 16;36(7):3-14. doi: 10.25318/82-003-x202500700001-eng.

ABSTRACT

BACKGROUND: Low staffing levels and high turnover rates are longstanding issues in long-term care (LTC) facilities that were further exacerbated by the COVID-19 pandemic. Consequently, residents and staff were disproportionately affected, with high morbidity and mortality rates. This study examines changes in staffing levels, overall and by direct care worker category, across the LTC facilities sector by ownership status in Canada before and during the pandemic. It also explores differences in facility expenditures allocated towards employee wages, benefits, and subcontracts across homes by ownership status.

DATA AND METHODS: Data were from the 2020 and 2021 Nursing and Residential Care Facility Survey, which collected information on facility characteristics, including expenses, revenue, ownership status, and staffing levels. Summary statistics and multivariate linear regression models were used to examine the association between staffing levels and ownership status, with analyses stratified by direct care worker category.

RESULTS: On average, public LTC facilities had higher staffing levels and spent a greater proportion of their total costs on employee wages and benefits before and during the pandemic, compared with for-profit and non-profit private facilities. While the total hours of care per resident day (HPRD) increased during the pandemic, there were notable variations by region, ownership status, and direct care worker category. For example, Ontario public nursing homes provided 10% more HPRD from registered nurses during the pandemic, compared with the period before.

INTERPRETATION: Staffing levels of direct care workers in LTC facilities, overall and separately, are associated with ownership status. Allocation of employee-related expenses also differed by ownership. Further research is needed to explore interactions between ownership status, staffing levels, and quality of care for residents.

PMID:40788999 | DOI:10.25318/82-003-x202500700001-eng

Ophthalmic Plast Reconstr Surg. 2025 Aug 11. doi: 10.1097/IOP.0000000000003007. Online ahead of print.

ABSTRACT

PURPOSE: To evaluate the subjective assessment of 8 orbital CT features for predicting dysthyroid optic neuropathy (DON).

METHODS: Scan montages from 137 orbits without DON and 121 with DON were each graded independently by 3 observers for 8 imaging features: namely, degree of apical crowding, extraocular muscle enlargement, expansion of orbital fat, clarity of the superior orbital fissure, fat prolapse through the superior orbital fissure, medial wall bowing, general orbital vascular congestion, and dilation of the superior ophthalmic vein. Gradings were analyzed individually and also averaged across observers. Associations with DON were assessed using univariate and multivariate logistic regression, and performance of the latter was assessed using area under the receiver-operating-characteristic curve, sensitivity, specificity, and calibration plots.

RESULTS: Unadjusted models showed apical crowding (p < 0.001), extraocular muscle enlargement (p < 0.001), vascular congestion (p = 0.001), and medial wall bowing (p < 0.001) were each associated with DON, across all observers. Models for observers 1 and 3 included only apical crowding, with a 1-unit grading-increase giving, respectively, a 2.88-fold and 3.04-fold increase in DON odds (p < 0.001). The observer 2 model included extraocular muscle enlargement (odds ratio: 2.95; p < 0.001) and vascular congestion (odds ratio: 2.57; p = 0.023). The “averaged-score” model for all observers included only apical crowding, with a 3.76-fold increased odds per unit increase in grading (p < 0.001). The models showed borderline-acceptable discrimination (area under the receiver-operating-characteristic curve: 0.68-0.75) and good calibration, with the averaged-score model performing best.

CONCLUSIONS: Apical crowding, extraocular muscle enlargement, vascular congestion, and medial wall bowing are key predictors of DON, with apical crowding being the most influential.

PMID:40788673 | DOI:10.1097/IOP.0000000000003007

Ophthalmic Plast Reconstr Surg. 2025 Aug 11. doi: 10.1097/IOP.0000000000002989. Online ahead of print.

ABSTRACT

PURPOSE: To examine long-term outcomes of brow lift procedures, comparing surgical and fixation methods.

METHODS: Inclusion required original human research, at least 1 brow lift surgery cohort, quantitative measurements for brow elevation with a measure of statistical spread, and a mean follow-up of at least 6 months. Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, article screening and data collection were conducted by 2 independent reviewers. Random-effects models were conducted to estimate pooled lateral, central, and medial brow elevation and pooled complication rates.

RESULTS: Of the 22 studies included, there were 2,127 brows, and the weighted average of follow-up intervals was 20.9 months. The lateral, central, and medial brow elevated significantly (p < 0.0001) by 3.8 mm, 3.02 mm, and 2.41 mm, respectively, with small/moderate heterogeneity. There were no significant differences between pre- and post-trichial long-term elevation or complication rates. Tined implant fixation had significantly greater lateral elevation (p = 0.0192) and significantly greater dysesthesia rates (p = 0.027) compared with suture fixation.

CONCLUSIONS: This study provides evidence supporting the long-term efficacy of brow lifts with a favorable safety profile. When choosing a technique, physicians should understand that while there were no significant differences between pretrichial and post-trichial brow lifts, tined implants for brow fixation trended towards greater lateral brow elevation and increased rates of dysesthesia compared to using sutures.

PMID:40788666 | DOI:10.1097/IOP.0000000000002989

Diabetes. 2025 Aug 11:db250067. doi: 10.2337/db25-0067. Online ahead of print.

ABSTRACT

The “omnigenic” hypothesis postulates that polygenic effects of common variants on typical complex traits coalesce via trans effects on the expression of a relatively sparse set of “core” effector genes and their encoded proteins in relevant tissues. The objective of this study was to identify core proteins for type 1 diabetes. We used summary statistics for single nucleotide polymorphism associations with plasma levels of 5,130 proteins in three large cohorts, including the UK Biobank, to compute genome-wide aggregated trans effects (GATE) scores for protein levels in two type 1 diabetes case-control studies (6,828 case individuals, 416,000 control individuals). GATE scores for 27 proteins were associated with type 1 diabetes. Of these, 14 were replicated between data sets, 11 had support in Mendelian randomization analysis, and 9 had experimental support in mouse models of autoimmune diabetes. The strongest associations were for immune checkpoints (PDCD1, CD5, TIGIT, and LAG3), chemokines, and innate immune system proteins (NCR1 and KLRB1). While PDCD1 is a known cause of monogenic autoimmune diabetes, neither it nor most of the core proteins identified here were previously reported as genome-wide association study hits for type 1 diabetes. These results identify possible drug targets with genetic support for causality and suggest that programmed cell death protein 1 agonists under development for other indications should be trialed for type 1 diabetes prevention.

ARTICLE HIGHLIGHTS: Demonstrating genetic evidence for a role of a protein in disease gives important support for its potential as a drug target. We aimed to identify proteins that have genetic evidence to support a causal role in the pathogenesis of type 1 diabetes. We found 27 core proteins had genetic evidence of causality for type 1 diabetes. Top hits included immune checkpoints (PDCD1, CD5, TIGIT, and LAG3) and innate immune system proteins (NCR1 and KLRB1). These results identify possible drug targets and suggest that programmed cell death protein 1 agonists should be trialed for type 1 diabetes prevention.

PMID:40788656 | DOI:10.2337/db25-0067

JAMA Netw Open. 2025 Aug 1;8(8):e2526321. doi: 10.1001/jamanetworkopen.2025.26321.

ABSTRACT

IMPORTANCE: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are associated with increased risk of diabetic retinopathy (DR) and nonarteritic anterior ischemic optic neuropathy (NAION). The risk of sight-threatening complications associated with GLP-1 RAs is underexamined.

OBJECTIVE: To investigate whether the use of GLP-1 RAs in patients with T2D is associated with the development of DR, NAION, or DR complications.

DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study of adults (aged ≥18 years) with T2D and a recent hemoglobin A1c level of 6.5% or higher was conducted between January 1, 2015, and September 30, 2022, using the TriNetX database. The cohort was divided into 2 groups, adjusted for baseline characteristics through propensity score matching (PSM), based on whether the individuals received prescriptions for a GLP-1 RA. The statistical analysis was conducted on October 10, 2024.

EXPOSURES: At least 2 prescriptions of a GLP-1 RA given 6 months apart.

MAIN OUTCOMES AND MEASURES: Cox proportional hazard regression models were used to evaluate the primary outcome: association between GLP-1 RAs and the risk of incident DR, NAION, or sight-threatening complications over a 2-year follow-up period.

RESULTS: After PSM, 185 066 individuals (mean [SD] age, 59.0 [12.5] years; 93 389 females [50.5%]) were prescribed GLP-1 receptor agonists. Use of GLP-1 RAs was associated with an increased incidence of DR (hazard ratio [HR], 1.07; 95% CI, 1.03-1.11), while no statistically significant difference was observed in the risk of NAION (HR, 1.26; 95% CI, 0.94-1.70). In a subgroup analysis of 32 695 patients with preexisting DR, GLP-1 RAs were not associated with progression to proliferative DR (HR, 1.06; 95% CI, 0.97-1.15) or diabetic macular edema (HR, 0.98; 95% CI, 0.95-1.01) but were associated with a lower occurrence of vitreous hemorrhages (HR, 0.74; 95% CI, 0.68-0.80), neovascular glaucoma (HR, 0.78; 95% CI, 0.68-0.88), or blindness (HR, 0.77; 95% CI, 0.73-0.82).

CONCLUSIONS AND RELEVANCE: In this cohort study of individuals with T2D, GLP-1 RA use was associated with a modestly increased risk of incident DR; however, fewer patients experienced sight-threatening DR complications, including blindness, even among those with preexisting DR. These findings suggest that all patients with T2D treated with GLP-1 RAs, regardless of preexisting DR, should be regularly screened and monitored for potential complications of T2D.

PMID:40788647 | DOI:10.1001/jamanetworkopen.2025.26321

JAMA Netw Open. 2025 Aug 1;8(8):e2526353. doi: 10.1001/jamanetworkopen.2025.26353.

ABSTRACT

IMPORTANCE: Characterizing population-level changes in type 1 diabetes (T1D) management can inform public health policies and interventions.

OBJECTIVE: To characterize trends and disparities in glycemic control and use of diabetes technology among US youths and adults with T1D.

DESIGN, SETTING, AND PARTICIPANTS: This serial, cross-sectional analysis used the Optum Labs Data Warehouse, a national, deidentified database of electronic health records, to identify US youths (aged <18 years) and adults (aged ≥18 years) with T1D. Data were obtained from records from January 1, 2009, to December 31, 2023.

EXPOSURES: Calendar years divided into 3-year study periods from 2009 to 2011 to 2021 to 2023.

MAIN OUTCOMES AND MEASURES: Glycemic control (mean hemoglobin A1c level, <7%) and use of diabetes technology (continuous glucose monitoring systems and/or insulin pumps) were defined using laboratory data and prescriptions, procedures, and diagnoses codes from electronic health records.

RESULTS: A total of 186 590 participants with T1D was identified (mean [SD] age, 40 [19] years; 96 766 [52%] male; 12 493 [7%] Hispanic, 2819 [2%] non-Hispanic Asian, 21 459 [12%] non-Hispanic Black, and 141 847 [76%] non-Hispanic White). Of these, 26 853 participants were youths (mean [SD] age, 12 [4] years; 14 060 [52%] male; 19 822 [74%] non-Hispanic White) and 159 737 were adults (mean [SD] age, 45 [16] years; 82 706 [52%] male; 122 025 [76%] non-Hispanic White). From the 2009-2011 to 2021-2023 study periods, the prevalence of glycemic control (mean hemoglobin A1c level <7%) increased from 7% (95% CI, 7%-8%) to 19% (95% CI, 19%-20%) in youths (P < .001 for trend) and 21% (95% CI, 21%-22%) to 28% (95% CI, 28%-29%) in adults (P < .001 for trend). During this same period, there was a substantial increase in the percentage of patients using continuous glucose monitoring (4% to 82% for youths; 5% to 57% for adults), insulin pumps (16% to 50% for youths; 11% to 29% for adults), and both devices concurrently (1% to 47% for youths; 1% to 22% for adults) (P < .001 for trend for all). The prevalence of glycemic control and use of diabetes technology were lowest in Hispanic, non-Hispanic Black, and Medicaid-insured youths and adults, and differences persisted or increased over time.

CONCLUSIONS AND RELEVANCE: In this cross-sectional study, there was a rapid increase in the use of diabetes technology and notable improvements in glycemic control among youths and adults with T1D during the past 15 years. Nonetheless, the prevalence of glycemic control remained low, and racial, ethnic, and socioeconomic differences grew over time.

PMID:40788645 | DOI:10.1001/jamanetworkopen.2025.26353