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BACKGROUND: Sleep is thought to play a major role in brain health and general wellbeing. However, few longitudinal studies have explored the relationship between sleep habits and imaging markers of brain health, particularly markers of brain waste clearance such as perivascular spaces (PVS), of neurodegeneration such as brain atrophy, and of vascular disease, such as white matter hyperintensities (WMH). We explore these associations using data collected over 6 years from a birth cohort of older community-dwelling adults in their 70s.METHOD: We analysed brain MRI data from ages 73, 76 and 79 years, and self-reported sleep duration, sleep quality and vascular risk factors from community-dwelling participants in the Lothian Birth Cohort 1936 (LBC1936) study. We calculated sleep efficiency (at age 76), quantified PVS burden (at age 73), and WMH and brain volumes (age 73 to 79), calculated the white matter damage metric, and used structural equation modelling (SEM) to explore associations and potential causative pathways between indicators related to brain waste cleaning (i.e., sleep and PVS burden), brain and WMH volume changes during the 8th decade of life.RESULTS: Lower sleep efficiency was associated with a reduction in normal-appearing white matter (NAWM) volume (β = 0.204, P = 0.009) from ages 73 to 79, but not concurrent volume (i.e. age 76). Increased daytime sleep correlated with less night-time sleep (r = -0.20, P < 0.001), and with increasing white matter damage metric (β = -0.122, P = 0.018) and faster WMH growth (β = 0.116, P = 0.026). Shorter night-time sleep duration was associated with steeper 6-year reduction of NAWM volumes (β = 0.160, P = 0.011). High burden of PVS at age 73 (volume, count, and visual scores), was associated with faster deterioration in white matter: reduction of NAWM volume (β = -0.16, P = 0.012) and increasing white matter damage metric (β = 0.37, P < 0.001) between ages 73 and 79. On SEM, centrum semiovale PVS burden mediated 5% of the associations between sleep parameters and brain changes.CONCLUSION: Sleep impairments, and higher PVS burden, a marker of impaired waste clearance, were associated with faster loss of healthy white matter and increasing WMH in the 8th decade of life. A small percentage of the effect of sleep in white matter health was mediated by the burden of PVS consistent with the proposed role for sleep in brain waste clearance.

Primary care has the potential to be transformed by artificial intelligence (AI) and, in particular, machine learning (ML). This review summarizes the potential of ML and its subsets in influencing two domains of primary care: pre-operative care and screening. ML can be utilized in preoperative treatment to forecast postoperative results and assist physicians in selecting surgical interventions. Clinicians can modify their strategy to reduce risk and enhance outcomes using ML algorithms to examine patient data and discover factors that increase the risk of worsened health outcomes. ML can also enhance the precision and effectiveness of screening tests. Healthcare professionals can identify diseases at an early and curable stage by using ML models to examine medical pictures, diagnostic modalities, and spot patterns that may suggest disease or anomalies. Before the onset of symptoms, ML can be used to identify people at an increased risk of developing specific disorders or diseases. ML algorithms can assess patient data such as medical history, genetics, and lifestyle factors to identify those at higher risk. This enables targeted interventions such as lifestyle adjustments or early screening. In general, using ML in primary care offers the potential to enhance patient outcomes, reduce healthcare costs, and boost productivity.

Micromechanical studies of mitotic chromosomes have revealed them to be remarkably extensible objects and informed early models of mitotic chromosome organization. We use a data-driven, coarsegrained polymer modeling approach, capable of generating ensembles of chromosome structures that are quantitatively consistent with experiments, to explore the relationship between the spatial organization of individual chromosomes and their emergent mechanical properties. In particular, we investigate the mechanical properties of our model chromosomes by axially stretching them. Simulated stretching led to a linear force-extension curve for small strain, with mitotic chromosomes behaving about ten-fold stiffer than interphase chromosomes. Studying the relaxation dynamics we found that chromosomes are viscoelastic solids, with a highly liquid-like, viscous behavior in interphase that becomes solid-like in mitosis. This emergent mechanical stiffness in our model originates from lengthwise compaction, an effective potential capturing the activity of loop-extruding SMC complexes. Chromosomes denature under large strains via unraveling, which is characterized by opening of large-scale folding patterns. By quantifying the effect of mechanical perturbations on the chromosome’s structural features, our model provides a nuanced understanding of in vivo mechanics of chromosomes.

Thioesters are considered to be “energy-rich” functional groups that are susceptible to attack by thiolate and amine nucleophiles while remaining hydrolytically stable at neutral pH, which enables thioester chemistry to take place in an aqueous medium. Thus, the inherent reactivity of thioesters enables their fundamental roles in biology and unique applications in chemical synthesis. Here, we investigate the reactivity of thioesters that mimic acyl-coenzyme A (CoA) species and S-acylcysteine modifications as well as aryl thioesters applied in chemical protein synthesis by native chemical ligation (NCL). We developed a fluorogenic assay format for the direct and continuous investigation of the rate of reaction between thioesters and nucleophiles (hydroxide, thiolate, and amines) under various conditions and were able to recapitulate previously reported reactivity of thioesters. Further, chromatography-based analyses of acetyl- and succinyl-CoA mimics revealed striking differences in their ability to acylate lysine side chains, providing insight into nonenzymatic protein acylation. Finally, we investigated key aspects of native chemical ligation reaction conditions. Our data revealed a profound effect of the tris-(2-carboxyethyl)phosphine (TCEP) commonly used in systems where thiol-thioester exchange occurs, including a potentially harmful hydrolysis side reaction. These data provide insight into the potential optimization of native chemical ligation chemistry.

This study investigates the borrowing and financial behavior of microbusiness owners in Barangay Batinguel, Dumaguete City, Negros Oriental, Philippines, focusing on sari-sari store owners. The research aims to determine their demographic profile, borrowing behavior, financial behavior, and the relationship between their demographic profile and financial and borrowing behavior. A descriptive method was employed, utilizing a self-made questionnaire to collect data from 19 registered sari-sari store owners selected through purposive sampling. Results revealed that the majority of respondents were aged 41 years or older, predominantly female, with family incomes of PHP 10,000 or less. Borrowing behavior varied, with most borrowing 1-2 times per year, and loan amounts ranging from PHP 3,000 to above PHP 10,000. Financial behavior assessments showed that respondents demonstrated a moderate level of financial literacy. The analysis indicated that demographic factors, such as age, sex, family income, educational attainment, years of operation, and monthly sales, influenced the financial behavior of the respondents. The study recommends increased access to financial literacy programs for microbusiness owners and the development of tailored financial support policies by financial institutions and government agencies. Future research should explore other factors affecting borrowing and financial behavior and expand the scope of the study to other regions in the Philippines.

Previous urinary tract infections (UTIs) can predispose one to future infections; however, the underlying mechanisms affecting recurrence are poorly understood. We previously found that UTIs in mice cause differential bladder epithelial (urothelial) remodelling, depending on disease outcome, that impacts susceptibility to recurrent UTI. Here we compared urothelial stem cell (USC) lines isolated from mice with a history of either resolved or chronic uropathogenic Escherichia coli (UPEC) infection, elucidating evidence of molecular imprinting that involved epigenetic changes, including differences in chromatin accessibility, DNA methylation and histone modification. Epigenetic marks in USCs from chronically infected mice enhanced caspase-1-mediated cell death upon UPEC infection, promoting bacterial clearance. Increased Ptgs2os2 expression also occurred, potentially contributing to sustained cyclooxygenase-2 expression, bladder inflammation and mucosal wounding—responses associated with severe recurrent cystitis. Thus, UPEC infection acts as an epi-mutagen reprogramming the urothelial epigenome, leading to urothelial-intrinsic remodelling and training of the innate response to subsequent infection.

OBJECTIVE The coronavirus disease 2019 (COVID-19) pandemic has necessitated the use of telehealth visits (THVs). The effects on neurosurgical practice have not been well characterized, especially concerning new-patient THVs. Therefore, the authors of this study reviewed their institution’s experience with outpatient clinic visits and THVs from before the COVID-19 pandemic to the present to focus on clinical metrics, rates of surgery, and the effects of implementing THVs in order to better understand their implications for clinical practice as more data emerge over time. METHODS The authors reviewed 15,677 consecutive new outpatient in-person visits (IPVs), THVs, and neurosurgical procedures/cases proceeding from their institution between 2018 and 2022 for trends and associations related to THVs. RESULTS Among spine patients, there was no difference in the proportion of encounters that led to surgery (surgical conversion rate) between THVs and IPVs (p = 0.49). Among cranial patients, THVs were negatively associated with conversion (OR 0.73, p = 0.03). On average, patients using THVs lived further from the hospital (p < 0.001); however, the patient catchment area appeared unchanged. The median distance to the hospital among THV patients was counterbalanced by a decreased distance for spine patients pursing IPVs (p < 0.001), with no significant change to case volume. There was no change in distance to the hospital among cranial patients. For both cranial and spine patients, surgical conversion was more likely among those who lived a great distance from the hospital if their initial encounter was an IPV (p = 0.007 and < 0.001, respectively). However, there was no relationship between distance from the hospital and surgical conversion among THV patients (p = 0.565). The availability of THVs did not significantly affect follow-up time (p = 0.837). For new patients at IPVs, there was no difference in time to the operating room between cranial and spine cases; for new patients at THVs, however, time to the operating room was significantly faster for cranial cases than for spine cases (p = 0.0018). CONCLUSIONS Compared to IPVs, THVs lead to decreased surgical conversion for cranial patients but not spine patients. THVs do not appear to increase the catchment area. For patients who live far from the hospital, an IPV is associated with surgical conversion. Surgical conversion is faster following cranial THVs than after spine THVs. THVs did not increase the duration of follow-up.

Background Personal protective equipment (PPE) adversely affects pulmonary gas exchange and may result in systemic hypercapnic hypoxaemia and headache. This study aimed to determine what extent PPE affects cerebral symptoms, global cerebral blood flow, and cognitive functional performance. Methods Higher surgical trainees participated in a randomized, repeated-measures, crossover study, completing 60 min of laparoscopic surgical simulation in both standard operating attire and type 3 PPE. Measurements were collected at baseline and after 60 min of simulation. The primary outcome measure was headache. Headache was examined using the validated visual analogue scale (VAS) and Environmental Symptoms Questionnaire C (ESQ-C), global cerebral blood flow with duplex ultrasonography, and visuospatial and executive gross/fine motor function with grooved peg board (GPB) and laparoscopic bead (LSB) board tasks. Results Thirty-one higher surgical trainees (20 men, 11 women) completed the study. Compared with standard operating attire, PPE increased headache assessment scores (mean(s.d.) VAS score 3.5(5.6) versus 13.0(3.7), P < 0.001; ESQ-C score 1.3(2.0) versus 5.9(5.1), P < 0.001) and was associated with poorer completion times for GPB-D (61.4(12.0) versus 71.1(12.4) s; P = 0.034) and LSB (192.5(66.9) versus 270.7(135.3) s; P = 0.025) tasks. Wearing PPE increased heart rate (82.5(13.6) versus 93.5(13.0) beats/min; P = 0.022) and skin temperature (36.6(0.4) versus 37.1(0.5)°C; P < 0.001), but decreased peripheral oxygen saturation (97.9(0.8) versus 96.8(1.0) per cent; P < 0.001). Female higher surgical trainees exhibited higher peripheral oxygen saturation across all conditions. No differences were observed in global cerebral blood flow as a function of attire, time or sex. Conclusion Despite no marked changes in global cerebral blood flow, type 3 PPE was associated with increased headache scores and cerebral symptoms (VAS and ESQ-C) alongside impaired executive motor function highlighting the clinical implications of PPE-induced impairment for cognitive–clinical performance.

We have recently reported the synthesis and application of boron–nitrogen dihydroindeno[1,2-b]fluorene derivatives as acceptors in organic photovoltaic devices. Their modest observed efficiencies may be related to the properties of their reduced congeners. In this work, we report two new members of this family of compounds prepared via the electrophilic borylation of 2,5-di- p-tolylpyrazine followed by an arylation of the boron center with ZnAr2 reagents. Two derivatives, 1 (Ar = 2,4,6-F3C6H2) and 2 (Ar = C6F5) were synthesized, and their radical anions, 1•− and 2•−, were formed via chemical reductions with CoCp*2 and CoCp2, respectively. Through comparison of structural parameters, as well as spectroscopic and computational data, the unpaired electron in the radical anions is localized in the planar core of the molecule, and dimerization is disfavored as a result. However, unlike the neutral starting materials, 1•− and 2•− are reactive toward ambient atmosphere. These observations suggest that the reduced compounds are stable toward intrinsic degradation pathways but subject to extrinsic degradation in device operation.

Chrimson is a red-light absorbing channelrhodopsin useful for deep-tissue optogenetics applications. Here, we present the Chrimson reaction dynamics from femtoseconds to seconds, analyzed with target analysis methods to disentangle spectrally and temporally overlapping excited- and product-state dynamics. We found multiple phases ranging from ≈100 fs to ≈20 ps in the excited-state decay, where spectral features overlapping with stimulated emission components were assigned to early dynamics of K-like species on a 10 ps time scale. Selective excitation at the maximum or the blue edge of the absorption spectrum resulted in spectrally distinct but kinetically similar excited-state and product-state species, which gradually became indistinguishable on the μs to 100 μs time scales. Hence, by removing specific protein conformations within an inhomogeneously broadened ensemble, we resolved slow protein backbone and amino acid side-chain motions in the dark that underlie inhomogeneous broadening, demonstrating that the latter represents a dynamic interconversion between protein substates.

Modeling the effects of the terrestrial carbon sink in the future depends upon not just current-day land use and land cover (LULC) but also the legacy of past LULC change (LULCC), which is often not considered. The age distribution of trees in the forest depends upon the history of past disturbances, while the nutrients in the soil depend upon past LULC. Thus, establishing the correct initial state of the vegetation and soil is crucial to model accurately the effect of biogeochemical cycling with environmental change in the future. This study models the effects of LULCC from 1750 to 2014 using the land-use harmonization dataset (LUH2) of land-use transitions with the terrestrial ecosystems model (TEM) for the conterminous US. Modeled LULC include plant functional types (PFTs) of potential vegetation, as well as managed cropland, pastureland, and urban areas. LULCC is treated using a cohort approach, in which a separate cohort occurs every year there is a land-use transition, thereby ensuring proper age structure of forests and regrowth with the correct soil nutrients. From 2000–2014 the modeled net ecosystem productivity (NEP) is 989 TgC yr−1 for the conterminous US but only −15 TgC yr−1 if accounting for carbon lost from land-use transitions and management. The hypothesis is that the initial state of the vegetation and soils significantly affects the future state of the terrestrial carbon sink. In this study, LULC remains constant in the future, with the NCAR CCSM4 RCP8.5 climate used to force the TEM-Hydro model. The following experiments are run from 2015 to 2100, including (a) restarting from existing cohorts in 2014 (RESTART), (b) reinitializing in 2015 based on condensing the cohorts for each PFT into a single cohort (CONDENSED), and (c) restarting from average cohort conditions for each PFT (AVERAGE). The NEP is too low when using condensed cohorts without reinitializing due to a larger increase in heterotrophic respiration (Rh) resulting from the assumption of mature forests. The carbon stocks are larger than using all the cohorts if condensed cohorts are reinitialized due to the assumption of mature, equilibrated forests. Where nitrogen-limited, forest regrowth is enhanced if regrowth starts from more nutrient-rich conditions. Water fluxes are dominated by environmental factors but can be slightly dependent upon the underlying carbon dynamics. It is therefore necessary to account for past disturbances when modeling future changes in carbon dynamics.

Frailty is a clinical syndrome associated with slow recovery after vascular surgery. However, the degree and length of functional impairment frail patients experience after surgery is unclear. The objective of this study was to prospectively measure changes in functional status among frail and non-frail patients undergoing a spectrum of different vascular surgery procedures.Patients consented to undergo elective minor and major vascular surgery procedures at an academic medical center between May 2018 and March 2019 were prospectively identified. Prior to surgery, all patients underwent provider assessment of frailty using the validated Clinical Frailty Scale (CFS), as well as baseline assessment of functional status using the Katz Activities of Daily Living (ADL) index and the Lawton Instrumental Activities of Daily Living (iADL) index. These same instruments were used to evaluate each patient's functional status at 2-weeks, 1-month, 1-year, and 2-year time points following surgery. Changes in iADL and ADL scores among frail (CFS ≥5) and non-frail patients were compared using paired Wilcoxon signed-rank tests and logistic regression models.A total of 126 patients were assessed before and after minor (55%) and major (45%) vascular procedures, of which 43 patients (34%) were determined to be frail prior to surgery. Frail patients were older and more likely than non-frail patients to have medical comorbidities including chronic kidney disease, chronic obstructive pulmonary disease, or diabetes (all P .05). When compared with the non-frail cohort, frail patients had significantly lower ADL and iADL scores before surgery and experienced a greater decline in ability to independently complete ADL and iADL activities after surgery that was sustained at 2 years (P .05 and P .001, respectively). After risk-adjustment, frailty was associated with an increased likelihood of decline in ADLs (odds ratio, 5.4; 95% confidence interval, 1.9-15.4; P .05) and iADLs (odds ratio, 6.3; 95% confidence interval, 2.6-15.1; P .001) at 2 years following surgery.Frail patients experience a significant decline in ability to perform ADL and iADLs that persists 2 years following vascular surgery. These data highlight the degree of functional decline occurring immediately following surgery, as well as risk for long-term, sustained impairment that should be shared with frail patients before undergoing a procedure.

The effect of small changes in the specimen-to-detector distance on the unit-cell parameters is examined for synchrotron powder diffraction in Debye–Scherrer (transmission) geometry with a flat area detector. An analytical correction equation is proposed to fix the shift in 2θ values due to specimen capillary displacement. This equation does not require the use of an internal reference material, is applied during the Rietveld refinement step, and is analogous to the specimen-displacement correction equations for Bragg–Brentano and curved-detector Debye–Scherrer geometry experiments, but has a different functional form. The 2θ correction equation is compared with another specimen-displacement correction based on the use of an internal reference material in which new integration and calibration parameters of area-detector images are determined. Example data sets showing the effect of a 3.3 mm specimen displacement on the unit-cell parameters for 25°C CeO2, including both types of displacement correction, are described. These experiments were performed at powder X-ray diffraction beamlines at the National Synchrotron Light Source II at Brookhaven National Laboratory and the Advanced Photon Source at Argonne National Laboratory.

Hypodiploid acute lymphoblastic leukemia (ALL) is an aggressive blood cancer with a poor prognosis despite intensive chemotherapy or stem cell transplant. Children and adolescents with positive end-of-induction minimal residual disease have an overall survival lower than 30%. However, data regarding therapeutic alternatives for this disease is nearly nonexistent, emphasizing the critical need for new or adjunctive therapies that can improve outcomes. We previously reported on the therapeutic efficacy of venetoclax (ABT-199) in hypodiploid B-lineage ALL but with limitations as monotherapy. In this study, we set out to identify drugs enhancing the anti-leukemic effect of venetoclax in hypodiploid ALL. Using a highthroughput drug screen, we identified dinaciclib, a cyclin-dependent kinase inhibitor that worked synergistically with venetoclax to induce cell death in hypodiploid cell lines. This combination eradicated leukemic blasts within hypodiploid ALL patient-derived xenografts mice with low off-target toxicity. Our findings suggest that dual inhibition of BCL-2 (venetoclax) and CDK9/MCL-1 (dinaciclib) is a promising therapeutic approach in hypodiploid ALL, warranting further investigation to inform clinical trials in this high-risk patient population.

To determine the association between ovarian reserve biomarkers and future fertility among late reproductive-age women.Cohort study of participants enrolled in Time to Conceive (TTC), a time-to-pregnancy cohort study of the ovarian reserve biomarkers.Community.Women aged 30-44 years without a history of infertility who provided a blood sample at enrollment in TTC and who agreed to future follow-up.Not applicable.The primary outcomes were probability of achieving a live birth3 years after enrollment in TTC, diagnosis of infertility at any time, and time-to-pregnancy in future pregnancy attempts.Women with diminished ovarian reserve, defined as those with an antimüllerian hormone (AMH) level0.7 ng/mL or follicle-stimulating hormone (FSH) level ≥10 mIU/mL, did not have low risk of future live birth (relative risk [RR], 1.32; 95% confidence interval [CI], 0.95-1.83 and RR, 1.28; 95% CI, 0.97-1.70, respectively) compared with women with normal ovarian reserve after adjusting for age at blood draw, race, obesity, use of hormonal contraception, and year of enrollment in original study. Among women in the cohort that attempted to conceive, there was not a significant association between diminished ovarian reserve, as measured by AMH or FSH, and risk of future infertility (RR, 0.65; 95% CI, 0.21-2.07 and RR,1.69; 95% CI, 0.86-3.31, respectively). Similarly, there was no association between AMH and FSH levels and future fecundability (fecundability ratio, 0.97; 95% CI, 0.59, 1.60; and fecundability ration, 0.86; 95% CI, 0.55-1.36, respectively).Diminished ovarian reserve is not associated with reduced future reproductive capacity. Given the lack of association, women should be cautioned regarding use biomarkers of ovarian reserve as predictors of their future reproductive capacity.

Quaternized nanocellulose (QNC), synthesized in this study, showed improved removal of both short chain and long chain PFAS by increasing the electrostatic interactions between the anionic functional groups of PFAS and the cationic quaternary ammonium groups of QNC.

Blue foods, sourced in aquatic environments, are important for the economies, livelihoods, nutritional security and cultures of people in many nations. They are often nutrient rich1, generate lower emissions and impacts on land and water than many terrestrial meats2, and contribute to the health3, wellbeing and livelihoods of many rural communities4. The Blue Food Assessment recently evaluated nutritional, environmental, economic and justice dimensions of blue foods globally. Here we integrate these findings and translate them into four policy objectives to help realize the contributions that blue foods can make to national food systems around the world: ensuring supplies of critical nutrients, providing healthy alternatives to terrestrial meat, reducing dietary environmental footprints and safeguarding blue food contributions to nutrition, just economies and livelihoods under a changing climate. To account for how context-specific environmental, socio-economic and cultural aspects affect this contribution, we assess the relevance of each policy objective for individual countries, and examine associated co-benefits and trade-offs at national and international scales. We find that in many African and South American nations, facilitating consumption of culturally relevant blue food, especially among nutritionally vulnerable population segments, could address vitamin B12 and omega-3 deficiencies. Meanwhile, in many global North nations, cardiovascular disease rates and large greenhouse gas footprints from ruminant meat intake could be lowered through moderate consumption of seafood with low environmental impact. The analytical framework we provide also identifies countries with high future risk, for whom climate adaptation of blue food systems will be particularly important. Overall the framework helps decision makers to assess the blue food policy objectives most relevant to their geographies, and to compare and contrast the benefits and trade-offs associated with pursuing these objectives.