Human population history at the crossroads of East and Southeast Asia since 11,000 years ago.

Past human genetic diversity and migration between southern China and Southeast Asia have not been well characterized, in part due to poor preservation of ancient DNA in hot and humid regions. We sequenced 31 ancient genomes from southern China (Guangxi and Fujian), including two ∼12,000- to 10,000-year-old individuals representing the oldest humans sequenced from southern China. We discovered a deeply diverged East Asian ancestry in the Guangxi region that persisted until at least 6,000 years ago. We found that ∼9,000- to 6,000-year-old Guangxi populations were a mixture of local ancestry, southern ancestry previously sampled in Fujian, and deep Asian ancestry related to Southeast Asian Hòabìnhian hunter-gatherers, showing broad admixture in the region predating the appearance of farming. Historical Guangxi populations dating to ∼1,500 to 500 years ago are closely related to Tai-Kadai and Hmong-Mien speakers. Our results show heavy interactions among three distinct ancestries at the crossroads of East and Southeast Asia.

Neuromodulator Signaling Bidirectionally Controls Vesicle Numbers in Human Synapses.

Neuromodulators bind to pre- and postsynaptic G protein-coupled receptors (GPCRs), are able to quickly change intracellular cyclic AMP (cAMP) and Ca2+ levels, and are thought to play important roles in neuropsychiatric and neurodegenerative diseases. Here, we discovered in human neurons an unanticipated presynaptic mechanism that acutely changes synaptic ultrastructure and regulates synaptic communication. Activation of neuromodulator receptors bidirectionally controlled synaptic vesicle numbers within nerve terminals. This control correlated with changes in the levels of cAMP-dependent protein kinase A-mediated phosphorylation of synapsin-1. Using a conditional deletion approach, we reveal that the neuromodulator-induced control of synaptic vesicle numbers was largely dependent on synapsin-1. We propose a mechanism whereby non-phosphorylated synapsin-1 "latches" synaptic vesicles to presynaptic clusters at the active zone. cAMP-dependent phosphorylation of synapsin-1 then removes the vesicles. cAMP-independent dephosphorylation of synapsin-1 in turn recruits vesicles. Synapsin-1 thereby bidirectionally regulates synaptic vesicle numbers and modifies presynaptic neurotransmitter release as an effector of neuromodulator signaling in human neurons.

Shifting fire regimes cause continent-wide transformation of threatened species habitat.

Human actions are causing widespread increases in fire size, frequency, and severity in diverse ecosystems globally. This alteration of fire regimes is considered a threat to numerous animal species, but empirical evidence of how fire regimes are shifting within both threatened species' ranges and protected areas is scarce, particularly at large spatial and temporal scales. We used a big data approach to quantify multidecadal changes in fire regimes in southern Australia from 1980 to 2021, spanning 415 reserves (21.5 million ha) and 129 threatened species' ranges including birds, mammals, reptiles, invertebrates, and frogs. Most reserves and threatened species' ranges within the region have experienced declines in unburnt vegetation (≥30 y without fire), increases in recently burnt vegetation (≤5 y since fire), and increases in fire frequency. The mean percentage of unburnt vegetation within reserves declined from 61 to 36% (1980 to 2021), whereas the mean percentage of recently burnt vegetation increased from 20 to 35%, and mean fire frequency increased by 32%, with the latter two trends primarily driven by the record-breaking 2019 to 2020 fire season. The strongest changes occurred for high-elevation threatened species, and reserves of high elevation, high productivity, and strong rainfall decline, particularly in the southeast of the continent. Our results provide evidence for the widely held but poorly tested assumption that threatened species are experiencing widespread declines in unburnt habitat and increases in fire frequency. This underscores the imperative for developing management strategies that conserve fire-threatened species in an increasingly fiery future.

Transcription-coupled H3.3 recycling: A link with chromatin states.

Histone variant H3.3 is incorporated into chromatin throughout the cell cycle and even in non-cycling cells. This histone variant marks actively transcribed chromatin regions with high nucleosome turnover, as well as silent pericentric and telomeric repetitive regions. In the past few years, significant progress has been made in our understanding of mechanisms involved in the transcription-coupled deposition of H3.3. Here we review how, during transcription, new H3.3 deposition intermingles with the fate of the old H3.3 variant and its recycling. First, we describe pathways enabling the incorporation of newly synthesized vs old H3.3 histones in the context of transcription. We then review the current knowledge concerning differences between these two H3.3 populations, focusing on their PTMs composition. Finally, we discuss the implications of H3.3 recycling for the maintenance of the transcriptional state and underline the emerging importance of H3.3 as a potent epigenetic regulator for both maintaining and switching a transcriptional state.

Limbic-predominant age-related TDP-43 encephalopathy in the oldest old: a population-based study.

Population-based cohort studies are essential for understanding the pathological basis of dementia in older populations. Previous studies have shown that limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) increases with age, but there have been only a few studies, which have investigated this entity in a population-based setting. Here we studied the frequency of LATE-NC and its associations with other brain pathologies and cognition in a population aged ≥ 85 years. The population-based Vantaa 85+ study cohort includes all 601 individuals aged ≥ 85 years who were living in Vantaa, Finland in 1991. A neuropathological examination was performed on 304 subjects (50.5%) and LATE-NC staging was possible in 295 of those. Dementia status and Mini-Mental State Examination (MMSE) scores were defined in the baseline study and 3 follow-ups (1994-99). The LATE-NC stages were determined based on TDP-43 immunohistochemistry, according to recently updated recommendations. Arteriolosclerosis was digitally assessed by calculating the average sclerotic index of five random small arterioles in amygdala and hippocampal regions, and frontal white matter. The association of LATE-NC with arteriolosclerosis and previously determined neuropathological variables including Alzheimer's disease neuropathological change (ADNC), Lewy-related pathology (LRP), hippocampal sclerosis (HS), and cerebral amyloid angiopathy (CAA), and cognitive variables were analysed by Fisher's exact test, linear and logistic regression (univariate and multivariate) models. LATE-NC was found in 189 of 295 subjects (64.1%). Stage 2 was the most common (28.5%) and stage 3 the second most common (12.9%), whereas stages 1a, 1b and 1c were less common (9.5%, 5.1% and 8.1%, respectively). Stages 1a (P < 0.01), 2 (P < 0.001) and 3 (P < 0.001) were significantly associated with dementia and lower MMSE scores. LATE-NC was associated with ADNC (P < 0.001), HS (P < 0.001), diffuse neocortical LRP (P < 0.002), and arteriolosclerosis in amygdala (P < 0.02). In most cases LATE-NC occurred in combination alongside other neuropathological changes. There were only six subjects with dementia who had LATE-NC without high levels of ADNC or LRP (2% of the cohort, 3% of the cases with dementia), and five of these had HS. In all multivariate models, LATE-NC was among the strongest independent predictors of dementia. When LATE-NC and ADNC were assessed in a multivariate model without other dementia-associated pathologies, the attributable risk was higher for LATE-NC than ADNC (24.2% vs. 18.6%). This population-based study provides evidence that LATE-NC is very common and one of the most significant determinants of dementia in the general late-life aged population.

Metformin in elderly type 2 diabetes mellitus: dose-dependent dementia risk reduction.

This study aimed to investigate the controversial association between metformin use and diabetes-associated dementia in elderly patients with type 2 diabetes mellitus (T2DM) and evaluate the potential protective effects of metformin, as well as its intensity of use and dose-dependency, against dementia in this population. The study used a time-dependent Cox hazards model to evaluate the effect of metformin use on the incidence of dementia. The case group included elderly patients with T2DM (≥60 years old) who received metformin, while the control group consisted of elderly patients with T2DM who did not receive metformin during the follow-up period. Our analysis revealed a significant reduction in the risk of dementia among elderly individuals using metformin, with an adjusted hazard ratio of 0.34 (95% confidence interval: 0.33 to 0.36). Notably, metformin users with a daily intensity of 1 defined daily dose (DDD) or higher had a lower risk of dementia, with an adjusted hazard ratio (95% confidence interval) of 0.46 (0.22 to 0.6), compared to those with a daily intensity of <1 DDD. Additionally, the analysis of cumulative DDDs of metformin showed a dose-response relationship, with progressively lower adjusted hazard ratio across quartiles (0.15, 0.21, 0.28, and 0.53 for quartiles 4, 3, 2 and 1, respectively), compared to never metformin users (P for trend < 0.0001). Metformin use in elderly patients with T2DM is significantly associated with a substantial reduction in the risk of dementia. Notably, the protective effect of metformin demonstrates a dose-dependent relationship, with higher daily and cumulative dosages of metformin showing a greater risk reduction.

Young human plasma-derived extracellular vesicles rescue and reactivate IL-1ß and TNF-α treated chondrocytes.

Osteoarthritis (OA) is a degenerative disease that affects millions of individuals worldwide. Despite its prevalence, the exact causes and mechanisms behind OA are still not fully understood, resulting in a lack of effective treatments to slow down or halt disease progression. Recent research has discovered that extracellular vesicles (EVs) present in the circulation of young mice have a remarkable ability to activate musculoskeletal stem cells in elderly mice. Conversely, EVs derived from elderly mice do not exhibit the same potential, indicating that EVs obtained from young individuals may hold promise to activate aging cells in degenerative tissue. However, it remains unknown whether EVs derived from young individuals can also address cartilage degeneration caused by aging. In this study, we first evaluated EVs derived from young human plasma (YEVs) and EVs derived from old human plasma (OEVs) in an in vitro experiment using chondrocytes. The results revealed that YEVs effectively stimulated chondrocyte proliferation and migration, while OEVs from old plasma did not exhibit a similar effect. Given that OA represents a more complex inflammatory microenvironment, we further determine whether the benefits of YEVs on chondrocytes can be maintained in this context. Our findings indicate that YEVs have the ability to positively regulate chondrocyte function and protect them against apoptosis induced by IL-1ß and TNF-α in an in vitro OA model. Furthermore, we discovered that lyophilized EVs could be stored under mild conditions without any alterations in their physical characteristics. Considering the exceptional therapeutic effects and the wide availability of EVs from young plasma, they hold significant promise as a potential approach to activate chondrocytes and promote cartilage regeneration in early-stage OA.

Physiological determinants of mechanical efficiency during advanced ageing and disuse.

This study aimed to determine which physiological factors impact net efficiency (ηnet) in oldest-old individuals at different stages of skeletal muscle disuse. To this aim, we examined ηnet, central haemodynamics, peripheral circulation, and peripheral factors (skeletal muscle fibre type, capillarization and concentration of mitochondrial DNA [mtDNA]). Twelve young (YG; 25 ± 2 years), 12 oldest-old mobile (OM; 87 ± 3 years), and 12 oldest-old immobile (OI; 88 ± 4 years) subjects performed dynamic knee extensor (KE) and elbow flexors (EF) exercise. Pulmonary oxygen uptake, photoplethysmography, Doppler ultrasound and muscle biopsies of the vastus lateralis and biceps brachii were used to assess central and peripheral adaptations to advanced ageing and disuse. Compared to the YG (12.1 ± 2.4%), the ηnet of lower-limb muscle was higher in the OM (17.6 ± 3.5%, P < 0.001), and lower in the OI (8.9 ± 1.9%, P < 0.001). These changes in ηnet during KE were coupled with significant peripheral adaptations, revealing strong correlations between ηnet and the proportion of type I muscle fibres (r = 0.82), as well as [mtDNA] (r = 0.77). No differences in ηnet were evident in the upper-limb muscles between YG, OM and OI. In view of the differences in limb-specific activity across the lifespan, these findings suggest that ηnet is reduced by skeletal muscle inactivity and not by chronological age, per se. Likewise, this study revealed that the age-related changes in ηnet are not a consequence of central or peripheral haemodynamic adaptations, but are likely a product of peripheral changes related to skeletal muscle fibre type and mitochondrial density. KEY POINTS: Although the effects of ageing and muscle disuse deeply impact the cardiovascular and skeletal muscle function, the combination of these factors on the mechanical efficiency are still a matter of debate. By measuring both upper- and lower-limb muscle function, which experience differing levels of disuse, we examined the influence of central and peripheral haemodynamics, and skeletal muscle factors linked to mechanical efficiency. Across the ages and degree of disuse, upper-limb muscles exhibited a preserved work economy. In the legs the oldest-old without mobility limitations exhibited an augmented mechanical efficiency, which was reduced in those with an impairment in ambulation. These changes in mechanical efficiency were associated with the proportion of type I muscle fibres. Recognition that the mechanical efficiency is not simply age-dependent, but the consequence of inactivity and subsequent skeletal muscle changes, highlights the importance of maintaining physical activity across the lifespan.

Maize miRNAs and their putative target genes involved in chilling stress response in 5-day old seedlings.

BACKGROUND: In the context of early sowing of maize as a promising adaptation strategy that could significantly reduce the negative effects of climate change, an in-depth understanding of mechanisms underlying plant response to low-temperature stress is demanded. Although microRNAs (miRNAs) have been recognized as key regulators of plant stress response, research on their role in chilling tolerance of maize during early seedling stages is scarce. Therefore, it is of great significance to explore chilling-responsive miRNAs, reveal their expression patterns and associated target genes, as well as to examine the possible functions of the conserved and novel miRNAs. In this study, the role of miRNAs was examined in 5d-old maize seedlings of one tolerant and one sensitive inbred line exposed to chilling (10/8 °C) stress for 6 h and 24 h, by applying high throughput sequencing. RESULTS: A total of 145 annotated known miRNAs belonging to 30 families and 876 potentially novel miRNAs were identified. Differential expression (DE) analysis between control and stress conditions identified 98 common miRNAs for both genotypes at one time point and eight miRNAs at both time points. Target prediction and enrichment analysis showed that the DE zma-miR396, zma-miR156, zma-miR319, and zma-miR159 miRNAs modulate growth and development. Furthermore, it was found that several other DE miRNAs were involved in abiotic stress response: antioxidative mechanisms (zma-miR398), signal transduction (zma-miR156, zma-miR167, zma-miR169) and regulation of water content (zma-miR164, zma-miR394, zma-miR396). The results underline the zma-miRNAs involvement in the modulation of their target genes expression as an important aspect of the plant's survival strategy and acclimation to chilling stress conditions. CONCLUSIONS: To our understanding, this is the first study on miRNAs in 5-d old seedlings' response to chilling stress, providing data on the role of known and novel miRNAs post-transcriptional regulation of expressed genes and contributing a possible platform for further network and functional analysis.

Effects of sleep quality on diurnal variation of brain volume in older adults: A retrospective cross-sectional study.

AIM: Brain volume is influenced by several factors that can change throughout the day. In addition, most of these factors are influenced by sleep quality. This study investigated diurnal variation in brain volume and its relation to overnight sleep quality. METHODS: We enrolled 1,003 healthy Koreans without any psychiatric disorders aged 60 years or older. We assessed sleep quality and average wake time using the Pittsburgh Sleep Quality Index, and divided sleep quality into good, moderate, and poor groups. We estimated the whole and regional brain volumes from three-dimensional T1-weighted brain MRI scans. We divided the interval between average wake-up time and MRI acquisition time (INT) into tertile groups: short (INT1), medium (INT2), and long (INT3). RESULTS: Whole and regional brain volumes showed no significance with respect to INT. However, the `interaction between INT and sleep quality showed significance for whole brain, cerebral gray matter, and cerebrospinal fluid volumes (p < .05). The INT2 group showed significantly lower volumes of whole brain, whole gray matter, cerebral gray matter, cortical gray matter, subcortical gray matter, and cerebrospinal fluid than the INT1 and INT3 groups only in the individuals with good sleep quality. CONCLUSION: Human brain volume changes significantly within a day associated with overnight sleep in the individuals with good sleep quality.

Serosurvey of Chikungunya Virus in Old World Fruit Bats, Senegal, 2020-2022.

We conducted a cross-sectional serosurvey for chikungunya virus (CHIKV) exposure in fruit bats in Senegal during 2020-2023. We found that 13.3% (89/671) of bats had CHIKV IgG; highest prevalence was in Eidolon helvum (18.3%, 15/82) and Epomophorus gambianus (13.7%, 63/461) bats. Our results suggest these bats are naturally exposed to CHIKV.

Everything OLD is new again: How structural, functional, and bioinformatic advances have redefined a neglected nuclease family.

Overcoming lysogenization defect (OLD) proteins are a conserved family of ATP-powered nucleases that function in anti-phage defense. Recent bioinformatic, genetic, and crystallographic studies have yielded new insights into the structure, function, and evolution of these enzymes. Here we review these developments and propose a new classification scheme to categorize OLD homologs that relies on gene neighborhoods, biochemical properties, domain organization, and catalytic machinery. This taxonomy reveals important similarities and differences between family members and provides a blueprint to contextualize future in vivo and in vitro findings. We also detail how OLD nucleases are related to PARIS and Septu anti-phage defense systems and discuss important mechanistic questions that remain unanswered.

Incidence and risk factors of prostate cancer among the Northern and Eastern parts of the United Arab Emirates population.

BACKGROUND: Prostate cancer (PCa) is a prevalent disease worldwide. However, the incidence and patient-specific risk factors of PCa in the Middle East, specifically in the United Arab Emirates, have not been previously reported. METHODS: We conducted a retrospective cohort study on 2377 men diagnosed with either benign prostatic hyperplasia (BPH) or PCa in the Northern and Eastern regions of the United Arab Emirates, excluding the Western part, which includes Abu Dhabi. The study spanned from January 2012 and December 2021. To calculate the PCa incidence rate, we utilized the world age-standardized incidence rates (W-ASIR) categorized by age groups. Patient-specific risk factors of PCa were identified through a multivariate logistic regression analysis of clinical data. RESULTS: A total of 247 cases of PCa and 2130 cases of BPH were included in the study. In our cohort, the W-ASIR for PCa was 21.3 per 100,000 men. The incidence of PCa showed an increasing trend with age, with the highest incidence observed among men aged 70 years and older. Accordingly, multivariate analysis revealed that age over 70 was associated with an increased risk of PCa (OR: 2.546, 95% confidence interval [CI]: 1.892-3.425, p < 0.01). On the other hand, preexisting conditions such as hypertension and diabetes mellitus were found to lower the risk of PCa (OR: 0.222, 95% CI: 0.163-0.302, p < 0.001) and (OR: 0.364, 95% CI: 0.205-0.648, p < 0.001), respectively. Additionally, metformin intake was associated with a reduced risk of PCa (OR: 0.385, 95% CI: 0.190-0.782, p = 0.008); while insulin usage increased the risk of PCa (OR: 2.586, 95% CI: 1.539-4.344, p < 0.001). Anti-BPH medications such as phosphodiesterase inhibitors (OR: 0.223, 95% CI: 0.069-0.723, p = 0.012) or 5-α reductase (OR: 0.206, 95% CI: 0.110-0.389, p < 0.000), were found to lower the risk of PCa. CONCLUSION: The findings underscore the high incidence of PCa in the United Arab Emirates, with age being a significant factor. Furthermore, the study highlights the influence of certain comorbidities and medications on the risk of developing PCa within the United Arab Emirates population.

Soil fungal community has higher network stability than bacterial community in response to warming and nitrogen addition in a subtropical primary forest.

Global change factors are known to strongly affect soil microbial community function and composition. However, as of yet, the effects of warming and increased anthropogenic nitrogen deposition on soil microbial network complexity and stability are still unclear. Here, we examined the effects of experimental warming (3°C above ambient soil temperature) and nitrogen addition (5 g N m-2 year-1) on the complexity and stability of the soil microbial network in a subtropical primary forest. Compared to the control, warming increased |negative cohesion|:positive cohesion by 7% and decreased network vulnerability by 5%; nitrogen addition decreased |negative cohesion|:positive cohesion by 10% and increased network vulnerability by 11%. Warming and decreased soil moisture acted as strong filtering factors that led to higher bacterial network stability. Nitrogen addition reduced bacterial network stability by inhibiting soil respiration and increasing resource availability. Neither warming nor nitrogen addition changed fungal network complexity and stability. These findings suggest that the fungal community is more tolerant than the bacterial community to climate warming and nitrogen addition. The link between bacterial network stability and microbial community functional potential was significantly impacted by nitrogen addition and warming, while the response of soil microbial network stability to climate warming and nitrogen deposition may be independent of its complexity. Our findings demonstrate that changes in microbial network structure are crucial to ecosystem management and to predict the ecological consequences of global change in the future. IMPORTANCE: Soil microbes play a very important role in maintaining the function and health of forest ecosystems. Unfortunately, global change factors are profoundly affecting soil microbial structure and function. In this study, we found that climate warming promoted bacterial network stability and nitrogen deposition decreased bacterial network stability. Changes in bacterial network stability had strong effects on bacterial community functional potentials linked to metabolism, nitrogen cycling, and carbon cycling, which would change the biogeochemical cycle in primary forests.

Mothers of twins had higher old-age survival than mothers of singletons in Estonian 19th-century birth cohorts.

STUDY QUESTION: Do the mothers of twins and singletons differ regarding post-partum and old-age mortality? SUMMARY ANSWER: Twin deliveries were associated with higher post-partum maternal mortality than singleton deliveries, but the lifetime post-partum mortality risk was similar for mothers of twins and singletons; survival of twinners was higher than survival of the mothers of singletons after the 67th lifespan percentile. WHAT IS KNOWN ALREADY: Twinning is typically associated with higher post-partum maternal mortality. The evidence about whether twinning incurs long-term survival costs of reproduction or is a trait pertinent to long-lived women is scarce and contradictory. STUDY DESIGN, SIZE, DURATION: The study is based on the data of the Estonian Family Register (operating from 1926 to 1943) and involves 5565 mothers of twins and 119 613 mothers of singletons born between 1850 and 1899. The subset for comparing maternal lifespans included 1703-1884 mothers of twins and 19 747-36 690 mothers of singletons. PARTICIPANTS/MATERIALS, SETTING, METHODS: Post-partum maternal mortality was analyzed in the whole sample (including mothers of a single child) by logistic regression. Most of the analyses were performed in samples where each mother of twins was matched against mothers of singletons based on parity (or number of deliveries), urban versus rural and inland versus coastal origin, whether their lifespan was known, date of birth and age at first birth. Lifespans were compared in linear mixed models. Quantile regression was used to analyze age-dependent variations in maternal mortality rates. All models were adjusted for relevant biodemographic covariates. MAIN RESULTS AND THE ROLE OF CHANCE: The twinning rate in the whole sample was 4.4%. During the year after giving birth, maternal mortality for twin deliveries was 0.75% (17/2273) and 0.37% (449/122 750) for singleton deliveries (OR = 2.05, 95% CI = 1.21-3.23). However, the lifetime post-partum mortality risk for mothers of twins (0.51%; 28/5557) and singletons (0.37%; 438/119 466) did not differ significantly (OR = 1.38, 95% CI = 0.91-1.98). The life spans of the mothers of twins and singletons did not differ in matched samples. Past the 67th lifespan percentile, the odds of survival were significantly higher for mothers of twins than mothers of singletons, as indicated by non-overlapping 95% confidence intervals. LIMITATIONS, REASONS FOR CAUTION: Relatively low number of individuals (22 802-28 335) with known age at death in matched datasets due to discontinuation of the register after 1943. WIDER IMPLICATIONS OF THE FINDINGS: The finding that mothers of twins had higher odds of old-age survival than mothers of singletons is consistent with the contention that twinners represent a non-random subset of women whose robust phenotypic quality allows them to outlive the mothers of singletons in old age. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by the Estonian Research Council grants PRG1137, PRG2248, and PSG669. The authors declare no competing interests. TRIAL REGISTRATION NUMBER: N/A.

An inactivated PDCoV vaccine induces robust neutralizing antibodies and immune protection in pigs lasting for three months.

Porcine deltacoronavirus (PDCoV), a novel enteropathogenic coronavirus, causes diarrhea mainly in suckling piglets and has the potential to infect humans. Whereas, there is no commercially available vaccine which can effectively prevent this disease. In this study, to ascertain the duration of immune protection of inactivated PDCoV vaccine, suckling piglets were injected subcutaneously with inactivated PDCoV vaccine using a prime/boost strategy at 3 and 17-day-old. Neutralizing antibody assay showed that the level of the inactivated PDCoV group was still ≥1:64 at three months after prime vaccination. The three-month-old pigs were orally challenged with PDCoV strain CZ2020. Two pigs in challenge control group showed mild to severe diarrhea at 10-11 day-post-challenge (DPC), while the inactivated PDCoV group had no diarrhea. High levels of viral shedding, substantial intestinal villus atrophy, and positive straining of viral antigens in ileum were detected in challenge control group, while the pigs in inactivated PDCoV group exhibited significantly reduced viral load, minor intestinal villi damage and negative straining of viral antigens. These results demonstrated that PDCoV was pathogenic against three-month-old pigs and inactivated PDCoV vaccine can provide effective protection in pigs lasting for three months.

The SIRT3/GSK-3ß/GLUT4 axis might be involved in maternal hypoxia-induced skeletal muscle insulin resistance in old male rat offspring.

Maternal hypoxia is strongly linked to insulin resistance (IR) in adult offspring, and altered insulin signaling for muscle glucose uptake is thought to play a central role. However, whether the SIRT3/GSK-3ß/GLUT4 axis is involved in maternal hypoxia-induced skeletal muscle IR in old male rat offspring has not been investigated. Maternal hypoxia was established from Days 5 to 21 of pregnancy by continuous infusion of nitrogen and air. The biochemical parameters and levels of key insulin signaling molecules of old male rat offspring were determined through a series of experiments. Compared to the control (Ctrl) old male rat offspring group, the hypoxic (HY) group exhibited elevated fasting blood glucose (FBG) (∼30%), fasting blood insulin (FBI) (∼35%), total triglycerides (TGs), and low-density lipoprotein cholesterol (LDL-C), as well as results showing impairment in the glucose tolerance test (GTT) and insulin tolerance test (ITT). In addition, hematoxylin-eosin (HE) staining and transmission electron microscopy (TEM) revealed impaired cellular structures and mitochondria in the longitudinal sections of skeletal muscle from HY group mice, which might be associated with decreased SIRT3 expression. Furthermore, the expression of insulin signaling molecules, such as GSK-3ß and GLUT4, was also altered. In conclusion, the present results indicate that the SIRT3/GSK-3ß/GLUT4 axis might be involved in maternal hypoxia-induced skeletal muscle IR in old male rat offspring.

Associations between prenatal exposure to per- and polyfluoroalkyl substances and plasma immune molecules in three-year-old children in China.

BACKGROUND: Many studies have reported that prenatal exposure to Per- and Polyfluoroalkyl Substances (PFASs) can disrupt immune function. However, little is known about the effects of PFASs on immune molecules. The study analyzed the association between prenatal exposure to mixed and single PFASs and plasma immune molecules in three-year-old children. METHODS: Ten PFASs were measured in umbilical cord serum, while peripheral blood samples were collected at age three to measure immune molecules. Associations between exposure to individual and combined PFASs and immune molecules were analyzed using Generalized Linear Models and Weighted Quantile Sum (WQS) regression. RESULTS: (1) Interleukin-4 (IL-4) increased by 23.85% (95% CI:2.99,48.94) with each doubling of Perfluorooctanoic Acid (PFOA), and Interleukin-6 (IL-6) increased by 39.07% (95%CI:4.06,85.86) with Perfluorotridecanoic Acid (PFTrDA). Elevated PFOA and Perfluorononanoic Acid (PFNA) were correlated with increases of 34.06% (95% CI: 6.41, 70.28) and 24.41% (95% CI: 0.99, 53.27) in Eotaxin-3, respectively. Additionally, the doubling of Perfluorohexane Sulfonic Acid (PFHxS) was associated with a 9.51% decrease in Periostin (95% CI: -17.84, -0.33). (2) The WQS analysis revealed that mixed PFASs were associated with increased IL-6 (ß = 0.37, 95%CI:0.04,0.69), mainly driven by PFTrDA, PFNA, and 8:2 Chlorinated Perfluoroethyl Sulfonamide (8:2 Cl-PFESA). Moreover, mixed PFASs were linked to an increase in Eotaxin-3 (ß = 0.32, 95% CI: 0.09,0.55), primarily influenced by PFOA, PFTrDA, and Perfluorododecanoic Acid (PFDoDA). CONCLUSIONS: Prenatal PFASs exposure significantly alters the levels of immune molecules in three-year-old children, highlighting the importance of understanding environmental impacts on early immune development.

Exploring the Association of Metabolic Syndrome with In-Hospital Survival of Older Patients Hospitalized with COVID-19: Beyond Chronological Age.

BACKGROUND: Despite the variability and complexity of geriatric conditions, few COVID-19 reports of clinical characteristic prognostication provide data specific to oldest-old adults (over age 85), and instead generally report broadly as 65 and older. OBJECTIVE: To examine metabolic syndrome criteria in adults across 25 hospitals with variation in chronological age. DESIGN AND PARTICIPANTS: This cohort study examined 39,564 hospitalizations of patients aged 18 or older with COVID-19 who received inpatient care between March 13, 2020, and February 28, 2022. EXPOSURE: ICU admission and/or in-hospital mortality. MAIN MEASURES: Metabolic syndrome criteria and patient demographics were examined as risk factors. The main outcomes were admission to ICU and hospital mortality. KEY RESULTS: Oldest old patients (≥ 85 years) hospitalized with COVID-19 accounted for 7.0% (2758/39,564) of all adult hospitalizations. They had shorter ICU length of stay, similar overall hospitalization duration, and higher rates of discharge destinations providing healthcare services (i.e., home health, skilled nursing facility) compared to independent care. Chronic conditions varied by age group, with lower proportions of diabetes and uncontrolled diabetes in the oldest-old cohort compared with young-old (65-74 years) and middle-old (75-84 years) groups. Evaluations of the effect of metabolic syndrome and patient demographics (i.e., age, sex, race) on ICU admission demonstrate minimal change in the magnitude of effect for metabolic syndrome on ICU admission across the different models. CONCLUSIONS: Metabolic syndrome measures are important individual predictors of COVID-19 outcomes. Building on prior examinations that metabolic syndrome is associated with death and ARDS across all ages, this analysis supports that metabolic syndrome criteria may be more relevant than chronological age as risk factors for poor outcomes attributed to COVID-19.

Impact of culture media on primary human corneal endothelial cells derived from old donors.

Corneal endothelial dysfunction is a major indication for corneal transplantation. However, a global shortage of donor corneal tissues and risks associated with corneal surgeries have prompted exploration of alternative options, including tissue-engineered grafts or cell injection therapy. Nonetheless, these approaches require a controlled culture of primary human corneal endothelial cells (HCEnCs). Although HCEnCs established from young donors are generally more proliferative and maintain a better phenotype, corneas from old donors are more frequently accessible from eye banks due to a lower corneal endothelial cell count than the necessary threshold required for transplantation. In this study, we investigated various culture media to evaluate which one is the most appropriate for stimulating the proliferation while maintaining cell morphology and function of HCEnCs derived from old donors (age >65 years). All experiments were performed on paired research-grade donor corneas, divided for the conditions under investigation in order to minimize the inter-donor variability. Cell morphology as well as expression of specific markers were assessed at both mRNA (CD166, SLC4A11, ATP1A1, COL8A1, α-SMA, CD44, COL1A1, CDKN2A, LAP2A and LAP2B) and protein (ZO-1, α-SMA, Ki67 and LAP2) levels. Results obtained showed how the Dual Media formulation maintained the hexagonal phenotype more efficiently than Single Medium, but cell size gradually increased with passages. In contrast, the Single Medium provided a higher proliferation rate and a prolonged in vitro expansion but acquired an elongated morphology. To summarize, Single medium and Dual media preserve morphology and functional phenotype of HCEnCs from old donor corneas at low passages while maintenance of the same cell features at high passages remains an active area of research. The new insights revealed within this work become particularly relevant considering that the elderly population a) is the main target of corneal endothelial therapy, b) represents the majority of corneal donors. Therefore, the proper expansion of HCEnCs from old donors is essential to develop novel personalised therapeutic strategies and reduce requirement of human corneal tissues globally.