Theileria orientalis Ikeda infection does not negatively impact growth performance or breeding soundness exam results in young beef bulls at bull test stations.

Introduction: Theileria orientalis Ikeda genotype is an emerging cattle disease in the US. Since 2017, when T. orientalis Ikeda was discovered in beef cattle in two counties in Virginia, cattle infections have risen to include ~67% of Virginia counties and 14 states. Consistent with New Zealand studies, many infected herds in Virginia were >90% positive upon initial testing without overt evidence of infection. Central bull tests present a unique opportunity to study the effects of T. orientalis Ikeda infections, as bulls from multiple source herds are consolidated. The objective of this study was to determine if infection with T. orientalis Ikeda affected the average daily gain (ADG), adjusted yearling weight (AYW) and breeding soundness of bulls at two test stations in Virginia over a period of years. Materials and methods: The bulls were fed and housed similarly to compare their growth performance and breeding soundness. For T. orientalis Ikeda testing, DNA was extracted from whole blood for quantitative polymerase chain reaction. Results: The number of bulls infected with T. orientalis Ikeda at initial delivery to the stations increased significantly over the years studied. Multivariable linear regression models, using Angus bulls from Virginia test stations, indicated no significant effect on ADG or AYW in bulls that became test positive during the test or were positive for the duration, compared to Angus bulls that were negative for the duration. At LOC A, the odds of passing a breeding soundness exam (BSE) were not significantly different for bulls that turned positive during the test or were positive for the duration, compared to bulls that were negative for the duration of the test. At LOC B, bulls that became positive during the test were 2.4 times more likely (95% CI: 1.165-4.995, p = 0.016) to pass their BSE compared to bulls that remained negative throughout the test. Discussion: We do not suppose that an obscured infection of T. orientalis Ikeda is protective for bulls to pass a BSE. However, this study demonstrates an obscured infection of T. orientalis Ikeda does not negatively affect weight gain or achievement of a satisfactory BSE rating at the central bull test stations in Virginia.

4f-Orbital mixing increases the magnetic susceptibility of Cp'3Eu.

Traditional models of lanthanide electronic structure suggest that bonding is predominantly ionic, and that covalent orbital mixing is not an important factor in determining magnetic properties. Here, 4f orbital mixing and its impact on the magnetic susceptibility of Cp'3Eu (Cp' = C5H4SiMe3) was analyzed experimentally using magnetometry and X-ray absorption spectroscopy (XAS) methods at the C K-, Eu M5,4-, and L3-edges. Pre-edge features in the experimental and TDDFT-calculated C K-edge XAS spectra provided unequivocal evidence of C 2p and Eu 4f orbital mixing in the π-antibonding orbital of a' symmetry. The charge-transfer configurations resulting from 4f orbital mixing were identified spectroscopically by using Eu M5,4-edge and L3-edge XAS. Modeling of variable-temperature magnetic susceptibility data showed excellent agreement with the XAS results and indicated that increased magnetic susceptibility of Cp'3Eu is due to removal of the degeneracy of the 7F1 excited state due to mixing between the ligand and Eu 4f orbitals.

Testing Parenting Self-Esteem as an Indicator of Mothers and Fathers Who Are at Risk for Aversive Responses to Disruptive Child Behavior.

Extensive literature demonstrates that parents of children with disruptive behaviors consistently report lower parenting self-esteem (i.e., satisfaction and efficacy) compared to parents of children without disruptive behaviors. However, little is known about whether having low parenting self-esteem results in negative parenting behavior while managing disruptive child behavior, and whether associations vary in strength depending on the clinical significance of the child's disruptive behavior. The current study examines 90 parent couples who were randomly assigned to interact with a 9- to 12-year-old confederate exhibiting either typical or disruptive behaviors. Parenting self-esteem moderated the association between disruptive child behavior and positive parenting behavior, such that mothers with low efficacy had a stronger positive association between disruptive child behavior and positive parenting behaviors. However, fathers with low efficacy had a stronger negative association between disruptive behaviors and positive parenting behavior. Exploratory analyses yielded mixed results. Specifically, mothers with low self-esteem and a child with ADHD had a stronger negative association between disruptive child behaviors and positive parenting compared to mothers who interacted with a confederate or did not have a child with ADHD. Results from the current study extend findings regarding the influence of parenting self-esteem on the association of disruptive child behavior and parenting behaviors, as moderating effects of parenting self-esteem was demonstrated for both mothers and fathers within the study.

How well can young adults and children discriminate between odors?

It is widely believed that people can distinguish between many odors although there is limited empirical evidence. Odor discrimination tasks are employed much less often than other measures of olfaction, but, interestingly, performance is typically ~ 75% correct. This less-than-perfect performance is rarely highlighted, although it suggests that people may not be as good at discriminating odors as is commonly believed. Odor discrimination is understudied in children, and although available evidence suggests that it improves with age, children perform better when the task is simpler. In the present study, we explored odor discrimination in children and young adults with a relatively simple same-different task using common and uncommon odors. We found that children perform as well as young adults, but that overall performance was less than perfect and depended on the odors to be discriminated. We found evidence that ability to discriminate between odors improves as the difference in pleasantness of the odors increases. In a second experiment, we tested this directly by exploring whether odors that differ in pleasantness and edibility, two dimensions that appear to be important in olfactory perception, are easier to discriminate than odors that are the same on those dimensions. We found further evidence that odors that differ in pleasantness are easier to discriminate.

The metabolic cost of breathing for exercise ventilations: effects of age and sex.

Given that there are both sex-based structural differences in the respiratory system and age-associated declines in pulmonary function, the purpose of this study was to assess the effects of age and sex on the metabolic cost of breathing (V̇o2RM) for exercise ventilations in healthy younger and older males and females. Forty healthy participants (10 young males 24 ± 3 yr; 10 young females 24 ± 3 yr; 10 older males 63 ± 3 yr, 10 older females 63 ± 6 yr) mimicked their exercise breathing patterns (voluntary hyperpnea) in the absence of exercise across a range of exercise intensities. At peak exercise, V̇o2RM represented a significantly greater fraction of peak oxygen consumption (V̇o2peak) in young females, 12.7 ± 4.0%, compared with young males, 10.7 ± 3.0% (P = 0.027), whereas V̇o2RM represented 13.5 ± 2.3% of V̇o2peak in older females and 13.2 ± 3.3% in older males. At relative ventilations, there was a main effect of age, with older males consuming a significantly greater fraction of V̇o2RM (6.6 ± 1.9%) than the younger males (4.4 ± 1.3%; P = 0.012), and older females consuming a significantly greater fraction of V̇o2RM (6.9 ± 2.5%) than the younger females (5.1 ± 1.4%; P = 0.004) at 65% V̇emax. Furthermore, both younger and older males had significantly better respiratory muscle efficiency than their female counterparts at peak exercise (P = 0.011; P = 0.015). Similarly, younger participants were significantly more efficient than older participants (6.5 ± 1.5% vs. 5.5 ± 2.0%; P = 0.001). Normal age-related changes in respiratory function, in addition to sex-based differences in airway anatomy, appear to influence the ventilatory responses and the cost incurred to breathe during exercise.NEW & NOTEWORTHY Here we show that at moderate and high-intensity exercise, older individuals incur a higher cost to breathe than their younger counterparts. However, as individuals age, the sex difference in the cost of breathing narrows. Collectively, our findings suggest that the normative age-related changes in respiratory structure and function, and sex differences in airway anatomy, appear to influence the ventilatory responses to exercise and the oxygen cost to breathe.

Vagus Nerve Stimulation (VNS) Modulates Synaptic Plasticity in the Infralimbic Cortex via Trk-B Receptor Activation to Reduce Drug-Seeking in Male Rats.

Drugs of abuse cause changes in the prefrontal cortex (PFC) and associated regions that impair inhibitory control over drug-seeking. Breaking the contingencies between drug-associated cues and the delivery of the reward during extinction learning reduces relapse. Vagus nerve stimulation (VNS) has previously been shown to enhance extinction learning and reduce drug-seeking. Here we determined the effects of VNS-mediated release of brain-derived neurotrophic factor (BDNF) on extinction and cue-induced reinstatement in male rats trained to self-administer cocaine. Pairing 10 d of extinction training with VNS facilitated extinction and reduced drug-seeking behavior during reinstatement. Rats that received a single extinction session with VNS showed elevated BDNF levels in the medial PFC as determined via an enzyme-linked immunosorbent assay. Systemic blockade of tropomyosin receptor kinase B (TrkB) receptors during extinction, via the TrkB antagonist ANA-12, decreased the effects of VNS on extinction and reinstatement. Whole-cell recordings in brain slices showed that cocaine self-administration induced alterations in the ratio of AMPA and NMDA receptor-mediated currents in Layer 5 pyramidal neurons of the infralimbic cortex (IL). Pairing extinction with VNS reversed cocaine-induced changes in glutamatergic transmission by enhancing AMPAR currents, and this effect was blocked by ANA-12. Our study suggests that VNS consolidates the extinction of drug-seeking behavior by reversing drug-induced changes in synaptic AMPA receptors in the IL, and this effect is abolished by blocking TrkB receptors during extinction, highlighting a potential mechanism for the therapeutic effects of VNS in addiction.

GPX3 supports ovarian cancer tumor progression in vivo and promotes expression of GDF15.

Objective: We previously reported that high expression of the extracellular glutathione peroxidase GPX3 is associated with poor patient outcome in ovarian serous adenocarcinomas, and that GPX3 protects ovarian cancer cells from oxidative stress in culture. Here we tested if GPX3 is necessary for tumor establishment in vivo and to identify novel downstream mediators of GPX3's pro-tumorigenic function. Methods: GPX3 was knocked-down in ID8 ovarian cancer cells by shRNA to test the role of GPX3 in tumor establishment using a syngeneic IP xenograft model. RNA sequencing analysis was carried out in OVCAR3 cells following shRNA-mediated GPX3 knock-down to identify GPX3-dependent gene expression signatures. Results: GPX3 knock-down abrogated clonogenicity and intraperitoneal tumor development in vivo, and the effects were dependent on the level of GPX3 knock-down. RNA sequencing showed that loss of GPX3 leads to decreased gene expression patterns related to pro-tumorigenic signaling pathways. Validation studies identified GDF15 as strongly dependent on GPX3. GDF15, a member of the TGF-ß growth factor family, has known oncogenic and immune modulatory activities. Similarly, GPX3 expression positively correlated with pro-tumor immune cell signatures, including regulatory T-cell and macrophage infiltration, and displayed significant correlation with PD-L1 expression. Conclusions: We show for the first time that tumor produced GPX3 is necessary for ovarian cancer growth in vivo and that it regulates expression of GDF15. The immune profile associated with GPX3 expression in serous ovarian tumors suggests that GPX3 may be an alternate marker of ovarian tumors susceptible to immune check-point inhibitors.

Vagus nerve stimulation (VNS) modulates synaptic plasticity in the rat infralimbic cortex via Trk-B receptor activation to reduce drug-seeking.

Drugs of abuse cause changes in the prefrontal cortex (PFC) and associated regions that impair inhibitory control over drug-seeking. Breaking the contingencies between drug-associated cues and the delivery of the reward during extinction learning reduces relapse. Vagus nerve stimulation (VNS) has previously been shown to enhance extinction learning and reduce drug-seeking. Here we determined the effects of VNS-mediated release of brain-derived neurotrophic factor (BDNF) on extinction and cue-induced reinstatement in rats trained to self-administer cocaine. Pairing 10 days of extinction training with VNS facilitated extinction and reduced drug-seeking behavior during reinstatement. Rats that received a single extinction session with VNS showed elevated BDNF levels in the medial PFC as determined via an enzyme-linked immunosorbent assay (ELISA). Systemic blockade of Tropomyosin receptor kinase B (TrkB) receptors during extinction, via the TrkB antagonist ANA-12, decreased the effects of VNS on extinction and reinstatement. Whole-cell recordings in brain slices showed that cocaine self-administration induced alterations in the ratio of AMPA and NMDA receptor-mediated currents in layer 5 pyramidal neurons of the infralimbic cortex (IL). Pairing extinction with VNS reversed cocaine-induced changes in glutamatergic transmission by enhancing AMPAR currents, and this effect was blocked by ANA-12. Our study suggests that VNS consolidates extinction of drug-seeking behavior by reversing drug-induced changes in synaptic AMPA receptors in the IL, and this effect is abolished by blocking TrkB receptors during extinction, highlighting a potential mechanism for the therapeutic effects of VNS in addiction.

Podocytes from hypertensive and obese mice acquire an inflammatory, senescent, and aged phenotype.

Patients with hypertension or obesity can develop glomerular dysfunction characterized by injury and depletion of podocytes. To better understand the molecular processes involved, young mice were treated with either deoxycorticosterone acetate (DOCA) or fed a high-fat diet (HFD) to induce hypertension or obesity, respectively. The transcriptional changes associated with these phenotypes were measured by unbiased bulk mRNA sequencing of isolated podocytes from experimental models and their respective controls. Key findings were validated by immunostaining. In addition to a decrease in canonical proteins and reduced podocyte number, podocytes from both hypertensive and obese mice exhibited a sterile inflammatory phenotype characterized by increases in NLR family pyrin domain containing 3 (NLRP3) inflammasome, protein cell death-1, and Toll-like receptor pathways. Finally, although the mice were young, podocytes in both models exhibited increased expression of senescence and aging genes, including genes consistent with a senescence-associated secretory phenotype. However, there were differences between the hypertension- and obesity-associated senescence phenotypes. Both show stress-induced podocyte senescence characterized by increased p21 and p53. Moreover, in hypertensive mice, this is superimposed upon age-associated podocyte senescence characterized by increased p16 and p19. These results suggest that senescence, aging, and inflammation are critical aspects of the podocyte phenotype in experimental hypertension and obesity in mice.NEW & NOTEWORTHY Hypertension and obesity can lead to glomerular dysfunction in patients, causing podocyte injury and depletion. Here, young mice given deoxycorticosterone acetate or a high-fat diet to induce hypertension or obesity, respectively. mRNA sequencing of isolated podocytes showed transcriptional changes consistent with senescence, a senescent-associated secretory phenotype, and aging, which was confirmed by immunostaining. Ongoing studies are determining the mechanistic roles of the accelerated aging podocyte phenotype in experimental hypertension and obesity.

Alternative splice variants of the mitochondrial fission protein DNM1L/Drp1 regulate mitochondrial dynamics and tumor progression in ovarian cancer.

Aberrant mitochondrial fission/fusion dynamics have been reported in cancer cells. While post translational modifications are known regulators of the mitochondrial fission/fusion machinery, we show that alternative splice variants of the fission protein Drp1 (DNM1L) have specific and unique roles in cancer, adding to the complexity of mitochondrial fission/fusion regulation in tumor cells. Ovarian cancer specimens express an alternative splice transcript variant of Drp1 lacking exon 16 of the variable domain, and high expression of this splice variant relative to other transcripts is associated with poor patient outcome. Unlike the full-length variant, expression of Drp1 lacking exon 16 leads to decreased association of Drp1 to mitochondrial fission sites, more fused mitochondrial networks, enhanced respiration, and TCA cycle metabolites, and is associated with a more metastatic phenotype in vitro and in vivo. These pro-tumorigenic effects can also be inhibited by specific siRNA-mediated inhibition of the endogenously expressed transcript lacking exon 16. Moreover, lack of exon 16 abrogates mitochondrial fission in response to pro-apoptotic stimuli and leads to decreased sensitivity to chemotherapeutics. These data emphasize the significance of the pathophysiological consequences of Drp1 alternative splicing and divergent functions of Drp1 splice variants, and strongly warrant consideration of Drp1 splicing in future studies.

Podocyte injury at young age causes premature senescence and worsens glomerular aging.

As life expectancy continues to rise, age-related diseases are becoming more prevalent. For example, proteinuric glomerular diseases typified by podocyte injury have worse outcomes in the elderly compared with young patients. However, the reasons are not well understood. We hypothesized that injury to nonaged podocytes induces senescence, which in turn augments their aging processes. In primary cultured human podocytes, injury induced by a cytopathic antipodocyte antibody, adriamycin, or puromycin aminonucleoside increased the senescence-related genes CDKN2A (p16INK4a/p14ARF), CDKN2D (p19INK4d), and CDKN1A (p21). Podocyte injury in human kidney organoids was accompanied by increased expression of CDKN2A, CDKN2D, and CDKN1A. In young mice, experimental focal segmental glomerulosclerosis (FSGS) induced by adriamycin and antipodocyte antibody increased the glomerular expression of p16, p21, and senescence-associated ß-galactosidase (SA-ß-gal). To assess the long-term effects of early podocyte injury-induced senescence, we temporally followed young mice with experimental FSGS through adulthood (12 m of age) and middle age (18 m of age). p16 and Sudan black staining were higher at middle age in mice with earlier FSGS compared with age-matched mice that did not get FSGS when young. This was accompanied by lower podocyte density, reduced canonical podocyte protein expression, and increased glomerular scarring. These results are consistent with injury-induced senescence in young podocytes, leading to increased senescence of podocytes by middle age accompanied by lower podocyte lifespan and health span.NEW & NOTEWORTHY Glomerular function is decreased by aging. However, little is known about the molecular mechanisms involved in age-related glomerular changes and which factors could contribute to a worse glomerular aging process. Here, we reported that podocyte injury in young mice and culture podocytes induced senescence, a marker of aging, and accelerates glomerular aging when compared with healthy aging mice.

Comparison of Continuous Sedatives in the Burn ICU on Delirium and Coma.

Lighter sedation targets over the past decade have resulted in improved outcomes for critically ill populations. Although guidelines exist for the general ICU population, these recommendations often exclude the burn population. The purpose of this study is to assess the impact of the initial continuous sedative on coma- and delirium-free days in critically ill patients with burns. This retrospective cohort study evaluated adult patients admitted to a burn intensive care unit at an academic medical center between January 2010 and September 2019. Patients were enrolled into 3 groups based on the depth of initial continuous sedation received (deep, light, or analgosedation). Intubated patients were randomly assessed for inclusion from the National V6 Burn Registry. Patients were included if they received a continuous sedative infusion for at least 48 h. A total of 107 patients were included in the study with 36, 41, and 30 patients receiving deep, light, and analgosedation, respectively. The primary outcome of coma- and delirium-free days was significantly different between sedation types with the most days free in analgosedation and the fewest in deep sedation (8 versus 3 days; P = 0.024). The composite primary outcome was divided into secondary outcomes of coma-free days and delirium-free days, with coma-free days being different (P = 0.00008). Other secondary outcomes of length of stay in the intensive care unit and hospital, time on mechanical ventilation, and survival to discharge were not statistically significant; however, a trend toward higher mortality in deep sedation was noted.

The Ploidy State as a Determinant of Hepatocyte Proliferation.

The liver's unique chromosomal variations, including polyploidy and aneuploidy, influence hepatocyte identity and function. Among the most well-studied mammalian polyploid cells, hepatocytes exhibit a dynamic interplay between diploid and polyploid states. The ploidy state is dynamic as hepatocytes move through the "ploidy conveyor," undergoing ploidy reversal and re-polyploidization during proliferation. Both diploid and polyploid hepatocytes actively contribute to proliferation, with diploids demonstrating an enhanced proliferative capacity. This enhanced potential positions diploid hepatocytes as primary drivers of liver proliferation in multiple contexts, including homeostasis, regeneration and repopulation, compensatory proliferation following injury, and oncogenic proliferation. This review discusses the influence of ploidy variations on cellular activity. It presents a model for ploidy-associated hepatocyte proliferation, offering a deeper understanding of liver health and disease with the potential to uncover novel treatment approaches.

Association of oxidized ApoB and oxidized ApoA-I with high-risk coronary plaque features in cardiovascular disease.

BACKGROUND: Oxidized apolipoprotein B (oxLDL) and oxidized ApoA-I (oxHDL) are proatherogenic. Their prognostic value for assessing high-risk plaques by coronary computed tomography angiography (CCTA) is missing. METHODS: In a prospective, observational study, 306 participants with cardiovascular disease (CVD) had extensive lipoprotein profiling. Proteomics analysis was performed on isolated oxHDL, and atherosclerotic plaque assessment was accomplished by quantitative CCTA. RESULTS: Patients were predominantly White, overweight men (58.5%) on statin therapy (43.5%). Increase in LDL-C, ApoB, small dense LDL-C (P < 0.001 for all), triglycerides (P = 0.03), and lower HDL function were observed in the high oxLDL group. High oxLDL associated with necrotic burden (NB; ß = 0.20; P < 0.0001) and fibrofatty burden (FFB; ß = 0.15; P = 0.001) after multivariate adjustment. Low oxHDL had a significant reverse association with these plaque characteristics. Plasma oxHDL levels better predicted NB and FFB after adjustment (OR, 2.22; 95% CI, 1.27-3.88, and OR, 2.80; 95% CI, 1.71-4.58) compared with oxLDL and HDL-C. Interestingly, oxHDL associated with fibrous burden (FB) change over 3.3 years (ß = 0.535; P = 0.033) when compared with oxLDL. Combined Met136 mono-oxidation and Trp132 dioxidation of HDL showed evident association with coronary artery calcium score (r = 0.786; P < 0.001) and FB (r = 0.539; P = 0.012) in high oxHDL, whereas Met136 mono-oxidation significantly associated with vulnerable plaque in low oxHDL. CONCLUSION: Our findings suggest that the investigated oxidized lipids are associated with high-risk coronary plaque features and progression over time in patients with CVD. CLINICALTRIALS: gov NCT01621594. FUNDING: National Heart, Lung, and Blood Institute at the NIH Intramural Research Program.

Tipología de las heridas atendidas en atención primaria: estudio transversal multicéntrico / Typology of wounds treated in primary care: Multicenter cross-sectional study

Introducción La atención a personas con heridas cutáneas es un importante problema de salud que afecta la calidad de vida de los pacientes y de su familia y tiene un gran impacto socioeconómico. Conocer la situación del problema es el primer paso para el planteamiento de diferentes abordajes sanitarios. En nuestro territorio, desde 2010 no se ha realizado ningún tipo de seguimiento sobre las heridas que tratamos, por lo que planteamos conocer la tipología y las características de las heridas activas en población asistida por atención primaria. Métodos Estudio descriptivo transversal multicéntrico realizado en una zona metropolitana de Cataluña en equipos de atención primaria y en residencias. Los participantes fueron todos los pacientes con heridas activas. Se utilizó un registro realizado por enfermeras referentes del paciente. Se realizó un análisis descriptivo de los datos. Resultados Participaron 1.978 personas, que presentaron 2.471 heridas. La prevalencia global fue del 0,22%. En pacientes domiciliarios la prevalencia fue del 3,58%, y en residencias, del 6,56%. El 46,5% fueron lesiones agudas y el 53,4% crónicas, con un tamaño medio de 3,13cm. De las heridas crónicas, 345 (26,2%) tenían una evolución superior a un año. Las lesiones más prevalentes fueron las úlceras venosas en los equipos de atención primaria y las lesiones por presión categoríaII en los centros residenciales. Conclusiones Los resultados de este estudio presentan una realidad objetiva sobre las lesiones que son atendidas en atención primaria, tanto en centros de atención primaria, en domicilio o en residencias, así como su descripción (AU)

Background The care of people with skin wounds is an important health problem, that affect the quality of life of patients and their families, and has a great socioeconomic impact. Knowing the situation of the problem is the first step for different health approaches. In our territory since 2010 no type of follow-up has been carried out on the wounds that we are treating, we propose to know the typology and characteristics of active wounds in the population assisted by Primary Care. Methods Multicenter cross-sectional descriptive study carried out in a metropolitan area of Catalonia in Primary Care Teams and residences. Participants were all patients with active wounds. A record made by the patient's referring nurses was used. A descriptive analysis of the data was performed. Results About 1,978 people participated, presenting 2,471 injuries. The overall prevalence was 0.22%. At home patients, the prevalence was 3.58% and in nursing homes, 6.56%. Of all the lesions, 46.5% were acute and 53.4% chronic, the mean size was 3.13cm. Of the chronic wounds, 345 (26.2%) had an evolution of more than 1year. The most prevalent injuries were venous ulcers in Primary Care Teams and categoryII pressure injuries in residential centers. Conclusions The results of this study present an objective reality about the injuries that are treated in primary care, both in Primary Care Centers, homes or residences, as well as their description (AU)

Inhibiting NLRP3 signaling in aging podocytes improves their life- and health-span.

The decrease in the podocyte's lifespan and health-span that typify healthy kidney aging cause a decrease in their normal structure, physiology and function. The ability to halt and even reverse these changes becomes clinically relevant when disease is superimposed on an aged kidney. RNA-sequencing of podocytes from middle-aged mice showed an inflammatory phenotype with increases in the NLRP3 inflammasome, signaling for IL2/Stat5, IL6 and TNF, interferon gamma response, allograft rejection and complement, consistent with inflammaging. Furthermore, injury-induced NLRP3 signaling in podocytes was further augmented in aged mice compared to young ones. The NLRP3 inflammasome (NLRP3, Caspase-1, IL1ß IL-18) was also increased in podocytes of middle-aged humans. Higher transcript expression for NLRP3 in human glomeruli was accompanied by reduced podocyte density and increased global glomerulosclerosis and glomerular volume. Pharmacological inhibition of NLRP3 with MCC950, or gene deletion, reduced podocyte senescence and the genes typifying aging in middle-aged mice, which was accompanied by an improved podocyte lifespan and health-span. Moreover, modeling the injury-dependent increase in NLRP3 signaling in human kidney organoids confirmed the anti-senescence effect of MC9950. Finally, NLRP3 also impacted liver aging. Together, these results suggest a critical role for the NLRP3 inflammasome in podocyte and liver aging.

A Redox Transmetalation Step in Nickel-Catalyzed C-C Coupling Reactions.

Ni-catalyzed C-H functionalization reactions are becoming efficient routes to access a variety of functionalized arenes, yet the mechanisms of these catalytic C-C coupling reactions are not well understood. Here, we report the catalytic and stoichiometric arylation reactions of a nickel(II) metallacycle. Treatment of this species with silver(I)-aryl complexes results in facile arylation, consistent with a redox transmetalation step. Additionally, treatment with electrophilic coupling partners generates C-C and C-S bonds. We anticipate that this redox transmetalation step may be relevant to other coupling reactions that employ silver salts as additives.

Polygenic risk scores point toward potential genetic mechanisms of type 2 myocardial infarction in people with HIV.

BACKGROUND: People with human immunodeficiency virus (HIV) infection (PWH) are at higher risk of myocardial infarction (MI) than those without HIV. About half of MIs in PWH are type 2 (T2MI), resulting from mismatch between myocardial oxygen supply and demand, in contrast to type 1 MI (T1MI), which is due to primary plaque rupture or coronary thrombosis. Despite worse survival and rising incidence in the general population, evidence-based treatment recommendations for T2MI are lacking. We used polygenic risk scores (PRS) to explore genetic mechanisms of T2MI compared to T1MI in PWH. METHODS: We derived 115 PRS for MI-related traits in 9541 PWH enrolled in the Centers for AIDS Research Network of Integrated Clinical Systems cohort with adjudicated T1MI and T2MI. We applied multivariate logistic regression analyses to determine the association with T1MI and T2MI. Based on initial findings, we performed gene set enrichment analysis of the top variants composing PRS associated with T2MI. RESULTS: We found that T1MI was strongly associated with PRS for cardiovascular disease, lipid profiles, and metabolic traits. In contrast, PRS for alcohol dependence and cholecystitis, significantly enriched in energy metabolism pathways, were predictive of T2MI risk. The association remained after the adjustment for actual alcohol consumption. CONCLUSIONS: We demonstrate distinct genetic traits associated with T1MI and T2MI among PWH further highlighting their etiological differences and supporting the role of energy regulation in T2MI pathogenesis.

[Typology of wounds treated in primary care: Multicenter cross-sectional study]. / Tipología de las heridas atendidas en atención primaria: estudio transversal multicéntrico.

BACKGROUND: The care of people with skin wounds is an important health problem, that affect the quality of life of patients and their families, and has a great socioeconomic impact. Knowing the situation of the problem is the first step for different health approaches. In our territory since 2010 no type of follow-up has been carried out on the wounds that we are treating, we propose to know the typology and characteristics of active wounds in the population assisted by Primary Care. METHODS: Multicenter cross-sectional descriptive study carried out in a metropolitan area of Catalonia in Primary Care Teams and residences. Participants were all patients with active wounds. A record made by the patient's referring nurses was used. A descriptive analysis of the data was performed. RESULTS: About 1,978 people participated, presenting 2,471 injuries. The overall prevalence was 0.22%. At home patients, the prevalence was 3.58% and in nursing homes, 6.56%. Of all the lesions, 46.5% were acute and 53.4% chronic, the mean size was 3.13cm. Of the chronic wounds, 345 (26.2%) had an evolution of more than 1year. The most prevalent injuries were venous ulcers in Primary Care Teams and categoryII pressure injuries in residential centers. CONCLUSIONS: The results of this study present an objective reality about the injuries that are treated in primary care, both in Primary Care Centers, homes or residences, as well as their description.

Comparison of Four Dietary Pattern Indices in Australian Baby Boomers: Findings from the Busselton Healthy Ageing Study.

The assessment of dietary patterns comprehensively represents the totality of the diet, an important risk factor for many chronic diseases. This study aimed to characterise and compare four dietary pattern indices in middle-aged Australian adults. In 3458 participants (55% female) from the Busselton Healthy Ageing Study (Phase Two), a validated food frequency questionnaire was used to capture dietary data between 2016 and 2022. Four dietary patterns [Australian Dietary Guideline Index 2013 (DGI-2013); the Mediterranean Diet Index (MedDiet); the Literature-based Mediterranean Diet Index (Lit-MedDiet); and the EAT-Lancet Index], were calculated and compared by measuring total and sub-component scores, and concordance (𝜌c). Cross-sectional associations between the dietary indices and demographic, lifestyle, and medical conditions were modelled with linear regression and restricted cubic splines. Participants had the highest standardised scores for the DGI-2013 followed by the EAT-Lancet Index and the MedDiet, with the lowest standardised scores observed for the Lit-MedDiet. The DGI-2013 had the lowest agreement with the other scores (𝜌c ≤ 0.47). These findings indicate that the diets included in this Australian cohort align more closely with the Australian Dietary Guidelines than with the other international dietary patterns, likely due to the wide variation of individual food group weightings in the construction of these indices.