Mechanistic Link Research Articles

Differential Exudation Creates Biogeochemically Distinct Microenvironments during Rhizosphere Evolution.

Plant roots and associated microbes release a diverse range of functionally distinct exudates into the surrounding rhizosphere with direct impacts on soil carbon storage, nutrient availability, and contaminant dynamics. Yet mechanistic linkages between root exudation and emergent biogeochemical processes remain challenging to measure nondestructively, in real soil, over time. Here we used a novel combination of in situ microsensors with high-resolution mass spectrometry to measure, nondestructively, changing exudation and associated biogeochemical dynamics along single growing plant roots (Avena sativa). We found that metabolite and dissolved organic carbon (DOC) concentrations as well as microbial growth, redox potential (EH), and pH dynamics vary significantly among bulk soil, root tip, and more mature root zones. Surprisingly, the significant spike of rhizosphere DOC upon root tip emergence did not significantly correlate with any biogeochemical parameters. However, the presence of sugars significantly correlated with declines in EH following the arrival of the root tip, likely due to enhanced microbial oxygen demand. Similarly, the presence of organic acids significantly correlated to declines in pH upon root tip emergence. Overall, our in situ measurements highlight how different exudates released along growing roots create functionally distinct soil microenvironments that evolve over time.

Macro- and Microstructural White Matter Differences in Neurologic Postacute Sequelae of SARS-CoV-2 Infection.

Neuropsychiatric complications of SARS-CoV-2 infection, also known as neurologic postacute sequelae of SARS-CoV-2 infection (NeuroPASC), affect 10%-60% of infected individuals. There is growing evidence that NeuroPASC is a multi system immune dysregulation disease affecting the brain. The behavioral manifestations of NeuroPASC, such as impaired processing speed, executive function, memory retrieval, and sustained attention, suggest widespread WM involvement. Although previous work has documented WM damage following acute SARS-CoV-2 infection, its involvement in NeuroPASC is less clear. We hypothesized that macrostructural and microstructural WM differences in NeuroPASC participants would accompany cognitive and immune system differences. In a cross-sectional study, we screened a total of 159 potential participants and enrolled 72 participants, with 41 asymptomatic controls (NoCOVID) and 31 NeuroPASC participants matched for age, sex, and education. Exclusion criteria included neurologic disorders unrelated to SARS-CoV-2 infection. Assessments included clinical symptom questionnaires, psychometric tests, brain MRI measures, and peripheral cytokine levels. Statistical modeling included separate multivariable regression analyses of GM/WM/CSF volume, WM microstructure, cognitive, and cytokine concentration between-group differences. NeuroPASC participants had larger cerebral WM volume than NoCOVID controls (β = 0.229; 95% CI: 0.017-0.441; t = 2.16; P = .035). The most pronounced effects were in the prefrontal and anterior temporal WM. NeuroPASC participants also exhibited higher WM mean kurtosis, consistent with ongoing neuroinflammation. NeuroPASC participants had more self-reported symptoms, including headache, and lower performance on measures of attention, concentration, verbal learning, and processing speed. A multivariate profile analysis of the cytokine panel showed different group cytokine profiles (Wald-type-statistic = 44.6, P = .046), with interferon (IFN)-λ1 and IFN-λ2/3 levels higher in the NeuroPASC group. NeuroPASC participants reported symptoms of lower concentration, higher fatigue, and impaired cognition compatible with WM syndrome. Psychometric testing confirmed these findings. NeuroPASC participants exhibited larger cerebral WM volume and higher WM mean kurtosis than NoCOVID controls. These findings suggest that immune dysregulation could influence WM properties to produce WM volume increases and consequent cognitive effects and headaches. Further work will be needed to establish mechanistic links among these variables.

Elevated Circulating Levels of Gut Microbe-Derived Trimethylamine N-Oxide Are Associated with Systemic Sclerosis.

Background/Objectives: Alterations in fecal microbial communities in patients with systemic sclerosis (SSc) are common, but the clinical significance of this observation is poorly understood. Gut microbial production of trimethylamine (TMA), and its conversion by the host to trimethylamine N-oxide (TMAO), has clinical and mechanistic links to cardiovascular and renal diseases. Direct provision of TMAO has been shown to promote fibrosis and vascular injury, hallmarks of SSc. We sought to determine levels of TMAO and related metabolites in SSc patients and investigate associations between the metabolite levels with disease features. Methods: This is an observational case:control study. Adults with SSc (n = 200) and non-SSc controls (n = 400) were matched for age, sex, indices of renal function, diabetes mellitus, and cardiovascular disease. Serum TMAO, choline, betaine, carnitine, γ-butyrobetaine, and crotonobetaine were measured using stable isotope dilution liquid chromatography tandem mass spectrometry. Results: Median TMAO concentration was higher (p = 0.020) in SSc patients (3.31 [interquartile range 2.18, 5.23] µM) relative to controls (2.85 [IQR 1.88, 4.54] µM). TMAO was highest among obese and male SSc participants compared to all other groups. Following adjustment for sex, BMI, age, race, and eGFR in a quantile regression model, elevated TMAO levels remained associated with SSc at each quantile of TMAO. Conclusions: Patients with SSc have increased circulating levels of TMAO independent of comorbidities including age, sex, renal function, diabetes mellitus, and cardiovascular disease. As a potentially modifiable factor, further studies examining the link between TMAO and SSc disease severity and course are warranted.

Medin, a link between vascular pathology and dementia?

Medin is a protein fragment derived from milk fat globule epidermal growth factor VIII (MFG-E8). Medin aggregates are present in the vessel wall of most subjects over 50 years of age. In this narrative review, we focus on the consequences of medin aggregation in relation to the development of dementia. Recent literature revealed medin as biomarker for dementia in CSF, specifically of a vascular subtype. Preclinical work showed that medin is associated with aging-related cerebral vascular dysfunction, vascular stiffening, hypertension, and. vascular amyloid β deposition. These findings position medin as a potential mechanistic link between aging, vascular pathology and dementia.

Transcript errors generate amyloid-like proteins in huwman cells

Aging is characterized by the accumulation of proteins that display amyloid-like behavior. However, the molecular mechanisms by which these proteins arise remain unclear. Here, we demonstrate that amyloid-like proteins are produced in a variety of human cell types, including stem cells, brain organoids and fully differentiated neurons by mistakes that occur in messenger RNA molecules. Some of these mistakes generate mutant proteins already known to cause disease, while others generate proteins that have not been observed before. Moreover, we show that these mistakes increase when cells are exposed to DNA damage, a major hallmark of human aging. When taken together, these experiments suggest a mechanistic link between the normal aging process and age-related diseases.

6824 Bile Acid Elevation in Nonalcoholic Steatohepatitis Correlates With Fibrogenesis and Mitochondrial Dysfunction In Vitro

Abstract Disclosure: N. Patel: None. Y. Li: None. M. Raul: None. C. Sottas: None. V. Papadopoulos: None. Nonalcoholic steatohepatitis (NASH) is the most severe form of nonalcoholic fatty liver disease. It is estimated that over 115 million adults are affected by NASH worldwide. The causes of NASH are unclear, and no treatment is yet available. Bile acids (BAs) are steroids synthesized in the liver, promoting lipid absorption. The levels of BAs are tightly regulated in the body. Patients diagnosed with NASH frequently exhibit increased levels of BAs in both liver tissue and plasma, indicating a potential association between elevated BA concentrations and the pathogenesis of NASH. In an in vivo study using a high-fat diet rat model of NASH, we measured plasma BA composition and levels. The results obtained indicated substantial increases in the concentrations of glycocholic acid (GCA), glycochenodeoxycholic acid (GCDCA), glycodeoxycholic acid (GDCA), and taurodeoxycholic acid (TDCA) in NASH compared to controls. These findings suggested their potential implication in the development of NASH. To elucidate the mechanistic link between changes in BA synthesis and fibrogenesis, in vitro experiments were conducted using the LX-2 humane hepatic stellate and Huh7 human hepatocellular carcinoma cells. First, the concentrations of the selected bile acids (GCA, GCDCA, GDCA, and TDCA) used in our studies were found to be non-toxic to the cells using the MTT assay. Subsequent qPCR analyses demonstrated the upregulation of key fibrotic genes (TGFβ, COL1A1, ACTA2) in LX-2 cells following exposure to individual bile acids GCA, GCDCA, GDCA, and TDCA. Immunocytochemistry (ICC) studies further demonstrated fibrogenesis by revealing increased expression of COL1A1 following treatment with each of the four bile acids. These data suggest that changes in BA formation are linked to fibrogenesis. We subsequently explored the impact of BAs on mitochondrial function using the Seahorse XF Cell Mito Stress Test in Huh7 cells. The results obtained revealed a reduction in the oxygen consumption rate and ATP production in response to BA treatment. This observation suggests a potential role for modified BAs in disrupting mitochondrial homeostasis, a recognized contributor to the progression of NASH. In summary, the data presented provide valuable insights into the complex effects of modified BAs on NASH pathogenesis, establishing connections between changes in BA composition and fibrogenesis, mitochondrial dysfunction. Presentation: 6/2/2024

Association between Respiratory Virus Infection and Development of De Novo Donor-Specific Antibody in Lung Transplant Recipients.

Chronic lung allograft dysfunction (CLAD) is the most common cause of long-term lung allograft failure. Several factors, including respiratory virus infection (RVI), have been associated with CLAD development, but the underlying mechanisms of these associations are not well understood. We hypothesize that RVI in lung transplant recipients elicits the development of donor-specific antibodies (DSAs), thus providing a mechanistic link between RVI and CLAD development. To test this hypothesis, we retrospectively evaluated for the presence of HLA antibodies in a cohort of lung transplant recipients with symptomatic RVI within the first four months post-transplant using sera at two time points (at/directly after the transplant and following RVI) and time-matched controls without RVI (post-transplant). We found a trend toward the development of de novo DSAs in those with symptomatic RVI versus controls [6/21 (29%) vs. 1/21 (5%), respectively, p = 0.09]. No cases or controls had DSA at baseline. We also found increased rates of CLAD and death among those who developed class II DSA versus those who did not (CLAD: 5/7 (71.4%) vs. 19/34 (54.3%), death: 5/7 (71.4%) vs. 17/35 (48.6%)). Prospective studies evaluating the temporal development of DSA after RVI in lung transplant patients and the subsequent outcomes are warranted.

Comparative Electroencephalographic Profile of a New Anesthetic and Anticonvulsant That Is Selective for the GABAAR Slow Receptor Subtype.

Anesthetics like propofol increase electroencephalography (EEG) power in delta frequencies (0.1-4 Hz), with a decrease of power in bandwidths >30 Hz. Propofol is nonselective for gamma amino butyric acid type A receptor subtypes (GABAAR) as it enhances all 3 GABAAR subtypes (slow, fast, and tonic). Our newly developed anesthetic class selectively targets GABAAR-slow synapses to depress brain responsiveness. We hypothesized that a selective GABAAR-slow agonist, KSEB 01-S2, would produce a different EEG signature compared to the broad-spectrum GABAAR agonist (propofol), and tested this using rat EEG recordings. Male rats were studied after Institutional Animal Care and Use Committees (IACUC) approval from the US Army Medical Research Institute of Chemical Defense and the University of Michigan. Rats were anesthetized using isoflurane (3%-5% induction, 1%-3% maintenance) with oxygen at 0.5 to 1.0 L/min. Stainless steel screws were placed in the skull and used to record subcranial cortical EEG signals. After recovery, either propofol or KSEB 01-S2 was administered and effects on EEG signals were analyzed. As previously reported, propofol produced increased power in delta frequencies (0.1-4 Hz) compared to predrug recordings and produced a decrease in EEG power >30 Hz but no significant changes were seen within ±20 seconds of losing the righting reflex. By contrast, KSEB 01-S2 produced a significant increase in theta frequency percent power (median 14.7%, 16.2/13.8, 75/25 confidence interval; to 34.7%, 35/31.8; P < .015) and a significant decrease in low gamma frequency percent power (16.9%, 18.6/15.8; to 5.45%, 5.5/5.39; P < .015) for all rats at ± 20 seconds of loss of consciousness (LOC). Both anesthetics produced a flattening of chaotic attractor plots from nonlinear dynamic analyses, like that produced by volatile and dissociative anesthetics at LOC. KSEB 01-S2 produced a markedly different EEG pattern, with a selective increase observed in the theta frequency range. KSEB 01-S2 also differs markedly in its activity at the GABAAR-slow receptor subtype, suggesting a possible mechanistic link between receptor subtype specificity and EEG frequency band signatures. Increased theta together with depressed gamma frequencies is interesting because GABAAR slow synapses have previously been suggested to underlie theta frequency oscillations, while fast synapses control gamma activity. These reciprocal effects support a previous model for theta and nested gamma oscillations based on inhibitory connections between GABAAR fast and slow interneurons. Although each anesthetic produced a unique EEG response, propofol and KSEB 01-S2 both increased slow wave activity and flattened chaotic attractor plots at the point of LOC.

Predictive musculoskeletal simulations reveal the mechanistic link between speed, posture and energetics among extant mammals

An unusual pattern among the scaling laws in nature is that the fastest animals are neither the largest, nor the smallest, but rather intermediately sized. Because of the enormous diversity in animal shape, the mechanisms underlying this have long been difficult to determine. To address this, we challenge predictive human musculoskeletal simulations, scaled in mass from the size of a mouse (0.1 kg) to the size of an elephant (2000 kg), to move as fast as possible. Our models replicate patterns observed across extant animals including: (i) an intermediate optimal body mass for speed; (ii) a reduction in the cost of transport with increasing size; and (iii) crouched postures at smaller body masses and upright postures at larger body masses. Finally, we use our models to determine the mechanical limitations of speed with size, showing larger animals may be limited by their ability to produce muscular force while smaller animals are likely limited by their ability to produce larger ground reaction forces. Despite their bipedal gait, our models replicate patterns observed across quadrupedal animals, suggesting these biological phenomena likely represent general rules and are not the result of phylogenetic or other ecological factors that typically hinder comparative studies.

Baseline Blood Pressure Was Associated with Hemispheric Cerebral Blood Flow in Acute Small Subcortical Infarcts

Introduction: While increased baseline blood pressure (BP) is a prevalent comorbidity in the acute phase of ischemic stroke, the association between baseline BP and the state of hemispheric perfusion in patients with acute small subcortical infarcts (SSIs) has not been studied in detail. The aim of this study was to investigate the relationship between baseline BP and hemispheric cerebral blood flow (CBF) in acute SSIs. Methods: This retrospective study included 101 patients with acute SSIs. Baseline hemispheric CBF was assessed through co-registration of baseline CT perfusion imaging and follow-up diffusion-weighted imaging. The association between baseline BP, CBF, and different cerebral small vessel disease (CSVD) biomarkers was assessed. Results: Baseline systolic BP (SBP) and diastolic BP (DBP) were negatively associated with contralateral hemispheric CBF after multivariate-adjusted linear analysis (SBP: β = −0.001, 95% CI: −0.002 to 0.000, p = 0.030; DBP: β = −0.002, 95% CI: −0.003∼0.001, p = 0.006). Among other CSVD biomarkers, the presence of any cerebral microbleeds showed a significant association with lower CBF in the contralateral hemisphere of the infarct lesion (r = −0.270, p = 0.035). Conclusion: In patients with acute SSIs, increased baseline BP was associated with reduced CBF in the contralateral hemisphere of the infarct lesion, which probably could be interpreted by the exacerbation of the CSVD burden, suggesting a potential mechanistic link between BP autoregulation dysfunction and the aggravation of neurovascular impairment in SSIs.

B-328 A Novel Pathway of Akt-Dependent PARP1 Activation Through the Nuclear Localization of EPRS1

Abstract Background Glutamyl-prolyl-tRNA synthetase (EPRS1) is the only bifunctional aminoacyl-tRNA synthetase (aaRS) and is essential for interpreting the genetic code. EPRS1, along with seven other aaRSs, forms the multi-tRNA synthetase complex (MSC). EPRS1 consists of two catalytic domains, GluRS and ProRS, connected by a linker region. Several aaRSs within the MSC, including EPRS1, can dissociate from the MSC in response to specific stimuli. This dissociation enables non-canonical activities distinct from their primary role in protein synthesis. Breast cancer cells harboring a loss-of-function mutation in phosphatase and tensin homolog (PTEN) are known to have more activity in the serine/threonine kinase Akt. Poly-(ADP)-ribose polymerase 1 (PARP1), plays a vital role in DNA damage repair (DDR). PARP1 deposits one or more ADP-Ribose moieties onto damaged DNA or other proteins in a process referred to as PARylation. We hope to connect Akt activation and PARP1 activity through the nuclear localization and noncanonical function of EPRS1. We hypothesize, that when Akt is activated, either through the loss of PTEN function or through stimuli such as heat shock or H2O2 treatment, will stimulate the nuclear localization of EPRS1 and modulate PARP1 activity. Methods To test our hypothesis, we evaluate Akt activation, EPRS1 localization, and PARP1 activity. Using pharmacological activators and inhibitors of Akt, we test if inhibitors and activators alone are sufficient to cause the nuclear localization of EPRS1. Biochemically, we isolate nuclear and cytosolic fractions used in various western blot analysis. We use a variety of assays for PARP1 activity and DDR that include immobilized histones, calculating IC50s of PARP1 inhibitors, comet assay, and confocal microscopy. To ascertain the connection between PARP1 and EPRS1 we use LC-MS/MS analysis and immunoprecipitation. Results We show, in both patient-derived and cultured breast cancer cells, elevated levels of EPRS1 not only in the cytoplasm, but also within the nucleus. We find that nuclear localization EPRS1 is facilitated by a nuclear localization sequence (NLS) located within the linker region of the protein. Breast cancer cells harboring a loss-of-function in PTEN exhibit higher levels of EPRS1 in the nucleus compared to PTEN-positive cells. In EPRS1 knockdown cells, there is diminished expression of multiple tumor-related transcription factors, DNA-damage repair, tumor cell survival, and PARP1 auto-PARylation. We demonstrate that nuclear EPRS1 binds to and shares an interactome with PARP1. Conclusions EPRS1-mediated regulation of PARP1 activity provides a new mechanistic link between PTEN loss in breast cancer cells, PARP1 activation, and cell survival and tumor growth. Targeting the non-canonical activity of EPRS1, without inhibiting canonical tRNA ligase activity, might provide a new therapeutic approach in breast and other forms of cancer, potentially supplementing existing cancer therapeutics.

MAD-microbial (origin of) Alzheimer's disease hypothesis: from infection and the antimicrobial response to disruption of key copper-based systems.

Microbes have been suspected to cause Alzheimer's disease since at least 1908, but this has generally remained unpopular in comparison to the amyloid hypothesis and the dominance of Aβ and Tau. However, evidence has been accumulating to suggest that these earlier theories are but a manifestation of a common cause that can trigger and interact with all the major molecular players recognized in AD. Aβ, Tau and ApoE, in particular appear to be molecules with normal homeostatic functions but also with alternative antimicrobial functions. Their alternative functions confer the non-immune specialized neuron with some innate intracellular defenses that appear to be re-appropriated from their normal functions in times of need. Indeed, signs of infection of the neurons by biofilm-forming microbial colonies, in synergy with herpes viruses, are evident from the clinical and preclinical studies we discuss. Furthermore, we attempt to provide a mechanistic understanding of the AD landscape by discussing the antimicrobial effect of Aβ, Tau and ApoE and Lactoferrin in AD, and a possible mechanistic link with deficiency of vital copper-based systems. In particular, we focus on mitochondrial oxidative respiration via complex 4 and ceruloplasmin for iron homeostasis, and how this is similar and possibly central to neurodegenerative diseases in general. In the case of AD, we provide evidence for the microbial Alzheimer's disease (MAD) theory, namely that AD could in fact be caused by a long-term microbial exposure or even long-term infection of the neurons themselves that results in a costly prolonged antimicrobial response that disrupts copper-based systems that govern neurotransmission, iron homeostasis and respiration. Finally, we discuss potential treatment modalities based on this holistic understanding of AD that incorporates the many separate and seemingly conflicting theories. If the MAD theory is correct, then the reduction of microbial exposure through use of broad antimicrobial and anti-inflammatory treatments could potentially alleviate AD although this requires further clinical investigation.

Dynamic modeling of wheeled biped robot and controller design for reducing chassis tilt angle

Abstract The wheeled-legged robot combines the advantages of wheeled and legged robots, making it easier to assist people in completing repetitive and time-consuming tasks in their daily lives. This paper presents a study on the kinematic and dynamic modeling, as well as the controller design, of a wheeled biped robot with a parallel five-bar linkage mechanism as its leg module. During the motion of the robot, the robot relies on the tilt angle of the inverted pendulum, and this angle often results in the tilting of the chassis of the robot, presenting challenges for the installation of upper-body payloads and sensor systems. The controller proposed in this paper, which is developed by decoupling the primary motions of the robot and designing a multi-objective, multilevel controller, addresses this issue. This controller employs the pendulum pitch angle of the equivalent inverted pendulum model as the control variable and compensates for the chassis tilt angle (CTA). This control method can effectively reduce the CTA of such robots and eliminate the need for additional counterweights. It also provides a more spacious structural design for accommodating upper-body devices. The effectiveness of this control framework is verified through variable height control, walking on flat ground, and carrying loads over rough terrain and slopes.

Synergy Between NK Cells and Monocytes in Potentiating Cardiovascular Disease Risk in Severe COVID-19.

Evidence suggests that COVID-19 predisposes to cardiovascular diseases (CVDs). While monocytes/macrophages play a central role in the immunopathogenesis of atherosclerosis, less is known about their immunopathogenic mechanisms that lead to CVDs during COVID-19. Natural killer (NK) cells, which play an intermediary role during pathologies like atherosclerosis, are dysregulated during COVID-19. Here, we sought to investigate altered immune cells and their associations with CVD risk during severe COVID-19. We measured plasma biomarkers of CVDs and determined phenotypes of circulating immune subsets using spectral flow cytometry. We compared these between patients with severe COVID-19 (severe, n=31), those who recovered from severe COVID-19 (recovered, n=29), and SARS-CoV-2-uninfected controls (controls, n=17). In vivo observations were supported using in vitro assays to highlight possible mechanistic links between dysregulated immune subsets and biomarkers during and after COVID-19. We performed multidimensional analyses of published single-cell transcriptome data of monocytes and NK cells during severe COVID-19 to substantiate in vivo findings. During severe COVID-19, we observed alterations in cardiometabolic biomarkers including oxidized-low-density lipoprotein, which showed decreased levels in severe and recovered groups. Severe patients exhibited dysregulated monocyte subsets, including increased frequencies of proinflammatory intermediate monocytes (also observed in the recovered) and decreased nonclassical monocytes. All identified NK-cell subsets in the severe COVID-19 group displayed increased expression of activation and tissue-resident markers, such as CD69 (cluster of differentiation 69). We observed significant correlations between altered immune subsets and plasma oxidized-low-density lipoprotein levels. In vitro assays revealed increased uptake of oxidized-low-density lipoprotein into monocyte-derived macrophages in the presence of NK cells activated by plasma of patients with severe COVID-19. Transcriptome analyses confirmed enriched proinflammatory responses and lipid dysregulation associated with epigenetic modifications in monocytes and NK cells during severe COVID-19. Our study provides new insights into the involvement of monocytes and NK cells in the increased CVD risk observed during and after COVID-19.

The Onset of Systemic Lupus Erythematosus Triggers Nucleus Pulposus Cell Pyroptosis to Exacerbate Intervertebral Disc Degeneration.

Systemic lupus erythematosus (SLE) is an autoimmune disorder marked by immune system dysregulation and autoantibodies production, causing widespread inflammation and damage across various body systems. Despite the prevalent back pain in SLE patients, the link between SLE and intervertebral disc (IVD) degeneration, a primary contributor to back pain, remains inadequately understood. This study explored the impact of SLE on IVD degeneration using the MRL/lpr mouse model, which effectively replicates human SLE manifestations. The study utilized MRL/lpr mice to investigate the effects of SLE on IVD degeneration. The mice were evaluated for typical SLE phenotypes and indicators of IVD degeneration, including IVD height, IVD score, tissue integrity, extracellular matrix degradation, and apoptosis of IVD cells. Additionally, the study examined nucleus pulposus (NP) pyroptosis and inflammatory cytokine secretion. Mechanistic analysis focused on the antioxidant pathway, specifically the expression levels of NRF2, HO-1, KEAP1, and the phosphorylation levels of p65. MRL/lpr mice displayed typical SLE phenotypes and exacerbated profiles of IVD degeneration, including reduced IVD height, lower IVD score, significant IVD tissue impairment, extracellular matrix degradation, and increased apoptosis of IVD cells. Notably, SLE stimulated NP pyroptosis and excessive secretion of inflammatory cytokines. Mechanistic analysis indicated that the progression of SLE impedes the antioxidant pathway by downregulating NRF2 and HO-1 expression, upregulating KEAP1, and enhancing phosphorylation levels of p65. Our findings highlight the mechanistic link between SLE and IVD degeneration, suggesting potential therapeutic targets for mitigating back pain in SLE patients.

Impact of lead and nickel contamination on metabolic health: Associations with diabetes mellitus in a pakistani cohort

Environmental exposure to heavy metals, particularly lead (Pb) and nickel (Ni), is implicated in chronic metabolic diseases, including diabetes mellitus (DM). This cross-sectional study assessed the Pb and Ni levels in groundwater using ICP-OES and urine samples collected from 2688 participants using ICP-MS. We aimed to establish the associations between Pb and Ni exposure and risk factors for DM and metabolic disorders. Groundwater analysis revealed the elevated levels of total dissolved solids, electrical conductivity, hardness, turbidity, Ni, and Pb, exceeding the WHO guidelines. The mean concentration of Pb in groundwater samples of study area was 0.025 mg/L which was higher than the WHO permissible limit of 0.01 mg/L. Similarly the mean concentration of Ni in groundwater samples of study area was 0.038 mg/L which was also higher than the WHO permissible limit of 0.02 mg/L. In human study, participants, categorized into Pb-detected and Ni-detected groups, exhibited significantly higher Pb and Ni levels and non-exposed non-diabetic groups. Ni-detected diabetics showed elevated Ni levels compared to non-exposed non-diabetics. Similarly, Pb-detected diabetics showed elevated Pb levels compared to non-exposed non-diabetics. These findings suggest a potential contribution of Pb and Ni exposure to DM development. The study also identified associations between heavy metal exposure and disruptions in various biomarkers related to DM, lipid profile, inflammation, oxidative stress, liver function, and kidney function. Pb-detected diabetics demonstrated elevated levels of glycemic index biomarkers, including fasting blood glucose (P < 0.0001) and HbA1c (P < 0.0001). Ni-detected diabetics exhibited increased inflammatory markers, such as CRP (P < 0.0001) and IL-6 (P < 0.0001). Both Pb and Ni exposure were associated with dyslipidemia, as indicated by elevated levels of total cholesterol (P < 0.0001) and LDL (P < 0.0001). Additionally, heavy metal exposure was linked to impaired liver and kidney function, supported by elevated levels of AST (P < 0.0001), ALT (P < 0.0001), creatinine (P < 0.0001), and blood urea nitrogen (P < 0.0001), with Pb exposure also associated with higher levels of MDA (P < 0.0001). Correlation analyses demonstrated significant associations between urinary Pb and Ni concentrations and various biomarkers related to DM and metabolic disorders. In conclusion, this study provides substantial evidence linking Pb and Ni exposure to the development of DM and metabolic disorders in a Pakistani population, emphasizing the need for strict regulations and preventive measures to reduce heavy metal contamination and safeguard public health. Future longitudinal studies and interventions are warranted to elucidate mechanistic links between heavy metal exposure and metabolic diseases.

Odour information enables patch choice by mammalian herbivores from afar, leading to predictable plant associational effects

Abstract Neighbouring plants can alter the susceptibility of high‐quality focal plants to herbivores by affecting herbivore patch choice. Herbivores can use plant odour to make patch‐scale foraging decisions from afar, but the actual information they rely on within complex plant odours is rarely defined. Revealing the information enabling patch choice by herbivores will provide the mechanistic link underpinning associational effects of plant neighbours arising from these foraging decisions. Here, our first aim was to test whether odour cues alone enable a mammalian herbivore to make patch choice decisions leading to predictable associational effects of neighbours on high‐quality focal plants. Our second aim was then to test whether artificial odour, designed to mimic the informative odour component within the whole odour profile of low‐quality neighbours, is as effective as real plants in influencing patch choice and associational refuge. We tested patch choice by African elephants, Loxodonta africana using a giant Y‐maze and real or artificial plant odours as the only cues for the neighbours of a high‐quality focal plant. We quantified the probability of various odour treatments being chosen in comparison with the odour of a focal plant alone. Compared with focal plants alone, we found that elephants were more likely to choose patches with the focal plant plus high‐quality neighbours of the same or different species, but less likely to choose patches with the focal plant plus low‐quality neighbours. We also demonstrated that an artificial subset of odours, designed to be informative, were as effective as real low‐quality neighbours in influencing patch choice and hence associational refuge to the focal plant. Our results demonstrate a key role of plant odour—and specifically informative components within complex odour profiles—in patch choice decisions by a mammalian herbivore, leading to plant associational effects on high‐quality focal plants. Understanding what olfactory information herbivores use when deciding which patches to visit or avoid, and how it affects focal plant susceptibility is important ecologically. Non‐random patch choice will not only affect individual fitness of herbivores, but also shape plant community dynamics through impacting plant survival and recruitment. Furthermore, artificially re‐creating odour information could offer a new tool to influence herbivore foraging decisions, with implications for wildlife management and conservation, including plant protection. Read the free Plain Language Summary for this article on the Journal blog.

Circular RNA hsa_circ_0081343 modulates trophoblast autophagy through Rbm8a nuclear translocation

IntroductionFetal growth restriction (FGR) is a kind of obstetric complication that seriously endangers fetal life. Recent studies reported significant reduction of hsa_circ_0081343 in human placenta developed in FGR and is involved in cell migration, invasion, and apoptosis of trophoblast by acting as microRNA sponges. Autophagy is required for invasion of trophoblast cells and for vascular remodeling during placentation. In this study, we aimed to explore the mechanistic link between hsa_circ_0081343 and autophagy. MethodsWe investigated the interactions between hsa_circ_0081343 and RNA-binding proteins were studied by RNA pull-down assay, mass spectrometry and RNA immunoprecipitation assay. The mechanism of nuclear translocation of Rbm8a were assessed by reverse transcription-quantitative PCR, Western blot, immunofluorescence and Co-Immunoprecipitation. Western blot, immunofluorescence and transmission electron microscopy were performed to elucidate the mechanism underlying hsa_circ_0081343 and/or Rbm8a mediated regulation of autophagy. Resultshsa_circ_0081343 served as an RNA-binding protein (RBP) sponge. RNA binding motif protein 8A (Rbm8a) was directly bound to hsa_circ_0081343 in the cytoplasm, while knockdown of hsa_circ_0081343 facilitated Rbm8a localization in the nucleus. We also identified Rbm8a as a potential import cargo for Importin13 (Ipo13), which transported Rbm8a across the nuclear membrane into the nucleus.Ipo13 recognized Rbm8a via a functional nuclear localization signal (NLS). Furthermore, the mechanistic study revealed that hsa_circ_0081343-mediated nuclear translocation of Rbm8a activated trophoblast autophagy. DiscussionOur results suggest that hsa_circ_0081343 could bind to RBP and the interaction between hsa_circ_0081343 and Rbm8a participate in regulating autophagy. These findings offer novel molecular targets and insights for a potential therapeutic strategy against FGR.

Distribution of lipid droplets in hippocampal neurons and microglia: impact of diabetes and exercise.

Neuroinflammation, aging, and neurodegenerative disorders are associated with excessive accumulation of neutral lipids in lipid droplets (LDs) in microglia. Type 2 diabetes mellitus (T2DM) may cause neuroinflammation and is a risk factor for neurodegenerative disorders. Here, we show that hippocampal pyramidal neurons contain smaller, more abundant LDs than their neighboring microglia. The density of LDs varied between pyramidal cells in adjacent subregions, with CA3 neurons containing more LDs than CA1 neurons. Within the CA3 region, a gradual increase in the LD content along the pyramidal layer from the hilus toward CA2 was observed. Interestingly, the high neuronal LD content correlated with less ramified microglial morphotypes. Using the db/db model of T2DM, we demonstrated that diabetes increased the number of LDs per microglial cell without affecting the neuronal LD density. High-intensity interval exercise induced smaller changes in the number of LDs in microglia but was not sufficient to counteract the diabetes-induced changes in LD accumulation. The changes observed in response to T2DM may contribute to the cerebral effects of T2DM and provide a mechanistic link between T2DM and neurodegenerative disorders.

Research on Mechanisms for University Connotation Construction and High-Quality Employment in the Context of New Quality Productivity

The introduction of the concept of new quality productivity has attracted a great deal of attention in the educational community. However, there is an urgent need to align it with policy orientation and advancements in science and technology moving forward. Colleges and universities themselves should be the leaders of advanced thinking and scientific and technological development, and play their due roles in line with the development of the times to provide quality and urgent talents and intellectual support. For this reason, this paper proposes that universities should consciously establish a set of regular operation mechanisms, namely, the linkage mechanism between “social demand” and “connotation construction,” and operate regularly under the guarantee of the system. This enables universities to lead or grasp the pulse of scientific and technological development, constantly improve the level of connotation construction, promote high-quality employment, and provide high-quality services for modernization and the great rejuvenation of the Chinese nation.