Mechanistic Link Research Articles

Comprehensive analysis of fused deposition modeling process conditions for enhancing mechanical properties and surface quality of 3D-Printed poly-ether-ether-ketone

Fused deposition modeling (FDM) technology is a convenient manufacturing approach for poly-ether-ether-ketone (PEEK) components. In this study, a comprehensive study of the influence of FDM process parameters on the mechanical property and surface quality of 3D-printed PEEK printed with different directions was carried out. The results show that crystallinity of PEEK materials and the pores/gaps between the printing filaments jointly affect the mechanical properties and surface quality of PEEK structural parts. Then, material-structure-property linkage mechanism was revealed. Through the research conducted, crucial processing parameters to enhance the mechanical properties and surface quality of PEEK samples was determined. High tensile strength (91.75 MPa, which was close to the performance of injection molded components) and surface quality (Ra 7.9 μm) was obtained by regulation the nozzle temperature and annealing temperature to improve the crystallinity. Meanwhile, tensile strength of z-Sample was increased from 7.36 MPa to 18.30 MPa (with an increase of 148.64%). High Young's modulus (3.09 GPa) and large plastic strain (exceed 13.91%) was achieved by regulation the nozzle temperature and printing speed to reduce the porosity between PEEK filaments.

Alternative splicing as a driver of natural variation in abscisic acid response.

Abscisic acid (ABA) is a crucial player in plant responses to the environment. It accumulates under stress, activating downstream signaling to implement molecular responses that restore homeostasis. Natural variance in ABA sensitivity remains barely understood, and the ABA pathway has been mainly studied at the transcriptional level, despite evidence that posttranscriptional regulation, namely, via alternative splicing, contributes to plant stress tolerance. Here, we identified the Arabidopsis accession Kn-0 as less sensitive to ABA than the reference Col-0, as shown by reduced effects of the hormone on seedling establishment, root branching, and stomatal closure, as well as by decreased induction of ABA marker genes. An in-depth comparative transcriptome analysis of the ABA response in the two variants revealed lower expression changes and fewer genes affected for the least ABA-sensitive ecotype. Notably, Kn-0 exhibited reduced levels of the ABA-signaling SnRK2 protein kinases and lower basal expression of ABA-reactivation genes, consistent with our finding that Kn-0 contains less endogenous ABA than Col-0. ABA also markedly affected alternative splicing, primarily intron retention, with Kn-0 being less responsive regarding both the number and magnitude of alternative splicing events, particularly exon skipping. We find that alternative splicing introduces a more ecotype-specific layer of ABA regulation and identify ABA-responsive splicing changes in key ABA pathway regulators that provide a functional and mechanistic link to the differential sensitivity of the two ecotypes. Our results offer new insight into the natural variation of ABA responses and corroborate a key role for alternative splicing in implementing ABA-mediated stress responses.

Neuroinflammation driven by human immunodeficiency virus-1 (HIV-1) directs the expression of long noncoding RNA RP11-677M14.2 resulting in dysregulation of neurogranin in vivo and in vitro

Neuroinflammation and synaptodendritic damage represent the pathological hallmarks of HIV-1 associated cognitive disorders (HAND). The post-synaptic protein neurogranin (Nrgn) is significantly reduced in the frontal cortex of postmortem brains from people with HIV (PWH) and it is associated with inflammatory factors released by infected microglia/macrophages. However, the mechanism involved in synaptic loss have yet to be elucidated. In this study, we characterized a newly identified long non-coding RNA (lncRNA) transcript (RP11-677M14.2), which is antisense to the NRGN locus and is highly expressed in the frontal cortex of HIV-1 individuals. Further analysis indicates an inverse correlation between the expression of RP11-677M14.2 RNA and Nrgn mRNA. Additionally, the Nrgn-lncRNA axis is dysregulated in neurons exposed to HIV-1 infected microglia conditioned medium enriched with IL-1β. Moreover, in vitro overexpression of this lncRNA impacts Nrgn expression at both mRNA and protein levels. Finally, we modeled the Nrgn-lncRNA dysregulation within an HIV-1-induced inflammatory environment using brain organoids, thereby corroborating our in vivo and in vitro findings. Together, our study implicates a plausible role for lncRNA RP11-677M14.2 in modulating Nrgn expression that might serve as the mechanistic link between Nrgn loss and cognitive dysfunction in HAND, thus shedding new light on the mechanisms underlying synaptodendritic damage.

In situ captured antibacterial action of membrane-incising peptide lamellae

Developing unique mechanisms of action are essential to combat the growing issue of antimicrobial resistance. Supramolecular assemblies combining the improved biostability of non-natural compounds with the complex membrane-attacking mechanisms of natural peptides are promising alternatives to conventional antibiotics. However, for such compounds the direct visual insight on antibacterial action is still lacking. Here we employ a design strategy focusing on an inducible assembly mechanism and utilized electron microscopy (EM) to follow the formation of supramolecular structures of lysine-rich heterochiral β3-peptides, termed lamellin-2K and lamellin-3K, triggered by bacterial cell surface lipopolysaccharides. Combined molecular dynamics simulations, EM and bacterial assays confirmed that the phosphate-induced conformational change on these lamellins led to the formation of striped lamellae capable of incising the cell envelope of Gram-negative bacteria thereby exerting antibacterial activity. Our findings also provide a mechanistic link for membrane-targeting agents depicting the antibiotic mechanism derived from the in-situ formation of active supramolecules.

The persistence of SARS-CoV-2 in tissues and its association with long COVID symptoms: a cross-sectional cohort study in China

Growing evidence suggests that symptoms associated with post-COVID-19 condition (also known as long COVID) can affect multiple organs and systems in the human body, but their association with viral persistence is not clear. The aim of this study was to investigate the persistence of SARS-CoV-2 in diverse tissues at three timepoints following recovery from mild COVID-19, as well as its association with long COVID symptoms. This single-centre, cross-sectional cohort study was done at China-Japan Friendship Hospital in Beijing, China, following the omicron wave of COVID-19 in December, 2022. Individuals with mild COVID-19 confirmed by PCR or a lateral flow test scheduled to undergo gastroscopy, surgery, or chemotherapy, or scheduled for treatment in hospital for other reasons, at 1 month, 2 months, or 4 months after infection were enrolled in this study. Residual surgical samples, gastroscopy samples, and blood samples were collected approximately 1 month (18-33 days), 2 months (55-84 days), or 4 months (115-134 days) after infection. SARS-CoV-2 was detected by digital droplet PCR and further confirmed through RNA in-situ hybridisation, immunofluorescence, and immunohistochemistry. Telephone follow-up was done at 4 months post-infection to assess the association between the persistence of SARS-CoV-2 RNA and long COVID symptoms. Between Jan 3 and April 28, 2023, 317 tissue samples were collected from 225 patients, including 201 residual surgical specimens, 59 gastroscopy samples, and 57 blood component samples. Viral RNA was detected in 16 (30%) of 53 solid tissue samples collected at 1 month, 38 (27%) of 141 collected at 2 months, and seven (11%) of 66 collected at 4 months. Viral RNA was distributed across ten different types of solid tissues, including liver, kidney, stomach, intestine, brain, blood vessel, lung, breast, skin, and thyroid. Additionally, subgenomic RNA was detected in 26 (43%) of 61 solid tissue samples tested for subgenomic RNA that also tested positive for viral RNA. At 2 months after infection, viral RNA was detected in the plasma of three (33%), granulocytes of one (11%), and peripheral blood mononuclear cells of two (22%) of nine patients who were immunocompromised, but in none of these blood compartments in ten patients who were immunocompetent. Among 213 patients who completed the telephone questionnaire, 72 (34%) reported at least one long COVID symptom, with fatigue (21%, 44 of 213) being the most frequent symptom. Detection of viral RNA in recovered patients was significantly associated with the development of long COVID symptoms (odds ratio 5·17, 95% CI 2·64-10·13, p<0·0001). Patients with higher virus copy numbers had a higher likelihood of developing long COVID symptoms. Our findings suggest that residual SARS-CoV-2 can persist in patients who have recovered from mild COVID-19 and that there is a significant association between viral persistence and long COVID symptoms. Further research is needed to verify a mechanistic link and identify potential targets to improve long COVID symptoms. National Natural Science Foundation of China, National Key R&D Program of China, Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, and New Cornerstone Science Foundation. For the Chinese translation of the abstract see Supplementary Materials section.

PD-L1- and IL-4-expressing basophils promote pathogenic accumulation of T follicular helper cells in lupus

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by anti-nuclear autoantibodies whose production is promoted by autoreactive T follicular helper (TFH) cells. During SLE pathogenesis, basophils accumulate in secondary lymphoid organs (SLO), amplify autoantibody production and disease progression through mechanisms that remain to be defined. Here, we provide evidence for a direct functional relationship between TFH cells and basophils during lupus pathogenesis, both in humans and mice. PD-L1 upregulation on basophils and IL-4 production are associated with TFH and TFH2 cell expansions and with disease activity. Pathogenic TFH cell accumulation, maintenance, and function in SLO were dependent on PD-L1 and IL-4 in basophils, which induced a transcriptional program allowing TFH2 cell differentiation and function. Our study establishes a direct mechanistic link between basophils and TFH cells in SLE that promotes autoantibody production and lupus nephritis.

Full pose measurement system for industrial robots kinematic calibration based on a sensorized spatial linkage mechanism

This paper presents a low-cost pose measuring device capable of simultaneously measuring all six coordinates (3 translations and 3 rotations) of a rigid body with respect to a given reference frame. The proposed system consists of a mechanical chain of rigid bodies and two encoders. The mechanism is a spatial four-bar linkage system with a symmetrical Revolute-Spherical-Spherical-Revolute (RSSR) kinematic structure, where two encoders measure the rotation of the revolute joints. The mechanism is investigated theoretically and solved kinematically using a numerical estimation method. The uncertainty of the pose determination, caused by the repeatability of the sensors, is estimated, as well as the achievable measurement range. A low uncertainty is achieved by a suitable design of the proposed kinematic chain. The mechanism is easy to realize with low tolerances and the correct definition of the length of the links allows a quite large workspace. The system can be profitably used in the calibration of robots or multi-axis machine tools where the actual pose of the gripper or spindle must be measured over the workspace of the machine. An experimental prototype is described, and the first experimental results are reported.

The Pathophysiological, Genetic, and Hormonal Changes in Preeclampsia: A Systematic Review of the Molecular Mechanisms.

Preeclampsia, a serious complication of pregnancy, involves intricate molecular and cellular mechanisms. Fetal microchimerism, where fetal cells persist within maternal tissues and in circulation, acts as a mechanistic link between placental dysfunction and maternal complications in the two-stage model of preeclampsia. Hormones, complements, and cytokines play pivotal roles in the pathophysiology, influencing immune responses, arterial remodeling, and endothelial function. Also, soluble HLA-G, involved in maternal-fetal immune tolerance, is reduced in preeclampsia. Hypoxia-inducible factor 1-alpha (Hif-α) dysregulation leads to placental abnormalities and preeclampsia-like symptoms. Alterations in matrix metalloproteinases (MMPs), endothelins (ETs), chemokines, and cytokines contribute to defective trophoblast invasion, endothelial dysfunction, and inflammation. Preeclampsia's genetic complexity includes circRNAs, miRNAs, and lncRNAs. CircRNA_06354 is linked to early-onset preeclampsia by influencing trophoblast invasion via the hsa-miR-92a-3p/VEGF-A pathway. The dysregulation of C19MC, especially miR-519d and miR-517-5p, affects trophoblast function. Additionally, lncRNAs like IGFBP1 and EGFR-AS1, along with protein-coding genes, impact trophoblast regulation and angiogenesis, influencing both preeclampsia and fetal growth. Besides aberrations in CD31+ cells, other potential biomarkers such as MMPs, soluble HLA-G, and hCG hold promise for predicting preeclampsia and its complications. Therapeutic interventions targeting factors such as peroxisome PPAR-γ and endothelin receptors show potential in mitigating preeclampsia-related complications. In conclusion, preeclampsia is a complex disorder with a multifactorial etiology and pathogenesis. Fetal microchimerism, hormones, complements, and cytokines contribute to placental and endothelial dysfunction with inflammation. Identifying novel biomarkers and therapeutic targets offers promise for early diagnosis and effective management, ultimately reducing maternal and fetal morbidity and mortality. However, further research is warranted to translate these findings into clinical practice and enhance outcomes for at-risk women.

Fusobacterium nucleatum: An Overview of Evidence, Demi-Decadal Trends, and Its Role in Adverse Pregnancy Outcomes and Various Gynecological Diseases, including Cancers

Gynecological and obstetric infectious diseases are crucial to women’s health. There is growing evidence that links the presence of Fusobacterium nucleatum (F. nucleatum), an anaerobic oral commensal and potential periodontal pathogen, to the development and progression of various human diseases, including cancers. While the role of this opportunistic oral pathogen has been extensively studied in colorectal cancer in recent years, research on its epidemiological evidence and mechanistic link to gynecological diseases (GDs) is still ongoing. Thus, the present review, which is the first of its kind, aims to undertake a comprehensive and critical reappraisal of F. nucleatum, including the genetics and mechanistic role in promoting adverse pregnancy outcomes (APOs) and various GDs, including cancers. Additionally, this review discusses new conceptual advances that link the immunomodulatory role of F. nucleatum to the development and progression of breast, ovarian, endometrial, and cervical carcinomas through the activation of various direct and indirect signaling pathways. However, further studies are needed to explore and elucidate the highly dynamic process of host–F. nucleatum interactions and discover new pathways, which will pave the way for the development of better preventive and therapeutic strategies against this pathobiont.

Periodontitis: A Plausible Modifiable Risk Factor for Neurodegenerative Diseases? A Comprehensive Review.

The aim of this comprehensive review is to summarize recent literature on associations between periodontitis and neurodegenerative diseases, explore the bidirectionality and provide insights into the plausible pathogenesis. For this purpose, systematic reviews and meta-analyses from PubMed, Medline and EMBASE were considered. Out of 33 retrieved papers, 6 articles complying with the inclusion criteria were selected and discussed. Additional relevant papers for bidirectionality and pathogenesis were included. Results show an association between periodontitis and Alzheimer's disease, with odds ratios of 3 to 5. A bidirectional relationship is suspected. For Parkinson's disease (PD), current evidence for an association appears to be weak, although poor oral health and PD seem to be correlated. A huge knowledge gap was identified. The plausible mechanistic link for the association between periodontitis and neurodegenerative diseases is the interplay between periodontal inflammation and neuroinflammation. Three pathways are hypothesized in the literature, i.e., humoral, neuronal and cellular, with a clear role of periodontal pathogens, such as Porphyromonas gingivalis. Age, gender, race, smoking, alcohol intake, nutrition, physical activity, socioeconomic status, stress, medical comorbidities and genetics were identified as common risk factors for periodontitis and neurodegenerative diseases. Future research with main emphasis on the collaboration between neurologists and dentists is encouraged.

A pollen selection system links self and interspecific incompatibility in the Brassicaceae.

Self-incompatibility and recurrent transitions to self-compatibility have shaped the extant mating systems underlying the nonrandom mating critical for speciation in angiosperms. Linkage between self-incompatibility and speciation is illustrated by the shared pollen rejection pathway between self-incompatibility and interspecific unilateral incompatibility (UI) in the Brassicaceae. However, the pollen discrimination system that activates this shared pathway for heterospecific pollen rejection remains unknown. Here we show that Stigma UI3.1, the genetically identified stigma determinant of UI in Arabidopsis lyrata × Arabidopsis arenosa crosses, encodes the S-locus-related glycoprotein 1 (SLR1). Heterologous expression of A. lyrata or Capsella grandiflora SLR1 confers on some Arabidopsis thaliana accessions the ability to discriminate against heterospecific pollen. Acquisition of this ability also requires a functional S-locus receptor kinase (SRK), whose ligand-induced dimerization activates the self-pollen rejection pathway in the stigma. SLR1 interacts with SRK and interferes with SRK homomer formation. We propose a pollen discrimination system based on competition between basal or ligand-induced SLR1-SRK and SRK-SRK complex formation. The resulting SRK homomer levels would be sensed by the common pollen rejection pathway, allowing discrimination among conspecific self- and cross-pollen as well as heterospecific pollen. Our results establish a mechanistic link at the pollen recognition phase between self-incompatibility and interspecific incompatibility.

Metastasis and the Microbiome: The Impact of Bacteria in Disseminated Colorectal Cancer.

Metastasis remains a leading cause of mortality for patients with solid tumors. An expanding body of literature suggests interplay between the host, gut, and tumoral microbiomes may play a role in cancer initiation and distant dissemination. These associations have been particularly well-studied in colorectal cancer, where gut dysbiosis and an endotoxin-induced inflammatory milieu foster premalignant polyp formation, setting the stage for carcinogenesis. Subsequent violation of the gut vascular barrier enables dissemination of bacterial agents to sites such as the liver, where they contribute to establishment of pre-metastatic niches, which promote tumor cell extravasation and metastatic outgrowth. Intriguingly, breakdown of this vascular barrier has been shown to be aided by the presence of tumoral bacteria. The presence of similar species, including Fusobacterium nucleatum and Escherichia Coli, in both primary and metastatic colorectal tumors, supports this hypothesis and their presence is associated with chemotherapy resistance and an overall poor prognosis. Specific gut microbial populations are also associated with differential response to immunotherapy, which has a growing role in microsatellite unstable colorectal cancers. Recent work suggests that modulation of gut microbiome using dietary modification, targeted antibiotics, or fecal microbiota transplantation may improve response to immunotherapy and oncologic outcomes. Elucidation of the precise mechanistic links between the microbiome and cancer dissemination will open the doors to additional therapeutic possibilities.

Computational assessment of carbon fabric reinforced polymer made prosthetic knee: Mechanics, finite element simulations and experimental evaluation.

A prosthetic knee is designed to replace the functionality of an anatomical knee in transfemoral amputees. The purpose of a prosthetic knee is to restore mobility and compensate amputees for their impairment. In the present research numerical modelling and simulation of a carbon fabric reinforced polymer made polycentric prosthetic knee with four-bar mechanism was performed. Virtual prototyping with computer-aided design and computer-aided engineering software ensured geometric and structural stability of the knee design. The linkage mechanism, instantaneous centre's location and trajectory were investigated using multibody dynamics and analytical formulations. Computational simulations with a non-linear finite element model were employed with joints, contact formulations and an orthotropic material model to predict the displacement, stress formulated and life of the knee prosthesis under static and cyclic loading conditions. Finite element analysis assessed the strength and durability of knee in accordance to standards. Maximum Principal stress of 155 MPa and life expectancy of 3.1 × 106 cycles were determined for the composite knee through numerical simulations ensuring a safe design. Experimental testing was also conducted as per standards and the percentage error was estimated to be 2.52%, thereby establishing the validity of the finite element model deployed. This type of simulation-based approach can be implemented to efficiently and affordably design and prototype a prosthetic knee with desired functioning criteria.

Compliant Contact Force Control for Aerial Manipulator of Adaptive Neural Network-Based Robust Control.

Aerial manipulators expand the application scenarios of manipulators into the air. To complete various operations, the contact force between the aerial manipulator and the target must be precisely controlled. In this study, we first established the mathematical models of the multirotor and the manipulator separately. Their mutual influence is regarded as each other's disturbance, and the overall linkage mechanism is established through analysis. Then, a robust sliding mode control strategy is developed for accurate trajectory tracking. The controller is derived from Lyapunov theory, which can ensure the stability of the closed-loop system. To compensate for the effect of system uncertainty, an adaptive radial basis function neural network is devised to approximate the part of the controller containing the model information. In addition, an impedance controller is designed to convert force control into position control to make the manipulator contact with the target compliantly. Finally, the simulation and experimental results indicate that the proposed method can guarantee the accuracy of the contact force and has good robustness.

A Mechanical Approach for Comparing Jaws in Fishes.

This paper aims to propose an quantitative engineering approach to study and compare the jaw mechanisms of different marine species, considering essential mechanical parameters generally used to evaluate the performance of industrial linkage mechanisms. By leveraging these parameters, the paper demonstrates how the species' characteristics and behaviors align with the findings of biologists, enabling a meaningful comparison that was not previously possible. Seven fish species from various families are chosen to maintain a generic approach.

Combining fecal 16 S rRNA sequencing and spinal cord metabolomics analysis to explain the modulatory effect of PPARα on neuropathic pain

BackgroundExisting evidence suggests that the composition of the gut microbiota is associated with neuropathic pain (NP), but the mechanistic link is elusive. Peroxisome proliferator-activated receptor α (PPARα) has been shown to be a pharmacological target for the treatment of metabolic disorders, and its expression is also involved in inflammatory regulation. The aim of this study was to investigate the important modulatory effects of PPARα on gut microbiota and spinal cord metabolites in mice subjected to chronic constriction injury. MethodsWe analyzed fecal microbiota and spinal cord metabolic alterations in mice from the sham, CCI, GW7647 (PPARα agonist) and GW6471 (PPARα antagonist) groups by 16 S rRNA amplicon sequencing and untargeted metabolomics analysis. On this basis, the intestinal microbiota and metabolites that were significantly altered between treatment groups were analyzed in a combined multiomics analysis. We also investigated the effect of PPARα on the polarization fractionation of spinal microglia. ResultsPPARα agonist significantly reduce paw withdrawal threshold and paw withdrawal thermal latency, while PPARα antagonist significantly increase paw withdrawal threshold and paw withdrawal thermal latency. 16 S rRNA gene sequencing showed that intraperitoneal injection of GW7647 or GW6471 significantly altered the abundance, homogeneity and composition of the gut microbiome. Analysis of the spinal cord metabolome showed that the levels of spinal cord metabolites were shifted after exposure to GW7647 or GW6471. Alterations in the composition of gut microbiota were significantly associated with the abundance of various spinal cord metabolites. The abundance of Licheniformes showed a significant positive correlation with nicotinamide, benzimidazole, eicosanoids, and pyridine abundance. Immunofluorescence results showed that intraperitoneal injection of GW7647 or GW6471 altered microglial activation and polarization levels. ConclusionOur study shows that PPARα can promote M2-type microglia polarization, as well as alter gut microbiota and metabolites in CCI mice. This study enhances our understanding of the mechanism of PPARα in the treatment of neuropathic pain.

Cerebrovascular dysfunction and depressive symptoms in preclinical models: insights from a scoping review.

Although existing literature supports associations between cerebrovascular dysfunction and the emergence of depression and depressive symptoms, relatively little is known about underlying mechanistic pathways that may explain potential relationships. As such, an integrated understanding of these relationships in preclinical models could provide insight into the nature of the relationship, basic mechanistic linkages, and areas in which additional investment should be targeted. This scoping review was conducted in MEDLINE, EMBASE, and Scopus to outline the relationship between depressive symptoms and cerebrovascular dysfunction in preclinical animal models with an additional focus on the areas above. From 3,438 articles initially identified, 15 studies met the inclusion criteria and were included in the review. All studies reported a positive association between the severity of markers for cerebrovascular dysfunction and that for depressive symptoms in rodent models and this spanned all models for either pathology. Specific mechanistic links between the two such as chronic inflammation, elevated vascular oxidant stress, and altered serotonergic signaling were highlighted. Notably, almost all studies addressed outcomes in male animals, with a near complete lack of data from females, and there was little consistency in terms of how cerebrovascular dysfunction was assessed. Across nearly all studies was a lack of clarity for any "cause and effect" relationship between depressive symptoms and cerebrovascular dysfunction. At this time, it is reasonable to conclude that a correlative relationship clearly exists between the two, and future investigation will be required to parse out more specific aspects of this relationship.NEW & NOTEWORTHY This scoping review presents a structured evaluation of all relevant existing literature linking cerebral vasculopathy to depressive symptom emergence in preclinical models. Results support a definite connection between vascular dysfunction and depressive symptoms, highlighting the importance of chronic elevations in inflammation and oxidant stress, and impaired serotonergic signaling. The review also identified significant knowledge gaps addressing male versus female differences and limited clear mechanistic links between cerebral vasculopathy and depressive symptoms.

An examination of state and trait urgency in individuals with binge-eating disorder.

Negative urgency (i.e., acting rashly when experiencing negative affect; NU), is a theorised maintenance factor in binge-eating type eating disorders. This study examined the association between trait NU and eating disorder severity, momentary changes in state NU surrounding episodes of binge eating, and the momentary mechanistic link between affect, rash action, and binge-eating risk. Participants were 112 individuals with binge-eating disorder (BED). Baseline measures included the UPPS-P Impulsive Behaviour Scale to assess trait NU and the Eating Disorders Examination to assess binge-eating frequency and global eating disorder severity. Ecological momentary assessment captured real-time data on binge eating, negative affect, and state NU. Multiple regression analysis revealed a strong association between trait NU and eating disorder severity. Generalised estimating equations showed that state NU increased before and decreased after binge-eating episodes, and that this pattern was not moderated by trait-level NU. Finally, a multilevel structural equation model indicated that increases in rash action mediated the momentary relationship between states of high negative affect and episodes of binge eating. These findings underscore the importance of both trait and state NU in binge-eating type eating disorders, and suggest NU as a potential key target for intervention.

The Impact of Inflammation on Thermal Hyperpnea: Relevance for Heat Stress and Febrile Seizures.

Extreme heat caused by climate change is increasing the transmission of infectious diseases, resulting in a sharp rise in heat-related illness and mortality. Understanding the mechanistic link between heat, inflammation, and disease is thus important for public health. Thermal hyperpnea, and consequent respiratory alkalosis, is crucial in febrile seizures and convulsions induced by heat stress in humans. Here, we address what causes thermal hyperpnea in neonates and how it is affected by inflammation. Transient receptor potential cation channel subfamily V member 1 (TRPV1), a heat-activated channel, is sensitized by inflammation and modulates breathing and thus may play a key role. To investigate whether inflammatory sensitization of TRPV1 modifies neonatal ventilatory responses to heat stress, leading to respiratory alkalosis and an increased susceptibility to hyperthermic seizures, we treated neonatal rats with bacterial LPS, and breathing, arterial pH, invitro vagus nerve activity, and seizure susceptibility were assessed during heat stress in the presence or absence of a TRPV1 antagonist (AMG-9810) or shRNA-mediated TRPV1 suppression. LPS-induced inflammatory preconditioning lowered the threshold temperature and latency of hyperthermic seizures. This was accompanied by increased tidal volume, minute ventilation, expired CO2, and arterial pH (alkalosis). LPS exposure also elevated vagal spiking and intracellular calcium concentrations in response to hyperthermia. TRPV1 inhibition with AMG-9810 or shRNA reduced the LPS-induced susceptibility to hyperthermic seizures and altered the breathing pattern to fast shallow breaths (tachypnea), making each breath less efficient and restoring arterial pH. These results indicate that inflammation exacerbates thermal hyperpnea-induced respiratory alkalosis associated with increased susceptibility to hyperthermic seizures, primarily mediated by TRPV1 localized to vagus neurons.

Exploring the influence of microbiota on gestational diabetes and its potential as a biomarker

Gestational diabetes mellitus (GDM) represents a significant health concern during pregnancy, impacting both maternal and fetal well-being. While conventional diagnostic protocols typically rely on blood glucose levels in the latter stages of pregnancy, there is a pressing need for early detection methods to mitigate potential risks. A plethora of glucose-based or non-glucose-based biomarkers have been investigated for their potential to predict GDM in early pregnancy. Though specific biomarkers showed promise in predicting GDM, their clinical usage has been constrained by the lack of validation and limitation in translating them into routine clinical use. This review aims to highlight and discuss the potential and practical utility of existing biomarkers and emergent biomarkers, such as microbiomes, in diagnosing GDM. A comprehensive analysis of recent studies reveals significant alterations in the composition and diversity of microbiota among women with GDM, suggesting their potential utility as predictive markers for this condition. For instance, distinct microbial profiles characterized by an increased abundance of Eisenbergiella, Tyzzerella 4, and Lachnospiraceae NK4A136, alongside decreased levels of Parabacteroides, Parasutterella, and Ruminococcaceae UCG 002, correlated with fasting blood glucose levels, hinting at their relevance in early GDM detection. Furthermore, proposed microbiota-targeted panels demonstrated promising predictive accuracy. Beyond gut microbiota, recent investigations have also explored the potential of oral microbiota as predictive biomarkers for GDM. Studies have highlighted the discriminatory capacity of specific oral microbes, such as Streptococcus in saliva and Leptotrichia in dental plaque, in distinguishing GDM from healthy pregnancies. Moreover, the examination of gut microbiota-derived metabolites has shown promising results in serum-based GDM prediction. These findings collectively underscore the potential of microbiota and its metabolites as valuable biomarkers for the early detection of GDM. However, further research is warranted to elucidate the mechanistic links between microbial dysbiosis and GDM pathogenesis, ultimately facilitating the development of targeted therapeutic interventions and personalized management strategies.