Functional Integrity Research Articles

Sling Results in Better Sleep Quality and Less Anxiety Early After Arthroscopic Rotator Cuff Repair: A Randomized Single-Blinded Trial.

Sleep disturbance is commonly reported by patients wearing an abduction brace after arthroscopic rotator cuff repair (ARCR). Although a sling has been proven noninferior to an abduction brace for function and repair integrity, there is no evidence-based medical support for the advantage of the sling in improving sleep quality compared with a brace. This study aimed to compare the effects of a sling and an abduction brace on sleep quality and clinical outcomes after ARCR. It was hypothesized that immobilization in a sling would result in better sleep quality while not deteriorating clinical outcomes and bone-tendon healing compared with an abduction brace. Randomized controlled trial; Level of evidence, 1. A total of 142 consecutive patients with rotator cuff tears were randomly assigned to 2 groups: (1) the brace group, receiving abduction brace immobilization for 6 weeks, and (2) the sling group, receiving sling immobilization after ARCR for 6 weeks. The primary outcome was the Pittsburgh Sleep Quality Index at 6 weeks postoperatively. Secondary outcomes-American Shoulder and Elbow Surgeons score, Self-rating Anxiety Scale, pain, satisfaction, and tendon healing (using ultrasonography)-were evaluated until 1 year postoperatively. Complete outcome measurements were obtained for 131 patients. The Pittsburgh Sleep Quality Index at 6 weeks was 11.1 ± 2.7 for the brace group and 9.2 ± 2.3 for the sling group (P < .001), indicating a statistically significant advantage for the sling group. The sling group also reported significantly lower Self-rating Anxiety Scale, lower pain level, and higher satisfaction scores at 6 weeks. No significant difference was observed in outcome measures between groups at 1 year. The tendon healing rates (91% vs 88%, respectively) were comparable between the brace and sling groups within the first 1 year (risk ratio, 1.03 [95% CI, 0.92-1.16]; P = .59). The use of a sling resulted in better sleep quality, less anxiety, and higher satisfaction compared with an abduction brace in the first 6 weeks after ARCR; nevertheless, functional outcomes and repair integrity were similar at 1 year postoperatively between the 2 groups. These findings indicate that a sling is appropriate for the postoperative care of ARCR. However, caution should be used when interpreting these results because the clinical relevance of sling-related benefits warrants further investigation. ChiCTR2200059967 (Chinese Clinical Trial Registry).

Euphorbium compositum SN improves the innate defenses of the airway mucosal barrier network during rhinovirus infection.

Rhinoviruses (RV) are the major cause of common colds in healthy individuals and are associated with acute exacerbations in patients with chronic lung diseases. Yet, no vaccines or effective treatment against RV are available. This study investigated the effect of Euphorbium compositum SN (ECSN6), a multicomponent, multitarget medication made from natural ingredients, on the mucosal barrier network during RV infection. Mucociliary-differentiated airway epithelial cell cultures were infected with RV or sham, and treated with 20% ECSN6 or placebo twice daily. Barrier integrity was assessed by measuring transepithelial resistance (TER), permeability to inulin, and expression and localization of intercellular junctions proteins (IJ). Ciliary beat frequency (CBF), expression of pro-inflammatory cytokines, antiviral interferons and mucins, and viral load were also measured. C57BL/6 mice were infected intranasally with RV or sham and treated with 40% ECSN6 or placebo twice daily. Inflammation of sinunasal mucosa, localization of E-cadherin, viral load and mucin gene expression were determined. ECSN6-treated, uninfected cell cultures showed small, but significant increase in TER over placebo, which was associated with enhanced localization of E-cadherin and ZO-1 to IJ. In RV-infected cultures, treatment with ECSN6, but not placebo prevented RV-induced (1) reduction in TER, (2) dissociation of E-cadherin and ZO-1 from the IJ, (3) mucin expression, and (4) CBF attenuation. ECSN6 also decreased RV-stimulated expression of pro-inflammatory cytokines and permeability to inulin. Although ECSN6 significantly increased the expression of some antiviral type I and type III interferons, it did not alter viral load. In vivo, ECSN6 reduced RV-A1-induced moderate inflammation of nasal mucosa, beneficially affected RV-A1-induced cytokine responses and Muc5ac mRNA expression and prevented RV-caused dissociation of E-cadherin from the IJ of nasal mucosa without an effect on viral clearance. ECSN6 prevents RV-induced airway mucosal barrier dysfunction and improves the immunological and mucociliary barrier function. ECSN6 may maintain integrity of barrier function by promoting localization of tight and adherence junction proteins to the IJ. This in turn may lead to the observed decrease in RV-induced pro-inflammatory responses in vitro. By improving the innate defenses of the airway mucosal barrier network, ECSN6 may alleviate respiratory symptoms caused by RV infections.

Mitigating effect of chitosan-coated zinc oxide nanoparticles on cryopreservation-induced DNA damage in human spermatozoa

Zinc, an essential micronutrient, is an important mediator of sperm function. Supplementation of zinc oxide nanoparticle (ZnONPs) to semen cryopreservation medium has shown beneficial effects on sperm function, mainly due to its antioxidant and membrane stabilization properties. However, the ZnONPs are known to be membrane impermeable. In the current study, we explored the beneficial properties of membrane permeable zinc oxide nanoparticles on semen cryopreservation outcome. For the study, 52 liquefied human ejaculates were cryopreserved with chitosan-coated ZnONPs and stored in liquid nitrogen for one week. Samples were thawed and assessed for the sperm functional characters and DNA integrity. Significantly higher motility (P < 0.05), prolonged survival (P < 0.05) and lower DNA damage (P < 0.05) was observed in spermatozoa of semen samples cryopreserved with chitosan-coated ZnONPs. In conclusion, the presence of chitosan-coated ZnONPs in the ejaculate prior to cryopreservation increases the survival and decreases DNA damage without compromising with the functional competence of spermatozoa.

EXTH-22. TARGETING MITOCHONDRIAL PROTEASE IN DIFFUSE GLIOMAS

Abstract BACKGROUND Targeting mitochondrial function has emerged as a promising therapeutic strategy in cancer treatment. TR107 is characterized as a specific activator of caseinolytic protease proteolytic subunit (ClpP) in the mitochondria, potentially affecting oncogenic pathways. Here, we investigated the effects of TR107 on adult malignant gliomas, IDH-wildtype and IDH-mutant METHODS We utilized patient-derived glioma cells to determine the efficacy of TR107 with cell viability, proliferation, cell cycle, and apoptosis assays. Immunofluorescent staining and electron microscopy (EM) were employed to uncover organelle morphological changes upon treatment. Mitochondrial function and ATP production were assessed in live cells utilizing Seahorse analysis. Global proteomics and RNA sequencing were performed to identify treatment-induced dysregulated pathways in glioma cells RESULTS Both IDH-wildtype and IDH-mutant glioma cell lines were highly sensitive to TR107, showing at least 100 times lower IC50 compared to the related compound ONC201. Genetic knock out of ClpP revealed that the growth inhibitory effects of TR107 are ClpP-dependent. Interestingly, IDH-mutant cell lines showed a more profound disintegration of mitochondrial morphology and dysregulation of mitochondrial function evidenced by an enhanced suppression of oxidative phosphorylation, mitochondrial complexes expression, mtDNA copy number, complex I activity, and ATP production, compared to IDH-wildtype cells. Six days of treatment with TR107 led to a complete inhibition of cell growth and up to 97% of cell death in IDH-mutant cells, while 50% of IDH-wildtype cells remained viable. Western blot, EM, and RNAsequencing analyses uncovered autophagy as a potential pro-survival mechanism in IDH-wildtype cells. Importantly, multiple metabolic and DNA repair-related pathways were affected by the treatment, suggested by global proteomics and RNA sequencing. Finally, TR107 was not affected by ABC transporters, supporting its potential use in brain tumor patients CONCLUSION TR107 demonstrated potent cytotoxic effects in patient-derived glioma cells by disrupting mitochondrial structural and functional integrity. TR107 efficacy in vivo is under investigation.

Exploring non-canonical targets in Alzheimer’s disease: a departure from the norm

AbstractAlzheimer’s disease (AD), a progressive neurodegenerative disorder, is characterized by neurological impairments such as visual and sensory difficulties, motor dysfunction, sphincter issues, incoordination, gait abnormalities, and cognitive decline. Despite advances in understanding AD pathophysiology and the expansion of therapeutic options over the past three decades, the disease remains incurable. Current therapies, even those specifically targeting AD, often fail to significantly alter its progression, underscoring the need for innovative treatment approaches beyond symptomatic relief. This calls for a re-examination of AD pathology to identify potential therapeutic targets that go beyond conventional strategies. This review highlights four of the most promising non-canonical therapeutic targets: oligodendrocytes, the blood–brain barrier (BBB), neuroimmunometabolism, and the coagulation system. These components are crucial for maintaining the integrity and proper function of neurons and the brain, playing key roles in the progression of AD. Oligodendrocytes, for example, are essential for myelination and neuronal support, while BBB dysfunction can lead to impaired clearance of toxic proteins. Neuroimmunometabolism offers insights into how metabolic processes influence immune responses in the brain and dysregulation of the coagulation system has been linked to increased neuroinflammation and vascular abnormalities in AD. Recent discoveries in these fields provide new avenues for understanding the disease and identifying potential therapeutic targets. By exploring these non-canonical pathways, future research may offer breakthroughs in treating AD, moving beyond symptomatic management towards disease-modifying strategies.

Cryopreservation of Noble Scallop Mimachlamys nobilis sperm: Optimization study of cooling rate and thawing temperature

In marine biology reproduction research, the cryopreservation of sperm is a crucial area, especially for economically valuable species. Effective freezing techniques help maintain genetic diversity and support sustainable development in aquaculture. This study examined the effects of freezing protocols and thawing methods on the cryopreservation of Mimachlamys nobilis sperm. Experimental results indicated that a cooling rate of 5 °C/min and an equilibration time of 5 minutes were the most suitable conditions for maintaining the structural and functional integrity of the sperm. Comparisons of different thawing temperatures showed that 38 °C provided the best results, minimizing ice recrystallization and cellular damage. Additionally, it was found that a 10 % concentration of DMSO effectively balanced protection and cytotoxicity, maintaining sperm viability and motility. Transmission electron microscopy further revealed the impact of freezing conditions on sperm, including damage to the plasma membrane, dissolution, blurring and swelling of the acrosome and mitochondria, and cristae fragmentation and loss. This study emphasizes the importance of optimizing freezing and thawing protocols and accurately controlling cryoprotectant concentration, providing key insights for the effective long-term preservation of M.nobilis sperm. This is significant for the conservation of marine organisms and aquaculture.

REM sleep behavior disorder: Relation between aggressiveness and emotions expressed in dream enactment and cognitive and anxiety/depression status

Aggressiveness and negative emotions in dreams reports of patients with alfa-synucleinopathies have been associated with cognitive dysfunction. Observation of dream enactment episodes could be a more precise method to capture dream content in patients with REM sleep behavior disorder (RBD). Our objective was to assess the relation between aggressive and emotional dream enactment episodes in patients with RBD and cognition and depression/anxiety.Motor events (ME) during REM sleep were classified by visual inspection of video-PSG files. Cognition and anxiety/depression were assessed with MoCA and the Hospital Anxiety and Depression Scale (HADS), respectively. Multivariate regression analysis was performed, with MoCA or HADS scores as predictors, age and DED as co-variates and aggressive, negative and positive ME frequency (raw values, per total and per complex indexes) as the dependent variable.We included 15 patients with isolated RBD and 12 and 4 with RBD associated with Parkinson's disease and Dementia with Lewy Bodies, respectively. They presented a total of 873 ME. There was a significant positive association between HADS score and violent/complex and negative emotion/complex indexes. There was a significant positive association between MoCA score and violent/complex index.A significant correlation between depression/anxiety severity and negative emotion and aggression ME frequency agrees with the dream continuity hypothesis and suggests that REM sleep acts as a regulator of emotional experience. Patients with a higher prevalence of aggressive ME had higher scores in cognitive testing, suggesting that the elaboration of these complex movements could depend on the integrity of cognitive functions.

Evaluation of the Detrimental Impact of Low-Intensity Laser Radiation on the Characteristics of Sperm Movement, Motion, and DNA Damage

It is generally accepted that low-level laser therapy promotes cellular energy production and increases the synthesis of ATP by triggering the mitochondrial electron transport chain's photosensitive cytochrome c oxidase complex. Nevertheless, this investigation aimed to examine the possible adverse impact on sperm function and DNA integrity of low-intensity laser radiation with a wavelength of 980 nm. Following standard analysis, forty semen samples were collected and categorized as either asthenospermic, oligospermic, or normospermic. The remaining semen was subjected to standard semen analysis, and the aliquots were divided into treatment and control groups. A continuous-wave 980 nm laser with an output power of 100 mW and an energy density of 10 J/cm2 was applied to the treated samples for 30 s. Divided samples underwent incubation at 37oC, and semen analysis was used to assess aliquots at 30 s and 2 h intervals. Following the incubation time, each sample was frozen in 250 mL at -80oC until DNA fragmentation was examined using flow cytometry. Thirty minutes after treatment, there was a noticeable increase in sperm movement; the rise was largest in oligospermic and asthenospermic samples (88%) while samples of normal sperm displayed the least increment (7.5%). There was no discernible increase in DNA damage in the treatment samples compared to the control samples. The treatment samples had 21.8% and the control samples had 25.3% of the DNA fragmentation index. The dynamics of sperm motion were noticeably altered. Short-term exposure to low-level laser radiation appeared to improve the motion and movement of treated sperm, and after 2 h, there was no increase in DNA damage. Asthenospermia and mitochondrial dysfunction may be related in some circumstances. To fully understand the ramifications of these results for possible medicinal applications, more research is needed. Our research's conclusions suggest that low-level laser stimulation is a useful and safe technique for identifying viable immotile spermatozoa in a particular sample. It may also cause these spermatozoa to move about, which could have positive therapeutic effects.

The impact of body position on neurofluid dynamics: present insights and advancements in imaging

The intricate neurofluid dynamics and balance is essential in preserving the structural and functional integrity of the brain. Key among these forces are: hemodynamics, such as heartbeat-driven arterial and venous blood flow, and hydrodynamics, such as cerebrospinal fluid (CSF) circulation. The delicate interplay between these dynamics is crucial for maintaining optimal homeostasis within the brain. Currently, the widely accepted framework for understanding brain functions is the Monro-Kellie’s doctrine, which posits a constant sum of intracranial CSF, blood flow and brain tissue volumes. However, in recent decades, there has been a growing interest in exploring the dynamic interplay between these elements and the impact of external factors, such as daily changes in body position. CSF circulation in particular plays a crucial role in the context of neurodegeneration and dementia, since its dysfunction has been associated with impaired clearance mechanisms and accumulation of toxic substances. Despite the implementation of various invasive and non-invasive imaging techniques to investigate the intracranial hemodynamic or hydrodynamic properties, a comprehensive understanding of how all these elements interact and are influenced by body position remains wanted. Establishing a comprehensive overview of this topic is therefore crucial and could pave the way for alternative care approaches. In this review, we aim to summarize the existing understanding of intracranial hemodynamic and hydrodynamic properties, fundamental for brain homeostasis, along with factors known to influence their equilibrium. Special attention will be devoted to elucidating the effects of body position shifts, given their significance and remaining ambiguities. Furthermore, we will explore recent advancements in imaging techniques utilized for real time and non-invasive measurements of dynamic body fluid properties in-vivo.

Characterization of Contusive Spinal Cord Injury by Monitoring Motor-Evoked Potential

This study involves longitudinal neuro-electrophysiological analysis using motor-evoked potentials (MEP) and the Basso, Beattie, and Bresnahan behavioral examinations (BBB) to evaluate moderate mid-thoracic contusive spinal cord injury (SCI) in a rat model. Objectives/Background: The objective of the study is to characterize the onset and progression of contusive SCI over an eight-week period using a clinically applicable tool in an in vivo model. The background highlights the importance of a reliable and reproducible injury model and assessment tools for SCI. Methods: The methods section describes the experimental setup, including randomly assigned rats in three groups: Sham, Control, and Injury (undergoing a moderate contusive SCI using the NYU-Impactor). MEP monitoring and BBB examinations are conducted at baseline and weekly for eight weeks post-injury. Results: The results indicate that the relative MEP power spectral decreased to 11% and 22% in the left and right hindlimbs, respectively, during the first week post-SCI. In the second week, a slight spontaneous recovery was observed, reaching 17% in the left and 31% in the right hindlimbs. Over the following four weeks post-SCI, continuing deterioration of MEP signal power was observed with no detectable recovery. Conclusions: SCI attenuates hindlimb MEP power spectral and reduces locomotion, though the changes in MEP and locomotion exhibit distinct temporal patterns. The MEP monitoring provides valuable insights into the functional integrity of motor pathways following SCI and offer a sensitive and reliable assessment. By implementing MEP monitoring, researchers can track the progression of SCI and evaluate the efficacy of therapeutic interventions quantitatively.

Enhancing of Rabbit Sperm Cryopreservation with Antioxidants Mito-Tempo and Berberine

Cryopreservation plays a critical role in animal breeding and the conservation of endangered species, but it often compromises sperm characteristics such as morphology, motility, and viability due to oxidative stress. This study explores the antioxidative effect of Mito-Tempo (MT) and Berberine (BER) to enhance post-thaw sperm quality in rabbits. Pooled rabbit sperm samples were supplemented with different concentrations (0.0, 0.5, 5, 10, 50 µmol/L) of MT and BER. Sperm motility was evaluated using computer-assisted semen analysis, while viability, apoptosis, reactive oxygen species (ROS) levels, acrosome integrity, and mitochondrial function were assessed through flow cytometry. The results revealed that MT at 5 and 10 µmol/L and BER at 10 µmol/L significantly improved total and progressive motility, mitochondrial activity, and sperm viability compared to the control group. Furthermore, 10 µmol/L BER enhanced acrosome integrity, while both 5 µmol/L MT and 10 µmol/L BER effectively reduced ROS levels and apoptosis. This study is the first to demonstrate the protective effects of MT and BER on rabbit sperm during cryopreservation. By mitigating oxidative stress and reducing apoptosis, these antioxidants markedly improved post-thaw sperm quality, positioning MT and BER as promising agents for improving sperm cryosurvival.

Crude Garden Cress Seed Oil (Lepidium sativum Linn.) Enhances Post-Thawed Boar Sperm Quality

This study aimed to examine the effects of crude garden cress seed oil (CGCSO) on frozen–thawed boar sperm qualities. Semen ejaculates (n = 12) were collected and further divided into six equal aliquots based on CGCSO concentrations (0, 0.5, 1, 1.5, 2, and 2.5% v/v) in the freezing extender. Semen samples were processed and cryopreserved utilizing the traditional liquid nitrogen vapor technique. Subsequently, semen samples were thawed in a thermos with warm water at 50 °C for 12 s and evaluated for sperm morphology using scanning electron microscopy, sperm motility using a CASA, sperm viability, acrosome integrity, mitochondrial function, MDA level, total antioxidant capacity (TAC), glutathione peroxidase (GSH-Px), and catalase (CAT) activity. The results indicated that 1% CGCSO resulted in superior post-thaw sperm characteristics, including enhanced sperm morphology, motility, viability, acrosome integrity, and mitochondrial function. Particularly, the total motile sperm increased by 16.5%, progressive motile sperm increased by 13.0%, viability improved by 15.1%, acrosome integrity increased by 14%, and mitochondrial function improved by 14.1% compared to the control group. CGCSO treatment at 1% and 1.5% exhibited the lowest level of MDA (45.73 ± 11.2 and 45.73 ± 11.3 µmol/L, respectively) compared to the other groups. The CGCSO-supplemented groups showed higher values of TAC, GSH-Px, and CAT than the control group but not significantly.

A Pro-Angiogenic Immunoprotective Membrane for Cell Therapies.

Immunoisolation strategies that rely on porous membranes play an important role in cell transplantation therapies to protect cells from the host's immune system. These membranes must possess immunoprotective properties while facilitating the transport of nutrients and cell products to maintain the functional integrity of encapsulated cells. An easy and scalable process is described to fabricate a dual function porous polymeric membrane that shields cells against immune cell attack and promotes vascularization to address the nutritional and oxygen requirements of transplanted cells. The fabrication process results in a membrane cross-section with a gradient of nanopores to micropores that support cell immunoisolation and interfacial vascularization requirements, respectively. The membranes demonstrate excellent cell compatibility and effectively prevent T cell transmigration without compromising glucose diffusion and oxygen permeability. In a murine subcutaneous implantation model, membranes are stable for 60 days and exhibit significantly reduced fibrous capsules, with enhanced vascularization near the membrane. These porous polymeric membranes can potentially be used as pro-angiogenic immunoprotective membranes for cell transplantation applications where maximizing cell viability and function is of critical importance.

Deep learning based highly accurate transplanted bioengineered corneal equivalent thickness measurement using optical coherence tomography

Corneal transplantation is the primary treatment for irreversible corneal diseases, but due to limited donor availability, bioengineered corneal equivalents are being developed as a solution, with biocompatibility, structural integrity, and physical function considered key factors. Since conventional evaluation methods may not fully capture the complex properties of the cornea, there is a need for advanced imaging and assessment techniques. In this study, we proposed a deep learning-based automatic segmentation method for transplanted bioengineered corneal equivalents using optical coherence tomography to achieve a highly accurate evaluation of graft integrity and biocompatibility. Our method provides quantitative individual thickness values, detailed maps, and volume measurements of the bioengineered corneal equivalents, and has been validated through 14 days of monitoring. Based on the results, it is expected to have high clinical utility as a quantitative assessment method for human keratoplasties, including automatic opacity area segmentation and implanted graft part extraction, beyond animal studies.

Distinct brain and neurocognitive transformations after bariatric surgery: a pilot study

BackgroundObese patients have worse outcomes after surgery and are at increased risk for perioperative neurocognitive disorders (PND). Our aim was to detail the cognitive trajectories of patients undergoing bariatric surgery (BS) and map distinct structural brain changes using magnetic resonance imaging (MRI) to better understand the association between the vulnerable brain, surgery, and the arc of PND.MethodsProspective pilot study with longitudinal comprehensive cognitive assessments and MRI were performed on obese patients scheduled for BS. We analyzed baseline cognitive function and high-resolution T1-/T2-weighted brain images on 19 obese patients [age, 54 (9) years, BMI, 40 (36, 42) kg m−2] and compared with 50 healthy control subjects [age, 52 (6) years; BMI, 25 (24, 27) kg m−2]. Patients were evaluated within five days of BS (baseline), immediately after (within 48h), and follow up at six months.ResultsAt baseline, obese patients had significant brain tissue changes seen in MRI and decreased cognitive scores compared to controls (MoCA 26 vs 28, P = 0.017). Surgery induced further gray matter volume and brain tissue changes along with reduced cognitive scores within the immediate postoperative period (MoCA 26 vs 24, P &amp;lt; 0.001). At six months, we observed reversal of brain alterations for most patients and a concomitant rebound of cognitive scores to patient’s baseline status.ConclusionsBariatric surgery resulted in worsening of preexisting brain structural integrity and lower cognitive function for obese patients compared to baseline. These distinct brain lesions are consistent with specific domains of cognition. Most of these changes reverted to patient’s baseline condition within six months after surgery.

CLSTN3B promotes lipid droplet maturation and lipid storage in mouse adipocytes

Interorganelle contacts facilitate material exchanges and sustain the structural and functional integrity of organelles. Lipid droplets (LDs) of adipocytes are responsible for energy storage and mobilization responding to body needs. LD biogenesis defects compromise the lipid-storing capacity of adipocytes, resulting in ectopic lipid deposition and metabolic disorders, yet how the uniquely large LDs in adipocytes attain structural and functional maturation is incompletely understood. Here we show that the mammalian adipocyte-specific protein CLSTN3B is crucial for adipocyte LD maturation. CLSTN3B employs an arginine-rich segment to promote extensive contact and hemifusion-like structure formation between the endoplasmic reticulum (ER) and LD, allowing ER-to-LD phospholipid diffusion during LD expansion. CLSTN3B ablation results in reduced LD surface phospholipid density, increased turnover of LD-surface proteins, and impaired LD functions. Our results establish the central role of CLSTN3B in the adipocyte-specific LD maturation pathway that enhances lipid storage and maintenance of metabolic health under caloric overload in mice of both sexes.

Sleep quality and the integrity of ascending reticular activating system – A multimodal MRI study

Sleep is crucial for maintaining brain homeostasis and individuals with insufficient sleep are prone to more pronounced brain atrophy as compared to sufficiently sleeping peers. Moreover, sleep quality deteriorates with ageing and ageing is also associated with cerebral structural and functional changes, pointing to their mutual bidirectional interrelationship. This study aimed at determining whether sleep quality and age, separately, affect brain integrity and subsequently, whether sleep significantly modulates the effect of age on brain structural and functional integrity. 113 healthy volunteers underwent a multi-modal MRI imaging to extract information about the microstructure and function of major nodes of the ascending reticular activating system. Sleep quality was assessed by self-administered Pittsburgh's sleep quality index (PSQI) questionnaire. Subject were divided into good (global PSQI score <5) and poor (global PSQI score ≥5) sleep quality group. Whereas only borderline correlations were found between sleep quality and MRI metrics, age exhibited widespread correlations with both functional and microstructural MRI metrics. The latter effect was significantly modulated by sleep quality in ascending reticular activating system, hypothalamus, thalamus and also hippocampus in MRI metrics associated with iron load, cellularity and connectivity, mainly in the subgroup with poor sleep quality. Ergo, our results indicate sleep quality as a substantial contributor to both microstructural and functional brain changes in ageing and call for further research in this emerging topic.

Rebalance the Inhibitory System in the Elderly Brain: Influence of Balance Learning on GABAergic Inhibition and Functional Connectivity.

Aging involves complex processes that impact the structure, function, and metabolism of the human brain. Declines in both structural and functional integrity along with reduced local inhibitory tone in the motor areas, as indicated by reduced γ-aminobutyric acid (GABA) levels, are often associated with compromised motor performance in elderly adults. Using multimodal neuroimaging techniques including magnetic resonance spectroscopy (MRS), diffusion magnetic resonance imaging (MRI), functional MRI as well as transcranial magnetic stimulation to assess short-interval intracortical inhibition (SICI), this study explores whether these age-related changes can be mitigated by motor learning. The investigation focused on the effects of long-term balance learning (3 months) on intracortical inhibition, metabolism, structural, and functional connectivity in the cortical sensorimotor network among an elderly cohort. We found that after 3 months of balance learning, subjects significantly improved balance performance, upregulated sensorimotor cortical GABA levels and ventral sensorimotor network functional connectivity (VSN-FC) compared to a passive control group. Furthermore, correlation analysis suggested a positive association between baseline VSN-FC and balance performance, between baseline VSN-FC and SICI, and between improvements in balance performance and upregulation in SICI in the training group, though these correlations did not survive the false discovery rate correction. These findings demonstrate that balance learning has the potential to counteract aging-related decline in functional connectivity and cortical inhibition on the "tonic" (MRS) and "functional" (SICI) level and shed new light on the close interplay between the GABAergic system, functional connectivity, and behavior.

Exploring transcriptomic mechanisms underlying pulmonary adaptation to diverse environments in Indian rams.

The Changthangi sheep thrive at high altitudes in the cold desert regions of Ladakh, India while Muzaffarnagri sheep are well-suited to the low altitude plains of northern India. This study investigates the molecular mechanisms of pulmonary adaptation to diverse environments by analyzing gene expression profiles of lung tissues through RNA sequencing. Four biological replicates of lung tissue from each breed were utilized to generate the transcriptomic data. Differences in gene expression analysis revealed discrete expression profiles in lungs of each breed. In Changthangi sheep, genes related to immune responses, particularly cytokine signaling, were significantly enriched. Pathway analysis highlighted the activation of NF-kB signaling, a key mediator of inflammation and immune response. Additionally, the gene network analysis indicated a strong association between cytokine signaling, hypoxia-inducible factor (HIF) and NF-kB activation, suggesting a coordinated response to hypoxic stress in lungs of Changthangi sheep. In Muzaffarnagri sheep, the gene expression profiles were enriched for pathways related to energy metabolism, homeostasis and lung physiology. Key pathways identified include collagen formation and carbohydrate metabolism, both of which are crucial for maintaining lung function and structural integrity. Gene network analysis further reinforced this by revealing a strong connection between genes associated with lung structure and function. Our findings shed light on the valuable insights into gene expression mechanisms that enable these sheep breeds to adapt to their respective environments and contribute to a better understanding of high altitude adaptation in livestock.

Sodium-glucose cotransporter protein 2 inhibition, plasma proteins, and ischemic stroke: A mediation Mendelian randomization and colocalization study

PurposeTo determine the effect of the sodium-glucose cotransporter protein 2 (SGLT2) inhibition on ischemic stroke (IS) and investigate the circulating proteins that mediate the effects of SGLT2 inhibition on IS. MethodsThe effects of SGLT2 inhibition on IS were evaluated using two-sample Mendelian randomization (MR) analyses. The 4,907 circulating proteins from the plasma proteome were assessed to identify potential mediators. Sensitivity, colocalization, and external validation analyses were conducted to validate critical findings. MR analyses were also used to evaluate the associations of SGLT2 inhibition with magnetic resonance imaging (MRI)-based biomarkers and functional prognoses post-IS. ResultsSGLT2 inhibition was significantly associated with decreased risks of IS (odds ratio (OR): 0.39, 95% confidence interval (CI): 0.25–0.61, p = 3.53 × 10-5) and cardioembolic stroke (OR: 0.16, 95% CI: 0.07–0.37, p = 1.82 × 10-5); the effect of SGLT2 inhibition on IS was indirectly mediated through pathways involving tryptophanyl-transfer RNA synthetase (WARS) (β: -0.08, 95% CI: -0.15 – -0.01, p = 0.034) and matrix metalloproteinase 12 (MMP12) (β: -0.06, 95% CI: -0.12 – -0.01, p = 0.016), with mediation proportions of 8.2% and 6.8%, respectively. The external validation confirmed the WARS mediating effect. In addition, the sensitivity and colocalization analyses and MR analyses of MRI biomarker-based and functional prognostic outcomes supported these results. ConclusionIn this study, we demonstrated from a genetic perspective that SGLT2 inhibitors prevent the development of IS and improve functional prognostic outcomes and brain microstructural integrity. WARS and MMP12 may act as potential mediators, presenting a novel approach for IS intervention.