Differential Changes Research Articles

Structural and Functional Properties of Lower Extremity Tendons in Men.

Comstock, BA, Flanagan, SD, Denegar, CR, Newton, RU, Häkkinen, K, Volek, JS, Maresh, CM, Kraemer, WJ. Structural and functional properties of lower extremity tendons in men. J Strength Cond Res XX(X): 000-000, 2024-The purpose of this study was to understand further patellar and Achilles tendon structure and function, body composition, and serum collagen turnover biomarkers in young men who performed heavy resistance training (RT, n = 13, age: 22.2 ± 1.4 years) compared with recreationally active men who were not resistance-trained (NR, n = 13, age: 22.8 ± 2.2 years). Tendon properties were measured at rest and during maximal voluntary isometric efforts using ultrasonography and dynamometry. Lean body mass (LBM) and bone mineral density (BMD) were assessed with dual X-ray absorptiometry. Serum collagen turnover markers were analyzed and related to tendon measures. Resistance-trained men had significantly (p ≤ 0.05) greater LBM and BMD compared with recreationally active men. Resistance-trained men also showed significantly greater patellar tendon (PT) stiffness (45%) and Young's modulus (36%), though the PT cross-sectional area (CSA) did not differ significantly between groups. Achilles tendon CSA was significantly larger in resistance-trained men. Still, other properties such as stiffness and modulus did not differ significantly between the groups. Serum collagen turnover markers showed no significant differences between groups and were not correlated to any tendon or bone biomarkers. The findings support that resistance-trained men have greater LBM and BMD. However now, it reveals that tendon adaptations differ, as not all measures were similarly affected in both tendons. The blood biomarkers did not show any obvious roles in explaining the differential changes in tendons. Heavy RT induces differential tendon changes potentially due to complex interactions of training variables.

Race/Ethnic Differences in In-Hospital Mortality after Acute Ischemic Stroke.

Stroke mortality has declined, with differential changes by race; stroke is now the 5th leading cause of death overall, but 2nd leading cause of death in Black individuals. Little is known about recent race/ethnic and sex trends in in-hospital mortality after acute ischemic stroke (AIS) and whether system-level factors contribute to possible differences. Using the National Inpatient Sample, adults (≥18 years) with a primary diagnosis of AIS from 2006 to 2017 (n=643,912) were identified. We assessed in-hospital mortality by race/ethnicity (White, Black, Hispanic, Asian/Pacific Islander [API], other), sex, and age. Hospitals were categorized by proportion of White patients served: "75% White hospitals", "50-75% White hospitals", and "<50% White hospitals". Using survey adjusted logistic regression, the association between race/ethnicity and odds of mortality was assessed, adjusting for key sociodemographic, clinical, and hospital characteristics (e.g., age, comorbidities, stroke severity, do not resuscitate orders, and palliative care). Overall, mortality decreased from 5.0% in 2006 to 2.9% in 2017 (p<0.001). Comparing 2012-2017 to 2006-2011, there was a 68% reduction in mortality odds overall after adjusting for covariates, most prominent in White individuals (69%) and smallest in Black individuals (57%). Compared to White patients, Black and Hispanic patients had lower odds of mortality (adjusted odds ratio (aOR) 0.82, 95% CI 0.78-0.87 and aOR 0.93, 95% CI 0.87-1.00), primarily driven by those >65 years (age x ethnicity interaction p < 0.0001). Compared to White men, Black, Hispanic, and API men, and Black women had lower aOR of mortality. The differences in mortality between White and all the other race/ethnic groups combined were most pronounced in 75% White hospitals (aOR 0.80, 0.74-0.87) compared to 50-75% White hospitals (aOR 0.85, 0.79-0.91) and <50% White hospitals (aOR 0.88, 0.81-0.95; interaction effect: p=0.005). AIS mortality decreased dramatically in recent years in all race/ethnic subgroups. Overall, while individuals of other race/ethnic subgroups had lower mortality odds compared to White individuals, this effect was significantly lower in hospitals serving predominantly White patients compared to those serving minority populations. White patients had higher , mortality than the other race/ethnic groups, a difference that was most striking in hospitals predominantly serving White patients. Further study is needed to understand these differences and to what extent sociocultural, biological, and system-level factors play a role.

Affective disorders: eliminate WArning signs And REstore functioning: AWARE. Results from a randomized controlled multimodular intervention study targeting functioning in patients with affective disorders.

There is a compelling need for innovative intervention strategies for patients with affective disorders, given their increasing global prevalence and significant associated disability and impaired functioning. This study aimed to investigate whether a comprehensive multimodule individualized intervention (AWARE), targeting known mediators of functioning, improves functioning in affective disorders. AWARE was a randomized, controlled, rater-blind clinical trial conducted at two centers in the Capital Region of Denmark (Clinicaltrials.gov, NCT04701827). Participants were adults with bipolar disorder or major depressive disorder and impaired functioning. Participants were randomized to the six-month AWARE intervention or treatment as usual (TAU). The AWARE intervention is based on the International Classification of Functioning, Disability and Health (ICF) Brief Core Set for Bipolar and Unipolar Disorder.The primary outcome was observation-based functioning using the Assessment of Motor and Process Skills (AMPS). Secondary outcomes were functioning, QoL, stress, and cognition. Between February 2021 and January 2023, 103 patients were enrolled; 50 allocated to AWARE treatment and 53 to TAU (96 included in the full analysis set). There was no statistically significant differential change over time between groups in the primary outcome (AMPS), however, both groups showed a statistically significant improvement at endpoint. The AWARE intervention had a statistically significant effect compared with TAU on secondary outcomes of patient-reported functioning, stress and cognition. Compared with TAU, the AWARE intervention was ineffective at improving overall functioning on the primary outcome, presumably due to the short duration of the intervention. Further development of effective treatments targeting functioning is needed.

Novel Octa-Structure Metamaterial Architecture for High Q-Factor and High Sensitivity in THz Impedance Spectroscopy.

Terahertz (THz) electric inductive-capacitive (ELC) resonant metamaterials (MMs) are well established tools that can be used to detect the presence of dielectric material (e.g., nanoparticles, bioparticles, etc.) spread on their surfaces within the gap of the capacitive plates of a nanoantenna array. In THz spectroscopy, the amount of the red shift in the resonance frequency (ΔF) plays an important role in the detection of nanoparticles and their concentration. We introduce a new LC resonant MM architecture in the ELC category that maximizes dielectric sensitivity. The newly proposed architecture has an octahedral structure with uniform capacitive gaps at each forty-five-degree interval, making the structure super-symmetric and polarization independent. The inductor core is condensed into a central solid circle connecting all the eight lobes of the octahedron, thereby completing the LC circuit. This ELC resonator has very large active areas (capacitor-gaps), with hotspots at the periphery of each unit cell. The MM structure is repeated in a clustered fashion, so that the peripheral hotspots are also utilized in dielectric sensing. This results in enhancing the quality factor of MM resonance, as well as in increasing ΔF. The research comprises a combination of rigorous system-level simulations along with THz impedance spectroscopy laboratory experiments. We achieved a highly sensitive MM sensor with sensitivity reaching 1600 GHz/RIU. This sensor is fully CMOS compatible and has promising potential applications in high-sensitivity bio-sensing, characterization of nanoparticles, and ultra-low-concentration dielectrics detection, as well as in sensing differential changes in the composition of substances deposited on the metasurface.

Supplemental Oxygen Use, Outcomes, and Spending in Patients With COPD in the Medicare Competitive Bidding Program

The Medicare Competitive Bidding Program (CBP), a policy that reduced durable medical equipment prices, was implemented starting in 2011. Legislation introduced in 2024 aims to remove supplemental oxygen from the CBP because of concerns that recent decreases in oxygen prescribing are due to lower prices set by the CBP, which may have decreased supply and, in turn, limited oxygen access for patients with chronic lung diseases. However, low-value prescribing of oxygen is also prevalent in practice, and decreased oxygen prescription rates may not have necessarily caused harm. Little is known about the association of the CBP with patient use, outcomes, or spending. To examine the association between the 2011 and 2013 implementation of the CBP and supplemental oxygen use, clinical outcomes, and supplemental oxygen spending among patients with chronic obstructive pulmonary disease (COPD). This cohort study used a difference-in-differences (DID) method to evaluate the association between implementation of the CBP and the outcomes of interest. Patients aged 65 to 100 years with COPD living in CBP areas were compared with those living in areas where the CBP was not yet or never implemented. The study included 100% fee-for-service Medicare data of beneficiaries enrolled between July 1, 2009, and December 31, 2015. The data analysis was performed between June 6, 2023, and August 16, 2024. The 2011 and 2013 implementation cycles of the Medicare CBP. The primary outcomes were new prescriptions of oxygen during a 6-month period among beneficiaries with COPD and discontinuation of oxygen during a 6-month period among beneficiaries with COPD previously prescribed oxygen. Secondary outcomes included switches between oxygen types (gas, liquid, or concentrator), all-cause mortality, all-cause unplanned hospitalizations, COPD hospitalizations, and mean monthly allowed charges (total spending) over a 6-month period. The analysis was performed using the Callaway-Sant'Anna method, a dynamic DID model for policies with staggered implementation. Among 5 753 308 Medicare beneficiaries with COPD (mean [SD] age, 79.2 [8.4] years; 55.1% female), 25.9% received supplemental oxygen for at least one 6-month period during the study. The CBP was not associated with differential changes in new oxygen prescribing (DID estimate, -0.19 percentage points; 95% CI, -2.45 to 2.08 percentage points) or oxygen discontinuations (DID estimate, -0.77 percentage points; 95% CI, -8.15 to 6.60 percentage points). Similarly, differential changes were not observed in the secondary outcomes of oxygen switches (DID estimate, -0.04 percentage points; 95% CI, -0.44 to 0.37 percentage points), all-cause mortality (DID estimate, 0.16 percentage points; 95% CI, -7.52 to 7.84 percentage points), all-cause unplanned hospitalizations (DID estimate, -0.20 percentage points; 95% CI, -10.94 to 10.53 percentage points), or COPD hospitalizations (DID estimate, -0.04 percentage points; 95% CI, -2.57 to 2.48 percentage points). Differential changes were observed for mean monthly allowed charges (DID estimate, -$326.22; 95% CI, -$434.76 to -$217.68). In this study, among beneficiaries with COPD, the Medicare CBP was associated with differentially lower spending but not differential changes in oxygen use or clinical outcomes. This study did not find evidence supporting ongoing policy efforts to remove supplemental oxygen from the CBP.

Circadian rhythm disruption modulates enteric neural precursor cells differentiation leading to gastrointestinal motility dysfunction via the NR1D1/NF-κB axis

ObjectivesCircadian rhythm disruption (CRD) is implicated with numerous gastrointestinal motility diseases, with the enteric nervous system (ENS) taking main responsibility for the coordination of gastrointestinal motility. The purpose of this study is to explore the role of circadian rhythms in ENS remodeling and to further elucidate the underlying mechanisms.MethodsFirst, we established a jet-lagged mice model by advancing the light/dark phase shift by six hours every three days for eight weeks. Subsequent changes in gastrointestinal motility and the ENS were then assessed. Additionally, a triple-transgenic mouse strain (Nestin-creERT2 × Ngfr-DreERT2: DTRGFP) was utilized to track the effects of CRD on the differentiation of enteric neural precursor cells (ENPCs). RNA sequencing was also performed to elucidate the underlying mechanism.ResultsCompared to the control group, CRD significantly accelerated gastrointestinal motility, evidenced by faster intestinal peristalsis (P < 0.01), increased fecal output (P < 0.01), and elevated fecal water content (P < 0.05), as well as enhanced electrical field stimulation induced contractions (P < 0.05). These effects were associated with an increase in the number of glial cells and nitrergic neurons in the colonic myenteric plexus. Additionally, ENPCs in the colon showed a heightened differentiation into glial cells and nitrergic neurons. Notably, the NR1D1/nuclear factor-kappaB (NF-κB) axis played a crucial role in the CRD-mediated changes in ENPCs differentiation. Supplementation with NR1D1 agonist or NF-κB antagonist was able to restore gastrointestinal motility and normalize the ENS in jet-lagged mice.ConclusionsCRD regulates the differentiation of ENPCs through the NR1D1/NF-κB axis, resulting in dysfunction of the ENS and impaired gastrointestinal motility in mice.

Microvascular blood flow disturbances predict poor outcome of revascularization in CLTI patients

Abstract Background We have recently established hypoxic microvascular remodelling as a critical pathomechanistic factor that limits oxygen diffusion to muscle in chronic limb threatening ischaemia (CLTI). Using animal models of experimental hind limb ischaemia we have also displayed the biological relevance of post-ischaemic microvascular remodelling in skeletal muscle. Our results indicate that differential microvascular changes associate to muscle damage and repair. The natural microvascular dynamics that inherently promote muscle recovery are defected in CLTI patients. Particularly, a progressive arterialization of capillaries in CLTI muscle differentiates the dynamics of the microvasculature from initially assisting muscle regeneration to aggravating ischaemic damage. Methods To establish the clinical relevance of the post-ischaemic microvascular changes in CLTI, we now have studied the effect of microvascular remodelling on the outcome of CLTI patients undergoing surgical or endovascular revascularization. Contrast enhanced ultrasound was used preoperatively to determine the microvascular status of CLTI patients (n=36) scheduled for immediate revascularization. Outcome events such as: hospitalization; reoperation; leg amputation; or death, were postoperatively followed from medical records up to 6 months after revascularization. Patients were grouped according to muscle capillary transit time (Tct) being either similar (n=18) or shorter (n=18) to that in the contralateral legs of the patients, and treatment outcomes were compared between groups. Results The results display consistent increases in postoperative event rates in all measured outcomes in the ShortTct group as compared to controls (at 1 month 8 vs. 2 events (rate ratio 4.00 (95%CI: 0.85-18.84, p=0.080)); at 3 months 13 vs. 4 events (rate ratio 3.25 (95%CI: 1.06-9.97, p=0.039)); at 6 months 17 vs. 9 events (rate ratio 1.89 (95%CI: 0.84-4.24, p=0.123))). For example, 5 vs. 0; 7 vs. 1; and 7 vs. 4 reoperations were detected in the ShortTct group as compared to controls at 1, 3 and 6 months, respectively. By 6 months after initial revascularization also 2 deaths were recorded in the ShortTct group as compared to no deaths in the controls. Conclusions Despite still small samples size in this study, these results suggest that microvascular blood flow disturbances, such as short preoperative muscle capillary transit time, can predict poor outcome of CLTI patients after revascularization. Importantly, the results also identify patients with microvascular blood flow disturbances a subgroup of CLTI patients that should likely receive more specialized care to improve outcomes. The results also call for immediate actions from the scientific community to improve clinical detection of microvascular alterations and to develop strategies to normalize microvascular function in CLTI patients.

Dynamic Expression of Genes Encoding Ubiquitin Conjugating Enzymes (E2s) During Neuronal Differentiation and Maturation: Implications for Neurodevelopmental Disorders and Neurodegenerative Diseases

Background: The ubiquitination process plays a crucial role in neuronal differentiation and function. Numerous studies have focused on the expression and functions of E3 ligases during these different stages, far fewer on E2 conjugating enzymes. In mice, as in humans, these E2s belong to 17 conjugating enzyme families. Objectives: We analyzed by real-time PCR the expression dynamics of all known E2 genes during an in vitro differentiation of mouse hippocampal neuronal cultures, and after, we analyzed their stimulation with N-methyl-D-aspartate (NMDA). Results: We found that 36 of the 38 E2 genes were expressed in hippocampal neurons. Many were up-regulated during neuritogenesis and/or synaptogenesis stages, such as Ube2h, Ube2b, and Aktip. Rapid and delayed responses to NMDA stimulation were associated with the increased expression of several E2 genes, such as Ube2i, the SUMO-conjugating E2 enzyme. We also observed similar expression profiles within the same E2 gene family, consistent with the presence of similar transcription factor binding sites in their respective promoter sequences. Conclusions: Our study indicates that specific expression profiles of E2 genes are correlated with changes in neuronal differentiation and activity. A better understanding of the regulation and function of E2s is needed to better understand the role played by the ubiquitination process in physiological mechanisms and pathophysiological alterations involved in neurodevelopmental or neurodegenerative diseases.

Understanding the formation process of positive customer engagement behaviors: a quantitative and qualitative interpretation

PurposeTo investigate the impact of cognition, emotion and other factors on positive customer engagement behaviors and to identify the differential formation processes and dynamic changes in these behaviors.Design/methodology/approachWe used cognitive appraisals and coping theory as well as justice theory, to analyze comment data from the Xiaomi Community with natural language processing and binary logistic regression.FindingsOur results indicate that cognition and emotion are unnecessary for positive customer engagement. Users expressing different cognitions and emotions exhibit varied positive engagement behaviors. The behavioral dimension was the most frequently combined, followed by the affective and cognitive dimensions. Managers should adopt material or spiritual incentives to encourage users with positive emotions and cognition to become loyal. Additionally, addressing comments with distributive justice cognition can promote positive customer engagement.Originality/valueThis study clarifies the complex interplay between cognition, emotion and customer engagement behaviors, providing actionable insights for brand managers to foster customer loyalty and positive customer engagement.

Age-associated imbalance in immune cell regeneration varies across individuals and arises from a distinct subset of stem cells.

The age-associated decline in immunity manifests as imbalanced adaptive and innate immune cells, which originate from the aging of the stem cells that sustain their regeneration. Aging variation across individuals is well recognized, but its mechanism remains unclear. Here, we used high-throughput single-cell technologies to compare mice of the same chronological age that exhibited early or delayed immune aging phenotypes. We found that some hematopoietic stem cells (HSCs) in earlyaging mice upregulated genes related to aging, myeloid differentiation, and stem cell proliferation. Delayed aging was instead associated with genes involved in stem cell regulation and the response to external signals. These molecular changes align with shifts in HSC function. We found that the lineage biases of 30% to 40% of the HSC clones shifted with age. Moreover, their lineage biases shifted in opposite directions in mice exhibiting an early or delayed aging phenotype. In earlyaging mice, the HSC lineage bias shifted toward the myeloid lineage, driving the aging phenotype. In delayedaging mice, HSC lineage bias shifted toward the lymphoid lineage, effectively counteracting aging progression. Furthermore, the anti-aging HSC clones did not increase lymphoid production but instead decreased myeloid production. Additionally, we systematically quantified the frequency of various changes in HSC differentiation and their roles in driving the immune aging phenotype. Taken together, our findings suggest that temporal variation in the aging of immune cell regeneration among individuals primarily arises from differences in the myelopoiesis of a distinct subset of HSCs. Therefore, interventions to delay aging may be possible by targeting a subset of stem cells.

Impacts of zero-fare transit policy on health and social determinants: protocol for a natural experiment study.

Population-level efforts are needed to increase levels of physical activity and healthy eating to reduce and manage chronic diseases such as obesity, cardiovascular disease, and type 2 diabetes. Interventions to increase public transit use may be one promising strategy, particularly for low-income communities or populations of color who are disproportionately burdened by health disparities and transportation barriers. This study employs a natural experiment design to evaluate the impacts of a citywide zero-fare transit policy in Kansas City, Missouri, on ridership and health indicators. In Aim 1, comparison to 9 similar cities without zero-fare transit is used to examine differential changes in ridership from 3 years before to 4 years after the adoption of zero-fare. In Aim 2, Kansas City residents are being recruited from a large safety net health system to compare health indicators between zero-fare riders and non- riders. Longitudinal data on BMI, cardiometabolic markers, and economic barriers to health are collected from the electronic health record from 2017 to 2024. Cross-sectional data on healthy eating and device-measured physical activity are collected from a subsample of participants as part of the study procedures (N = 360). Numerous baseline characteristics are collected to account for differences between Kansas City and comparison city bus routes (Aim 1) and between zero-fare riders and non-riders within Kansas City (Aim 2). Evidence on how zero-fare transit shapes population health through mechanisms related to improved economic factors, transportation, physical activity, and healthy eating among low-income groups is expected.

Role of dopamine in reward expectation and predictability during execution of action sequences.

Reward-associated cues serve different functions depending on whether they precede or terminate action sequences. Cues that precede action sequences and signal opportunity for reward could serve as GO signals to initiate the sequence, whereas sequence termination cues could serve as response feedback by signaling reward delivery. Reward expectation during sequence execution depends on these cues and might condition whether behavior is habitual or goal-directed. However, it remains unknown how sequence initiation and termination cues differentially affect reward expectation and contribute to habit learning. Further, while mesolimbic dopamine plays a key role in cue-induced reward expectation and sequence learning, how dynamic changes in dopamine signals differ depending on the response strategy is unclear. Here, we determined how mesolimbic DA signals change over training during cue-mediated sequence learning, depending on the type of cue and the nature of behavioral control. We found sequence initiation and termination cues differentially affect reward expectation during action sequences, with the termination cue contributing to habit and automaticity. Distinct response strategies induced by sequence initiation and termination cues induced differential changes in mesolimbic DA signals that captured variations in reward expectation along sequence execution. Notably, habit-like behavior induced by the sequence termination cue was associated with a rapid shift in DA signals from reward retrieval to the cue. This habit-like behavior was reflected in behavioral inflexibility and attenuated DA reward prediction error signals. Finally, using optogenetics, we provide evidence that phasic DA activity elicited by the sequence termination cue is critical for the development of habit-like behavior.

Early Effects of the End-Stage Renal Disease Treatment Choices Model on Kidney Transplant Waitlist Additions.

Despite the mortality benefit of kidney transplantation over dialysis, only 13% of patients with end-stage kidney disease are on the transplant waitlist. Given the low rates of transplant waitlisting in the US, Medicare launched the End-Stage Renal Disease Treatment Choices (ETC) Model in 2021, the largest mandatory trial of payment incentives in kidney disease, which randomized 30% of healthcare markets to financial bonuses/penalties to improve kidney transplantation and home dialysis use. This study examines the effect of ETC payment adjustments on US kidney transplant waitlist additions. Using data from the Organ Procurement and Transplantation Network registry, we examined kidney transplant waitlisting trends between 01/01/2017 and 06/30/2022. Participants were divided into intervention and control arms of the ETC Model. Using an interrupted time series design, we compared slope changes in waitlist additions post-ETC Model implementation (implementation date: 01/01/2021) between the two arms, while accounting for differential changes during the COVID-19 pandemic. Results were stratified by race and ethnicity (White, Black, Hispanic, and other). To examine balance between the two ETC arms, we conducted supplementary analyses using United States Renal Data System and Medicare data. Following implementation of the ETC Model, there were 5,550 waitlist additions in the intervention and 11,332 additions in the control arm (versus 14,023 and 30,610 additions before the ETC Model). Post-ETC, there were no significant differences in kidney transplant waitlist additions between the two arms for the overall cohort (slope difference 6.9 new listings/month, 95% CI: -7.4 to 21.1) or among either White (slope difference 2.6/month, 95% CI -3.0 to 8.1), Black (slope difference 2.2/month, 95% CI: -4.3 to 8.7), or Hispanic (slope difference 0.2/month, 95% CI: -4.5 to 4.9) patients. In the 18 months following implementation, the ETC Model was not associated with significant changes in new kidney transplant waitlist additions.

Pulmonary sarcoidosis: differences in lung function change over time

IntroductionGiven the heterogeneity of sarcoidosis, predicting disease course of patients remains a challenge. Our aim was to determine whether the 3-year change in pulmonary function differed between pulmonary function phenotypes...

Understanding the relationship between inflammation, apoptosis, and diabetes osteoporosis: A bioinformatics approach and experimental verification.

Diabetes osteoporosis (DOP) is a chronic metabolic bone disease. This study aimed to identify potential biomarkers of DOP and explore their underlying mechanisms through bioinformatics methods and experimental verification. Bioinformatics methods were used to identify differentially expressed genes (DEGs) for DOP based on GEO data and the GeneCards database. GO and KEGG enrichment analyses were used to search the key pathways. The STRING website was used to construct a protein-protein interaction (PPI) network and identify key genes. Then, 50 mg/mL glucose was used to interveneosteoblasts (OBs).CCK-8 and Alizarin Red staining were used to investigate the proliferation and differentiation changes in OBs. Flowcytometry was used to investigate apoptosis. The membrane protein chip, WB, and RT-PCR were used to verify the expression of key targets or pathways about DOP. Forty-two common genes were screened between DOP-related targets and DEGs. GO and KEGG enrichment analysis showed that DOP was mainly associated with cytokine-cytokine receptor interactions, and apoptosis. PPI network analysis showed that TNF, IL1A, IL6, IL1B, IL2RA, Fas ligand (FASLG), and Fas cell surface death receptor (FAS) were key up-regulated genes in the occurrence of DOP. The experiment results show that 50 mg/mL glucose significantly inhibited OBs proliferation but presented an increase in apoptosis. Membrane protein chip, WB, and RT-PCR-verified a significantly active in the expression of TNF/FASLG/FAS pathway. High glucose activated the TNF-α/FAS/FASLG pathway and induced the inflammatory microenvironment and apoptosis, then impaired osteogenic differentiation of OBs. These may be an important mechanism for the occurrence and development of DOP.

Differential Treatment Responses of Maltreated and Neglected Children and Adolescents Following an Evidence-based Multisystemic Intervention.

Limited studies have investigated differential treatment responses to family-based treatment programs and subgroup trajectories in youth in a high-risk context. This study pioneered an examination of Multisystemic Therapy for Child Abuse and Neglect (MST-CAN) and built on prior research that identified subgroups with different psychopathologies. Participants included 208 parent-child dyads enrolled in the MST-CAN evaluation in Switzerland. Parents reported their children's (Mage = 10.27years, SDage = 3.5, 44.2% girls, 55.8% boys, 98.6% White) emotional and behavioral problems. Longitudinal data were examined to analyze the differential changes within the pre- and post-treatment (T1 and T2) subgroups. The T1 cluster and T2 cluster were cross-tabulated to examine changes in the symptom class over time. Overall, the treatment proved to be highly beneficial. Subgroup analyses revealed that four out of the five subgroups (80%) showed positive changes in at least two outcome measures. The treatment was most successful for children with externalizing symptoms. Children with multiple symptoms also showed improvements across different symptoms. Regarding specific symptoms, children with anxious-avoidant symptoms benefited from the treatment. Additionally, the treatment was beneficial for children with normative emotions and behavior. Meanwhile, the treatment did not have any significant effects for children with internalizing symptoms. Notably, child neglect was reduced in three (60%) subgroups. The symptom class remained stable across time for children with externalizing and multiple symptoms. Ultimately, MST-CAN reduced emotional and behavioral problems and child neglect in most families. Understanding children's differential treatment responses to complex treatment programs is essential to adequately address different needs.

TDCS Cranial Nerve Co-Stimulation: Unveiling Brainstem Pathways Involved in Trigeminal Nerve Direct Current Stimulation in Rats.

The effects of transcranial direct current stimulation (tDCS) are typically attributed to the polarization of cortical neurons by the weak electric fields it generates in the cortex. However, emerging evidence indicates that certain tDCS effects may be mediated through the co-stimulation of peripheral or cranial nerves, particularly the trigeminal nerve (TN), which projects to critical brainstem nuclei that regulate the release of various neurotransmitters throughout the central nervous system. Despite this, the specific pathways involved remain inadequately characterized. In this study, we examined the effects of acute transcutaneous TN direct current stimulation (TN-DCS) on tonic (i.e. mean spike rate and spike rate over time) and phasic (number of bursts, spike rate per burst, burst duration, and inter-burst interval) activities while simultaneously recording single-neuron activity across three brainstem nuclei in rats: the locus coeruleus (LC), dorsal raphe nucleus (DRN), and median raphe nucleus (MnRN). We found that TN-DCS significantly modulated tonic activity in the LC, with notable interactions between stimulation amplitude, polarity, and time epoch affecting mean spike rates. Similar effects were observed in the DRN regarding tonic activity. Further, phasic activity in the LC was influenced by TN-DCS, with changes in burst number, duration, and inter-burst intervals linked to stimulation parameters. Conversely, MnRN tonic activity following TN-DCS remained unchanged. Importantly, xylocaine administration to block TN abolished the effects on tonic activities in both the LC and DRN. These results suggest that tDCS effects may partially arise from indirect modulation of the TN, leading to altered neuronal activity in DRN and LC. Besides, the differential changes in tonic and phasic LC activities underscore their complementary roles in mediating TN-DCS effects on higher cortical regions. This research bears significant translational implications, providing mechanistic insights that could enhance the efficacy of tDCS applications and deepen our understanding of its neurophysiological effects.

Single-cell sequencing analysis revealed that NEAT1 was a potential biomarker and therapeutic target of prostate cancer.

Prostate cancer (PCa) usually manifests atypical symptoms in the early stage, and once symptoms appear, most PCa patients have developed to the advanced stage, failing to undergo radical surgery. In this study, PCa occurrence-related biomarkers were explored based on single-cell RNA sequencing (scRNA-seq) data. scRNA-seq data of prostate normal (Normal), benign prostatic hyperplasia (BPH), and PCa (Tumor) samples were acquired from the Gene Expression Omnibus (GEO). Cellular subsets associated with PCa occurrence were obtained using cell annotation. Additionally, the mRNA expression of nuclear enriched abundant transcript 1 (NEAT1) was detected by quantitative real-time PCR (qRT-PCR). The effects of NEAT1 on cell proliferation and apoptosis were analyzed by 5-ethynyl-2-deoxyuridine (EdU) and flow cytometry. Subsequently, cell-derived xenograft (CDX) models were constructed and divided into the LV-NC and LV-shNEAT1 groups. After the tumor tissues of CDX model mice in each group were extracted, the cell growth and Ki67 expression were observed separately using hematoxylin-eosin (H&E) staining and immunohistochemistry (IHC). Ten cellular subsets were obtained via cell annotation, and significantly differential changes were observed between Basal intermediate and Luminal during the course of BPH to PCa. NEAT1-Luminal was highly recruited in the Tumor group with low stemness and high malignancy scores. Matrix metallopeptidase 7 (MMP7)- keratin 17 (KRT17)-Basal intermediate had high ratios in the Tumor group with low stemness and high malignancy scores. The results of pseudotime analysis revealed that NEAT1-Luminal in the Tumor group were consistently distributed with tumor stage cells. In vitro assays showed that NEAT1 expression was elevated in PCa cells, and NEAT1 knockdown could inhibit cell proliferation and induce apoptosis. CDX assays indicated that silencing NEAT1 could reduce the growth rate of PCa tumor volume in CDX model mice. H&E staining results showed that nuclei of tumor cells were reduced and exhibited lighter color in the LV-shNEAT1 group compared with the LV-NC group. IHC results showed that Ki67 positivity was significantly lower in the LV-shNEAT1 group than in the LV-NC group. NEAT1 expression is increased in PCa, and NEAT1 can be a potential biomarker and therapeutic target for PCa.

Hypermethylation in Ovarian Cancer of Long Non-Coding RNA Genes: &lt;i&gt;HOTAIR&lt;/i&gt;, &lt;i&gt;GAS5&lt;/i&gt;, &lt;i&gt;LINC00472&lt;/i&gt;, &lt;i&gt;LINC00886&lt;/i&gt;, &lt;i&gt;TUG1&lt;/i&gt;

Recently, more and more data have been accumulating indicating the role of long non-coding RNAs (lncRNAs) in the regulation of biological processes in cells, as well as in the mechanisms of cancer development and progression. Aberrant methylation of promoter regions of both protein genes and lncRNA genes can disrupt their expression and functional activity. Using bioinformatics databases, six lncRNA genes (GAS5, HOTAIR, LINC00472, LINC00886, SNHG17 and TUG1) with CpG islands, differentially expressed and presumably hypermethylated in tumors of patients with ovarian cancer (OC) were selected. A statistically significant (p 0.05) increase in the methylation level in tumours was demonstrated in a sample of 93 OC specimens using methylation-specific real-time PCR assay. Moreover, for the genes LINC00472, LINC00886, SNHG17 and TUG1, hypermethylation in OC was detected for the first time. 5 genes (except SNHG17) showed a further increase in methylation levels at a more advanced stage, and 4 genes (except SNHG17 and LINC00886) showed a significant association with metastasis. Using real-time RT-PCR, differential changes in the expression level of the GAS5, HOTAIR, SNHG17 and TUG1 genes and a significant correlation of methylation with expression for the GAS5 gene were shown. Thus, hypermethylation associated with the progression and/or development of OC was detected for six lncRNA genes, which is important for elucidating the epigenetic processes involved in the pathogenesis of OC and can be used as new biomarkers of OC.

8236 Hepatocyte Vitamin D Receptor (VDR) Regulates Liver Regeneration

Abstract Disclosure: J.E. Gunton: None. Harendran Elangovan [1], Rebecca A. Stokes [1], Jeremy Keane [1], Sarinder Chahal [1], Caroline Samer [1], Miguel Agoncillo [1], Josephine Yu [1], Jennifer Chen [1], Michael Downes 2, Ronald M. Evans 2, Christopher Liddle [1],2, Jenny E. Gunton [1] [1]Centre for Diabetes, Obesity and Endocrinology, The Westmead Institute for Medical Research, University of Sydney, Westmead, NSW, Australia 2 Salk Institute for Biological Studies, La Jolla, CA. USA Background: Vitamin D signals through the vitamin D receptor (VDR) to induce its end-organ effects. Hepatic stellate cells control development of liver fibrosis in response to stressors and vitamin D signaling decreases fibrogenesis. VDR expression in hepatocytes, however, is low in healthy liver, and the role of VDR in hepatocyte proliferation is unclear. Methods: In these studies, hepatocyte-VDR null mice (hVDR) were used to assess the role of VDR and vitamin D signaling in hepatic regeneration. Mice underwent 2/3 partial hepatectomy and liver regeneration and function were studied. Results: hVDR mice had impaired liver regeneration with impaired hepatocyte proliferation. This was associated with significant differential changes in bile salts. Notably, mice lacking hepatocyte VDR had significant increases in expression of conjugated bile acids after partial hepatectomy, consistent with failure to normalize hepatic function by the 14-day time point tested. CDCA (chenodeoxycholate) is an FXR ligand, which was increased after surgery in controls but not in hVDR mice. FXR signaling is important for hepatocyte proliferation. Real-time PCR of hVDR and control livers showed significant changes in expression of cell cycle genes including cyclins D1 and E1 and cyclin-dependent kinase 2. Gene expression profiling of hepatocytes treated with vitamin D or control showed regulation of groups of genes involved in liver proliferation, hepatitis, liver hyperplasia / hyperproliferation and liver necrosis / cell death. Conclusions: Together these studies demonstrate an important functional role for VDR in hepatocytes during liver regeneration. Combined with the known profibrotic effects of impaired VDR signaling in stellate cells, these studies provide a mechanism whereby vitamin D deficiency would both reduce hepatocyte proliferation and permit fibrosis, leading to significant liver compromise. Presentation: 6/2/2024