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Abstract Background Breast cancer (BC) is a significant health challenge, ranking as the second leading cause of cancer-related death and the primary cause of mortality among women aged 45 to 55. Early detection is crucial for optimal prognosis. Among various treatment options available for cancer, chemotherapy remains the predominant approach. However, its patient-friendliness is hindered by cytotoxicity, adverse effects, multi-drug resistance, potential for recurrence, and high costs. This review explores extensively studied phytomolecules, elucidating their molecular mechanisms. It also emphasizes the importance of combination therapy, highlighting recent advancements in the exploration of diverse drug delivery systems and novel routes of administration. The regulatory considerations are crucial in translating these approaches into clinical practices. Results Consequently, there is growing interest in exploring the relationship between diet, cancer, and complementary and alternative medicine (CAM) in cancer chemotherapy. Phytochemicals like berberine, curcumin, quercetin, lycopene, sulforaphane, resveratrol, epigallocatechin gallate, apigenin, genistein, thymoquinone have emerged as promising candidates due to their pleiotropic actions on target cells through multiple mechanisms with minimal toxicity effects. This review focuses on extensively studied phytomolecules, elucidating their molecular mechanisms. It also emphasizes the importance of combination therapy, highlighting recent advancements in the exploration of diverse drug delivery systems and novel routes of administration. The regulatory considerations are crucial in translating these approaches into clinical practices. Conclusion The present review provides a comprehensive understanding of the molecular mechanisms, coupled with well-designed clinical trials and adherence to regulatory guidelines, which pave the way for nutrition-based combination therapies to become a frontline approach in early-stage BC treatment. Graphical Abstract

There is ample evidence for the impacts of recent climatic changes on ecology. Climate plays a major role in the population dynamic of birds. Hornbills are confined to Asia and Africa with only two species present in Sri Lanka. In this study, we utilized field observations and filtered e-bird records to generate current and future climatic models for the two hornbill species in Sri Lanka (Ocyceros gingalensis and Anthracoceros coronatus). Critical reduction of predicted ecological niches was observed in Anthracoceros coronatus throughout the period considered (2000–2100). Special conservation interventions are required for these two species. However, predicted suitable ecological niches for the Ocyceros gingalensis show little reduction towards the wet zone of Sri Lanka. This shift in species distribution boundaries coincides with periods of global warming suggesting a possible connection. This study provides supporting evidence for the possible influence of climate change on hornbill species distribution.

Abstract Background Alzheimer’s disease and related dementias (ADRD) are among the most feared age-related conditions. The aim of this study was to evaluate a brief psychological intervention to promote adaptive coping in older adults experiencing heightened fear of ADRD and investigate positive downstream effects on health-related secondary outcomes, including frequency of reported memory failures, psychosocial functioning, and quality of life. Methods Eighty-one older adults were recruited and randomized into REFRAME or active control intervention arms. Both groups received psycho-education and training in mindful monitoring of fears related to ADRD. The REFRAME group received an additional behavioral activation component intended to disrupt maladaptive avoidant coping (i.e., avoidance) strategies. Both groups completed 3-weeks of intervention exercises with accompanying questionnaires (baseline, mid- and post-intervention and 4-week follow-up). Results Adherence was strong (> 75%). We observed a significant reduction in ADRD-related fear and avoidance in both groups. Significant reductions were also observed for frequency of self-reported memory failures, anxiety, and depression. Depression was significantly reduced in the REFRAME group compared to the control group. Significant increases in participants’ ability to participate in social activities and well-being were also observed. Conclusions Findings suggest that a brief psychological intervention can mitigate ADRD-related fears and avoidant coping in older adults, and that benefits extend to broader health-related outcomes including anxiety, depression, social functioning, and well-being. Addressing ADRD-related fear has implications for healthy aging and risk reduction, as individuals may be more likely to engage in activities that are protective against ADRD but were previously avoided. Trial registration : https://clinicaltrials.gov/ct2/show/NCT04821960 .

Background: The expeditious changes of the world today present massive challenges and demand rapid modifications in our education system. Focusing on concept-based learning and core understanding of topics for practical application is the cornerstone for a better outcome. Didactic Lectures (DL) are the most widely used method; however, in the current changing face of our education system, newer techniques like Self-directed Learning (SDL), SDL with Focussed Discussion (SDL-FD) and Problem-based Learning (PBL), which encourage active participation by the learner are being increasingly employed for better understanding of the subject. Aim and Objectives: To examine the effect of transition from traditional to newer methods on student performance. Material and Methods: We conducted a retrospective study involving 409 students, over two years, to evaluate the scores attained in examinations among topics delivered by different modalities namely DL, SDL, PBL and SDL-FD. Results: The scores achieved were higher among topics delivered by DL when compared with SDL and PBL approach which were statistically significant. The score of DL when compared with SDL-FD was higher, however did not have statistical significance. Conclusion: DL may help the learner immensely in a scenario of an examination-oriented evaluation. However, it may limit the learners' ability to question and ponder over the subject matter, mindlessly clinging to facts dissipated in class room. We recommend that a unified approach along with activities of self-learning and discussions, may tremendously improve the outcome.

Empowering the Participant Voice (EPV) is an NCATS-funded six-CTSA collaboration to develop, demonstrate, and disseminate a low-cost infrastructure for collecting timely feedback from research participants, fostering trust, and providing data for improving clinical translational research. EPV leverages the validated Research Participant Perception Survey (RPPS) and the popular REDCap electronic data-capture platform. This report describes the development of infrastructure designed to overcome identified institutional barriers to routinely collecting participant feedback using RPPS and demonstration use cases. Sites engaged local stakeholders iteratively, incorporating feedback about anticipated value and potential concerns into project design. The team defined common standards and operations, developed software, and produced a detailed planning and implementation Guide. By May 2023, 2,575 participants diverse in age, race, ethnicity, and sex had responded to approximately 13,850 survey invitations (18.6%); 29% of responses included free-text comments. EPV infrastructure enabled sites to routinely access local and multi-site research participant experience data on an interactive analytics dashboard. The EPV learning collaborative continues to test initiatives to improve survey reach and optimize infrastructure and process. Broad uptake of EPV will expand the evidence base, enable hypothesis generation, and drive research-on-research locally and nationally to enhance the clinical research enterprise.

Stakeholder engagement is a vital, yet under-accessed and under-studied, resource for tackling wicked environmental problems. This paper examines mental models – cognitive representations of “real” systems – refined through group model building (GMB) with stakeholders concerned with environmental issues in the US state of Oklahoma. During GMB, a diverse group of high-level decision makers met with a variety of physical and social scientists to collaborate on mental models concerning three environmental focus areas in Oklahoma: encroachment of eastern red cedar, grid and infrastructure resilience, and marginal water use and re-use. We ask: how do individuals from diverse stakeholder groups describe causes and consequences of key environmental problems in Oklahoma? Results from this analysis advance efforts toward developing socially sustainable solutions for environmental problems in Oklahoma and beyond.

Arsenic contamination poses a significant public health risk worldwide, with chronic exposure leading to various health issues. Detecting and monitoring arsenic exposure accurately remains challenging, necessitating the development of sensitive detection methods. In this study, we introduce a novel approach using fast-scan cyclic voltammetry (FSCV) coupled with carbon-fiber microelectrodes (CFMs) for the electrochemical detection of As3+. Through an in-depth pH study using tris buffer, we optimized the electrochemical parameters for both acidic and basic media. Our sensor demonstrated high selectivity, distinguishing the As3+ signal from those of As5+ and other potential interferents under ambient conditions. We achieved a limit of detection (LOD) of 0.5 μM (37.46 ppb) and a sensitivity of 2.292 nA/μM for bare CFMs. Microscopic data confirmed the sensor’s stability at lower, physiologically relevant concentrations. Additionally, using our previously reported double-bore CFMs, we simultaneously detected As3+-Cu2+ and As3+-Cd2+ in tris buffer, enhancing the LOD of As3+ to 0.2 μM (14.98 ppb). To our knowledge, this is the first study to use CFMs for the rapid and selective detection of As3+ via FSCV. Our sensor’s ability to distinguish As3+ from As5+ in a physiologically relevant pH environment showcases its potential for future in vivo studies.

Abstract Plant precursor miRNAs (pre-miRNA) have conserved evolutionary footprints that correlate with mode of miRNA biogenesis. In plants, base to loop and loop to base modes of biogenesis have been reported. Conserved structural element(s) in pre-miRNA play a major role in turn over and abundance of mature miRNA. Pre-miR396c sequences and secondary structural characteristics across Oryza species are presented. Based on secondary structure, twelve Oryza pre-miR396c sequences are divided into three groups, with the precursor from halophytic Oryza coarctata forming a distinct group. The miRNA-miRNA* duplex region is completely conserved across eleven Oryza species as are other structural elements in the pre-miRNA, suggestive of an evolutionarily conserved base-to-loop mode of miRNA biogenesis. SNPs within O. coarctata mature miR396c sequence and miRNA* region have the potential to alter target specificity and association with the RNA-induced silencing complex. A conserved SNP variation, rs10234287911 (G/A), identified in O. sativa pre-miR396c sequences alters base pairing above the miRNA-miRNA* duplex. The more stable structure conferred by the ‘A10234287911’ allele may promote better processing vis-à-vis the structure conferred by ‘G10234287911’ allele. We also examine pri- and pre-miR396c expression in cultivated rice under heat and salinity and their correlation with miR396c expression.

Background: Modern anesthesia practice utilizes preemptive analgesia for providing pain relief postoperatively using oral drugs such as pregabalin and gabapentin which are otherwise used for chronic pain management. We aimed to determine which among the two is more proficient. Materials and Methods: This randomized double-blinded control study was done among 72 subjects undergoing lower abdominal surgeries under the subarachnoid block and they were randomly divided into three groups: Group 1 received a single dose of tablet pregabalin 150 mg orally, Group 2 received tablet gabapentin 600 mg orally, and Group 3 received placebo drug orally (tablet B-complex) 2 h before subarachnoid block. Pain scores, time of 1st rescue analgesic, total number of rescue analgesics, sedation score, and occurrence of side effects were also noted for 24 h. The data were analyzed using SPSS 16 with Chi-square/Fisher's exact test or analysis of variance/Kruskal–Wallis test. A statistically significant difference was considered when P < 0.05. Results: Pain scores were lesser in Group 1 and 2 except at 2nd h. Total rescue analgesic time among maximum subjects in Group 1 was 4 h 30 min, in Group 2 was 3 h 30 min and 4 h, whereas in Group 3 was 3 h (P < 0.001). The total dose of analgesics in the first 24 h was 2 doses in Group 1, 2 doses in Group 2, and 3 doses in Group 3 (P < 0.001). Sedation score was more on Group 1 and 2 in comparison to Group 3 with no side effects in all groups. Conclusions: We conclude that pregabalin to be the effective preemptive drug because of its lesser pain intensity scores and good sedation property.

Neurotoxic heavy metals, such as Cd2+, pose a significant global health concern due to their increased environmental contamination and subsequent detrimental health hazards they pose to human beings. These metal ions can breach the blood-brain barrierblood–brain barrier, leading to severe and often irreversible damage to the central nervous system and other vital organs. Therefore, developing a highly sensitive, robust, and rapid in vivo detection method for these hazardous heavy metal ions is of the utmost importance for early detection, thus initiating timely therapeutics. Detecting ultra-low levels of toxic metal ions in vivo and obtaining accurate speciation information remains a challenge with conventional analytical techniques. In this study, we fabricated a novel carbon carbon-fiber microelectrode (CFM)-based sensor that can detect Cd2+ ions using fast-scan cyclic voltammetry by electrodepositing gold nanoparticles (AuNP). We optimized electrochemical parameters that generate a unique cyclic voltammogram (CV) of Cd2+ at a temporal resolution of 100 ms with our novel sensor. All our experiments were performed in tris buffer that mimics the artificial cerebellum fluid. We established a calibration curve resulting in a limit of detection (LOD) of 0.01 µM with a corresponding sensitivity of 418.02 nA/ µM. The sensor’s selectivity was evaluated in the presence of other metal ions, and it was noteworthy to observe that the sensor retained its ability to produce the distinctive Cd2+ CV, even when the concentration of other metal ions was 200 times higher than that of Cd2+. We also found that our sensor could detect free Cd2+ ions in the presence of complexing agents. Furthermore, we analyzed the solution chemistry of each of those Cd2+–ligand solutions using a geochemical model, PHREEQC. The concentrations of free Cd2+ ions determined through our electrochemical data align well with geochemical modeling data, thus validating the response of our novel sensor. Furthermore, we reassessed our sensor’s LOD in tris buffer based on the concentration of free Cd2+ ions determined through PHREEQC analysis, revealing an LOD of 0.00132 µM. We also demonstrated the capability of our sensor to detect Cd2+ ions in artificial urine samples, showcasing its potential for application in actual biological samples. To the best of our knowledge, this is the first AuNP-modified, CFM-based Cd2+ sensor capable of detecting ultra-low concentrations of free Cd2+ ions in different complex matrices, including artificial urine at a temporal resolution of 100 ms, making it an excellent analytical tool for future real-time, in vivo detection, particularly in the brain.

Abstract Introduction Alzheimer's disease and related dementias (ADRD) are among the most feared conditions. However, research around ADRD‐specific fear and avoidance behaviors is lacking. Here, we validated a novel measure of fear and avoidance specific to memory loss, the Fear and Avoidance of Memory Loss (FAM) scale, and examined associations between fear avoidance and psychosocial functioning in older adults. Methods We assessed FAM Scale internal reliability and concurrent validity, and candidate subscales across two samples (total N = 813). We then examined associations between fear avoidance and memory performance, anxiety, depressive symptoms, sleep, social functioning, and quality of life. Results We identified two subscales: fear and avoidance, which yielded strong psychometric validity. Higher fear was associated with memory failures and sleep disturbance. Higher avoidance was associated with memory failures, poorer verbal memory, reduced social functioning, and quality of life. Discussion We present the first measure of fear avoidance specific to memory loss. We propose that targeting fear avoidance can promote ADRD risk reduction and resiliency.

College-in-prison programs are positioned to expand substantially under the reinstatement of Pell Grant eligibility for people in prison. While this change will enable more students who have been systemically excluded from higher education to attend college, degree completion is rare during incarceration and post-release. Student perspectives can shed light on both the value of college-in-prison and the financial barriers to realizing its value. This study analyzes data from 12 focus groups with 105 total college-in-prison student participants, 114 student survey responses, and 45 stakeholder interviews. The data were collected between 2018-2022 during a process evaluation of the College-in-Prison Reentry Initiative, which provided funding to college-in-prison programs in New York State as part of the Manhattan District Attorney's Office Criminal Justice Investment Initiative. The findings demonstrate that students value college-in-prison, describing how it fostered self-reflection and personal growth and provided them with a skillset that may help them gain employment upon release. However, students also raised concerns about reenrolling and completing their degrees following release. Intentional, holistic reentry support could address the largely financial barriers to reenrollment. In so doing, students will be more likely to earn their college degrees after incarceration and experience the full value of a college education.

Objective: The diagnosis of any dental pathology can vary from being simple to challenging. While the use of cone beam computed tomography (CBCT) is well established, magnetic resonance imaging (MRI) remains a proof of concept. This systematic review aims to compare the diagnostic ability of MRI with CBCT in diagnosing periapical pathosis. Materials and Methods: This systematic search was performed using the electronic databases of MEDLINE, Cochrane Library, Google Scholar, and Science Direct to identify relevant articles from 2010 to 2020. The search terms used were magnetic resonance imaging, cone beam computed tomography, diagnosis, and periapical diseases. Result: In total, 3218 potentially relevant abstracts and titles were identified. After removing duplicates, 1288 articles were reviewed for titles and abstracts, and 29 articles were selected for full-text reading. From those, 19 articles were finally selected that included original research studies, case reports, and case series and were included for systematic review. Most of the studies included in this review suggested that the combined use of CBCT and MRI is needed for a better and more precise diagnosis of complex periapical pathoses. The main advantage of MRI is its ability to image soft tissues usingnonionizing radiation, and the main disadvantage in the case of CBCT is overdiagnosis of the lesion. Conclusion: MRI has various advantages over CBCT with similar diagnostic utility. When diagnosing periapical pathogens, both MRI and CBCT are needed for an accurate diagnosis.

Protecting and enhancing forest carbon sinks is considered a natural solution for mitigating climate change. However, the increasing frequency, intensity, and duration of droughts due to climate change can threaten the stability and growth of existing forest carbon sinks. Extreme droughts weaken plant hydraulic systems, can lead to tree mortality events, and may reduce forest diversity, making forests more vulnerable to subsequent forest disturbances, such as forest fires or pest infestations. Although early warning metrics (EWMs) derived using satellite remote sensing data are now being tested for predicting post-drought plant physiological stress and mortality, applications of unmanned aerial vehicles (UAVs) are yet to be explored extensively. Herein, we provide twenty-four prospective approaches classified into five categories: (i) physiological complexities, (ii) site-specific and confounding (abiotic) factors, (iii) interactions with biotic agents, (iv) forest carbon monitoring and optimization, and (v) technological and infrastructural developments, for adoption, future operationalization, and upscaling of UAV-based frameworks for EWM applications. These UAV considerations are paramount as they hold the potential to bridge the gap between field inventory and satellite remote sensing for assessing forest characteristics and their responses to drought conditions, identifying and prioritizing conservation needs of vulnerable and/or high-carbon-efficient tree species for efficient allocation of resources, and optimizing forest carbon management with climate change adaptation and mitigation practices in a timely and cost-effective manner.

Delta-beta Thalassemia is a rare variant of thalassemia with elevated Hb F. Heterozygous and homozygous state of delta-beta thalassemia present with features similar to Hereditary Persistence of Fetal Haemoglobin (HPFH) and beta thalassemia intermedia. Here, we describe a case of 8-month-old female child with anaemia and splenomegaly. Haemoglobin electrophoresis showed 100% HbF and no HbA and HbA2. Patient was put on haematinics and advised a repeat haemoglobin electrophoresis after completion of 1 year of age, and family screening. Hb electrophoresis of the patient at the age of 2 years mirrored the earlier findings and her father, mother and brother showed increased Hb F with normal HbA2 levels. A final diagnosis of homozygous delta-beta thalassemia in the case with sibling and parents being heterozygous delta-beta thalassemia trait was rendered. Haemoglobin electrophoresis with red cell indices forms an important diagnostic clue in differentiating delta-beta thalassemia from other thalassemia syndromes

Solid pseudopapillary neoplasm is an unusual neoplasm of the pancreas with uncertain to low malignant potential. It accounts for 1% of pancreatic neoplasms and 3% of cystic lesions, harbouring better prognosis than other neoplasms of the pancreas having close differential diagnosis. Patients are commonly young women presenting with abdominal discomfort. Aim was to study the cytomorphological features of solid pseudopapillary neoplasm of pancreas diagnosed on Fine Needle Aspiration Cytology (FNAC) and its cyto-histological correlation. Cytology smears of five solid pseudopapillary neoplasms reported over the last five years were retrieved from the archives of pathology. The smears were evaluated for cytomorphological features and correlated with histopathology. All five cases had characteristic features on cytology such as pseudorossettes, cells having fine chromatin, indented nucleus and vacuolated cytoplasm. Histopathological correlation was available in all cases out of which four had features consistent with solid pseudopapillary neoplasm. However, one case was diagnosed as acinarcell carcinoma which was confirmed by immunohistochemistry. The cytomorphology on FNAC plays a pivotal role in the management of the patient. Surgical resection of the neoplasm can be done with retention of the uninvolved pancreas to avoid subsequent complications.

Background: Dental caries is a multifactorial disease that results from an imbalance between pathological and protective factors. The imbalance produced will favor demineralization of enamel. If detected early, noncavitated lesions can be reverted with the help of remineralizing agents. Aim: To compare remineralizing potential of novel agent-Nigella sativa with conventional remineralizing agents. Materials and Methods: An in vitro study was done to compare remineralizing potential of N. sativa with conventional remineralizing agents. Sixty-four human premolars were covered with nail varnish except for 4 mm × 4 mm exposed window on the facial aspect, which was treated with 37% phosphoric acid for 30 s. Samples are then randomly divided into four groups (n = 16): Group I – N. sativa, Group II – 5% sodium fluoride, Group III – Casein phosphopeptide-amorphous calcium phosphate, and Group IV – Control. The samples in each group were treated with the remineralizing agent, after which they were rinsed with deionised water, dried, and stored in artificial saliva. The same procedure is repeated for the span of 14 days. Depth of demineralization and remineralization were analyzed using the confocal laser scanning microscopy. Data were analyzed using the Statistical Package SPSS 22.0 (SPSS Inc., Chicago, IL) and level of significance was set at P < 0.05. Kruskal–Wallis test was used to analyze the depth of demineralization and remineralization among groups followed by post-hoc Mann–Whitney test to compare demineralization and remineralization between the groups. Results: Group I specimens showed greater depth of remineralization (1558.83) compared to other groups, which is statistically significant (P < 0.001). Conclusion: Herbal product like N. sativa can be considered as a promising remineralizing agent in treating noncavitated demineralized carious lesions.

Background: Postrestorative sensitivity is frequently associated with composite restorations. Dentin desensitizers are used commonly for the management of postrestorative sensitivity. This study aimed to evaluate the effect of four desensitizing agents on the bond strength of composite restoration. Materials and Methods: Sixty-five human premolars are used for the study. The occlusal surface of each tooth is flattened using a diamond disk to expose the dentin. The specimens are then etched with 35% phosphoric acid for 15 s and divided into five groups (n = 13) Group I – VivaSens, Group II – MS Coat F, Group III – Gluma, Group IV – Systemp, and Group V – Control. Single-step adhesive (Single Bond Universal, 3M) will be applied on the specimens and restored with composite material (Filtek Z350XT, 3 M). Shear bond strength is tested using universal testing machine at a crosshead speed of 1 mm/min. Statistically multiple group comparison was done using one-way analysis of variance followed by Tukey's test for group-wise comparison analysis. Results: Systemp desensitizer showed improved bond strength values than others desensitizers and control group. Conclusions: Systemp desensitizer can be considered as a promising option for preventing postoperative sensitivity associated with resin composite restorations without altering its shear bond strength to dentin.

Federal funding for firearm-related research in the health sciences has incurred Congressional restrictions and executive actions. Little is known about the funding landscape for published scholarship in this field. This study’s aim was to characterize the number and sources of funding, including federal and non-federal sources, for firearm-related research articles published in health sciences journals. We performed a scoping review of original, empirical, peer-reviewed articles related to firearms published in health science journals and indexed in PubMed between January 2000 and December 2019, using the PRISMA extension for Scoping Review checklist. Four reviewers independently screened each article twice for inclusion. Included articles were reviewed again to identify funding sources. Articles were characterized as having explicitly declared funding, explicitly declared no funding, or no explicit funding declaration. Among articles with funding, we examined proportions by funding source. 812 articles met the inclusion criteria. 119 (14.7%) of the articles declared not having received any funding, and 240 (29.6%) had no funding declaration. 453 (55.8%) of the articles declared at least one source of funding. Of those, 221 (48.8%) reported at least one federal grant, and 232 (51.2%) reported at least one philanthropic grant. The number of published articles increased by 328.6% between 2000 and 2019. While the volume increased during the study period, the proportion of articles with funding was lower in 2019 (55.6%) than it was in 2000 (87.5%; proportion difference: 31.9%; 95% CI: 16.7%–47.2%). This study highlights the continued funding limitations in this field despite a growing volume of research.

Pore modulation via hydrothermal carbonization (HTC) needs investigation due to its crucial effect on surface that influences its multirole utilization of such ultraporous sorbents in applications of energy storage- hydrogen and capacitive- as well as for pollutant abatement- carbon capture and dye removal. Hence, loblolly pine was hydrothermally carbonized followed by KOH activation to synthesize superactivated hydrochars (SAH). The resulting SAHs had specific surface area (SSA) 1462–1703 m2/g, total pore (TPV) and micropore volume (MPV) of 0.62–0.78 cm3/g and 0.33–0.49 cm3/g, respectively. The SAHs exhibit excellent multifunctional performance with remarkably high atmospheric CO2 capture of 145.2 mg/g and high pressure cryogenic H2 storage of 54.9 mg/g. The fabricated supercapacitor displayed substantial specific capacitance value of maximum 47.2 Fg−1 at 1 A g−1 in 6 M KOH and highest MB dye removal of 719.4 mg/g. Higher HTC temperature resulted in increased surface porosity as higher SSA, TPV benefitted H2 storage and MB dye removal while superior MPV favored CO2 capture. Moderate HTC temperature ensured higher mesopore-to-macropore volume ratio favoring electrochemical performance. Isotherm modelling of the adsorbates was compared using models: Langmuir, Freundlich, Langmuir- Freundlich and Temkin.

BackgroundDementia is the most feared disease associated with aging. Prolonged fears about memory loss and dementia can have harmful consequences even in the absence of cognitive decline. Fear of dementia is associated with poorer health outcomes and psychological well-being and increased memory failures in older adults. ObjectiveWe will conduct a randomized controlled trial to determine the feasibility of a tailored, web-based mindfulness program to reduce fear of memory loss and increase quality of life in older adults experiencing heightened fear. MethodsEighty participants will be recruited and divided into 2 groups (40 in each group). One group will receive psychoeducation plus mindfulness training. A second group will receive psychoeducation, mindfulness training, and additional modules targeting maladaptive behavioral avoidance (ie, social and cognitive withdrawal). ResultsOur recent etiological model posits that maladaptive behavioral avoidance strategies critically underlie psychosocial dysfunction associated with fear of memory loss. Thus, we predict better outcomes in the second group, including reduced fear of memory loss (primary outcome), Alzheimer disease, anxiety, and subjective memory failures, and increased quality of life (secondary outcomes). Outcome measures will be applied at 5 time points (before, baseline, interim, and after the intervention, and at 3-month follow-up). Data will be analyzed using mixed models and correlations. ConclusionsResults from this study will contribute to the current literature on dementia-related fear and improve our understanding of how to effectively address and reduce these fears. Trial RegistrationClinicalTrials.gov NCT04821960; https://clinicaltrials.gov/ct2/show/NCT04821960. International Registered Report Identifier (IRRID)PRR1-10.2196/30514

Abstract Background Excess reactive oxygen species (ROS) and muscle weakness occur in parallel in multiple pathological conditions. However, the causative role of skeletal muscle mitochondrial ROS (mtROS) on neuromuscular junction (NMJ) morphology and function and muscle weakness has not been directly investigated. Methods We generated mice lacking skeletal muscle‐specific manganese‐superoxide dismutase (mSod2KO) to increase mtROS using a cre‐Lox approach driven by human skeletal actin. We determined primary functional parameters of skeletal muscle mitochondrial function (respiration, ROS, and calcium retention capacity) using permeabilized muscle fibres and isolated muscle mitochondria. We assessed contractile properties of isolated skeletal muscle using in situ and in vitro preparations and whole lumbrical muscles to elucidate the mechanisms of contractile dysfunction. Results The mSod2KO mice, contrary to our prediction, exhibit a 10–15% increase in muscle mass associated with an ~50% increase in central nuclei and ~35% increase in branched fibres (P

Abstract Background We previously showed that caveolin-1 (cav-1), an integral membrane protein, is required for the synthesis of matrix proteins by glomerular mesangial cells (MC). In a previous study to understand how cav-1 is involved in regulating matrix production, we had identified significant upregulation of the antifibrotic protein follistatin in cav-1 knockout MC. Follistatin inhibits the profibrotic effects of several members of the transforming growth factor beta superfamily, in particular the activins. Here, we characterize the molecular mechanism through which cav-1 regulates the expression of follistatin. Methods Kidneys from cav-1 wild type and knockout (KO) mice were analyzed and primary cultures of MC from cav-1 wild-type and KO mice were utilized. FST promoter deletion constructs were generated to determine the region of the promoter important for mediating FST upregulation in cav-1 KO MC. siRNA-mediated down-regulation and overexpression of Sp1 in conjunction with luciferase activity assays, immunoprecipitation, western blotting and ChiP was used to assess the role of Sp1 in transcriptionally regulating FST expression. Pharmacologic kinase inhibitors and specific siRNA were used to determine the post-translational mechanism through which cav-1 affects Sp1 activity. Results Our results establish that follistatin upregulation occurs at the transcript level. We identified Sp1 as the critical transcription factor regulating activation of the FST promoter in cav-1 KO MC through binding to a region within 123 bp of the transcription start site. We further determined that the lack of cav-1 increases Sp1 nuclear levels and transcriptional activity. This occurred through increased phosphoinositide 3-kinase (PI3K) activity and downstream protein kinase C (PKC) zeta-mediated phosphorylation and activation of Sp1. Conclusions These findings shed light on the transcriptional mechanism by which cav-1 represses the expression of a major antifibrotic protein, and can inform the development of novel antifibrotic treatment strategies.

Molecular targets to reduce muscle weakness and atrophy due to oxidative stress have been elusive. Here we show that activation of Sarcoplasmic Reticulum (SR) Ca2+ ATPase (SERCA) with CDN1163, a novel small molecule allosteric SERCA activator, ameliorates the muscle impairment in the CuZnSOD deficient (Sod1-/-) mouse model of oxidative stress. Sod1-/- mice are characterized by reduced SERCA activity, muscle weakness and atrophy, increased oxidative stress and mitochondrial dysfunction. Seven weeks of CDN1163 treatment completely restored SERCA activity and reversed the 23% reduction in gastrocnemius mass and 22% reduction in specific force in untreated Sod1-/- versus wild type mice. These changes were accompanied by restoration of autophagy protein markers to the levels found in wild-type mice. CDN1163 also reversed the increase in mitochondrial ROS generation and oxidative damage in muscle tissue from Sod1-/- mice. Taken together our findings suggest that the pharmacological restoration of SERCA is a promising therapeutic approach to counter oxidative stress-associated muscle impairment. Keywords: CDN1163, Skeletal muscle, CuZnSod1, SERCA, Oxidative stress

A comprehensive study was performed to analyze turbine wake characteristics by using a Proper-Orthogonal-Decomposition (POD) method to identify the dominant flow features from a comprehensive experimental database. The wake flow characteristics behind a typical three-bladed horizontal-axis wind turbine (HAWT) were measured in a large-scale wind tunnel with a scaled turbine model placed in a typical offshore Atmospheric Boundary Layer (ABL) wind under a neutral stability condition. A high-resolution Particle Image Velocimetry (PIV) system was used to achieve detailed flow field measurements to characterize the turbulent flows and wake vortex structures behind the turbine model. Statistically averaged measurements revealed the presence of the characteristic helical-tip vortex filament along with a unique secondary vortex filament emanating from 60% of the blade span measured from the hub. Both filaments breakup in the near-wake region (~0.6 rotor diameter downstream) to form shear layers, contrary to previous computational and experimental observations in which vortex filaments break up in the far wake. A Proper-Orthogonal-Decomposition (POD) analysis, based on both velocity and vorticity-based formulations, was used to extract the coherent flow structures, predominantly comprised of tip and midspan vortex elements. The reconstructions showed coherence in the flow field prior to the vortex breakup which subsequently degraded in the turbulent shear layer. The accuracy of the POD reconstructions was validated qualitatively by comparing the prediction results between the velocity and vorticity-based formulations as well as the phase-averaged PIV measurement results. This early vortex breakup was attributed to the reduced pitch between consecutive helical turns, the proximity between midspan filaments and blade tips as well as the turbulence intensity of the incoming boundary layer wind.

The genome of Asian cultivated rice (Oryza sativa L.) shows the presence of six organelle-specific and one plasma membrane (OsNHX1-7) NHX-type cation proton antiporters. Of these, vacuolar-localized OsNHX1 is extensively characterized. The genus Oryza consists of 27 species and 11 genome-types, with cultivated rice, diploid O. sativa, having an AA-type genome. Oryza NHX1 orthologous regions (gene organization, 5′ upstream cis elements, amino acid residues/motifs) from closely related Oryza AA genomes cluster distinctly from NHX1 regions from more ancestral Oryza BB, FF and KKLL genomes. These sequence-specific distinctions also extend to two separate intron retention (IR) events involving Oryza NHX1 transcripts that occur at the 5′ and 3′ ends of the NHX1 transcripts. We demonstrate that the IR event involving the 5′ UTR is present only in more recently evolved Oryza AA genomes while the IR event governing retention of the 13th intron of Oryza NHX1 (terminal intron) is more ancient in origin, also occurring in halophytic wild rice, Oryza coarctata (KKLL). We also report presence of a retro-copy of the OcNHX1 cDNA in the genome of O. coarctata (rOcNHX1). Preferential species and tissue specific up- or down-regulation of the correctly spliced NHX1 transcript/5′ UTR/13th intron-retaining splice variants under salinity was observed. The implications of IR on NHX1 mRNA stability and ORF diversity in Oryza spp. is discussed.

Abstract Background We have previously shown that the deletion of the superoxide scavenger, CuZn superoxide dismutase, in mice (Sod1−/− mice) results in increased oxidative stress and an accelerated loss of skeletal muscle mass and force that mirror the changes seen in old control mice. The goal of this study is to define the effect of oxidative stress and ageing on muscle weakness and the Excitation Contraction (EC) coupling machinery in age‐matched adult (8–10 months) wild‐type (WT) and Sod1−/− mice in comparison with old (25–28 months) WT mice. Methods In vitro contractile assays were used to measure muscle contractile parameters. The activity of the sarcoplasmic reticulum Ca2+ ATPase (SERCA) pump was measured using an NADH‐linked enzyme assay. Immunoblotting and immunofluorescence techniques were used to measure protein expression, and real‐time reverse transcription PCR was used to measure gene expression. Results The specific force generated by the extensor digitorum longus muscle was reduced in the Sod1−/− and old WT mice compared with young WT mice along with significant prolongation of time to peak force, increased half relaxation time, and disruption of intracellular calcium handling. The maximal activity of the SERCA calcium uptake pump was significantly reduced in gastrocnemius muscle from both old WT (≈14%) and adult Sod1−/− (≈33%) mice compared with young WT mice along with increased expression of sarcolipin, a known inhibitor of SERCA activity. Protein levels of the voltage sensor and calcium uptake channel proteins dihydropyridine receptor α1 and SERCA2 were significantly elevated (≈45% and ≈57%, respectively), while the ratio of calstabin, a channel stabilizing protein, to ryanodine receptor was significantly reduced (≈21%) in Sod1−/− mice compared with young WT mice. The changes in calcium handling were accompanied by substantially elevated levels of global protein carbonylation and lipid peroxidation. Conclusions Our data suggest that the muscle weakness in Sod1−/− and old WT mice is in part driven by reactive oxygen species‐mediated EC uncoupling and supports a role for reduced SERCA pump activity in compromised muscle function. The novel quantitative mechanistic data provided here can lead to potential therapeutic interventions of SERCA dysfunction for sarcopenia and muscle diseases.

Objective: A decline in mitochondrial function and biogenesis as well as increased reactive oxygen species (ROS) are important determinants of aging. With advancing age, there is a concomitant reduction in circulating levels of insulin-like growth factor-1 (IGF-1) that is closely associated with neuronal aging and neurodegeneration. In this study, we investigated the effect of the decline in IGF-1 signaling with age on astrocyte mitochondrial metabolism and astrocyte function and its association with learning and memory. Methods: Learning and memory was assessed using the radial arm water maze in young and old mice as well as tamoxifen-inducible astrocyte-specific knockout of IGFR (GFAP-CreTAM/igfrf/f). The impact of IGF-1 signaling on mitochondrial function was evaluated using primary astrocyte cultures from igfrf/f mice using AAV-Cre mediated knockdown using Oroboros respirometry and Seahorse assays. Results: Our results indicate that a reduction in IGF-1 receptor (IGFR) expression with age is associated with decline in hippocampal-dependent learning and increased gliosis. Astrocyte-specific knockout of IGFR also induced impairments in working memory. Using primary astrocyte cultures, we show that reducing IGF-1 signaling via a 30–50% reduction IGFR expression, comparable to the physiological changes in IGF-1 that occur with age, significantly impaired ATP synthesis. IGFR deficient astrocytes also displayed altered mitochondrial structure and function and increased mitochondrial ROS production associated with the induction of an antioxidant response. However, IGFR deficient astrocytes were more sensitive to H2O2-induced cytotoxicity. Moreover, IGFR deficient astrocytes also showed significantly impaired glucose and Aβ uptake, both critical functions of astrocytes in the brain. Conclusions: Regulation of astrocytic mitochondrial function and redox status by IGF-1 is essential to maintain astrocytic function and coordinate hippocampal-dependent spatial learning. Age-related astrocytic dysfunction caused by diminished IGF-1 signaling may contribute to the pathogenesis of Alzheimer's disease and other age-associated cognitive pathologies. Keywords: Primary astrocytes, IGF-1, Amyloid, Mitochondria, ROS, Alzheimer's disease

A subset of anti-dsDNA autoantibodies (autoAbs), cell-penetrating Abs, may play a pathogenic role in lupus nephritis. However, the pathogenic role(s) of the Abs has not been well explored. In this study the pathological effects of a positively charged CDR3-VH-containing and cell-penetrating anti-dsDNA monoclonal mouse autoAb 2C10 immunoglobulin G (IgG) and its recombinant VH domain were investigated in a mouse mesangial cell line with respect to activation of signaling molecules and transcription of pro-inflammatory cytokines. The IgG and VH reduced cell viability in cytotoxicity assays and delayed cell cycle progress in flow cytometric analysis. Western blotting experiments showed that they activated p38, MAPKAPK-2, RSK-1, Bcl-2 and ATF-2 in the associated pathway; RSK-1 activation was regulated by p38; p38 also activated MAPKAPK-2 and ATF-2; MAPKAPK-2 regulated RSK-1 activation, and Bcl-2 was up-regulated by RSK-1. The IgG and VH remarkably stimulated the transcription of pro-inflammatory cytokines, TNF-α, IL-6 and IL-1β And the transcription was regulated by p38 activation. These results indicate that the cell-penetrating autoAbs such as 2C10 may play a pathogenic role in mesangial cells mainly through activation of p38 signaling pathway in combination with the stimulation of pro-inflammatory cytokine production.