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Background: Particulate steroids are thought to exert their effects for long durations at injection sites. However, these types of steroids carry higher risks when used in epidural steroid injections. Catastrophic spinal cord complications, including sudden-onset paraplegia, have been reported due to intravascular particulate steroid preparations that cause embolisms and occlusion of blood vessels, resulting in spinal cord infarctions. Clinicians, therefore, recommend nonparticulate steroids to mitigate these adverse events. To our knowledge, this is the first retrospective study that addresses the effectiveness and safety of methylprednisolone, dexamethasone, and betamethasone when used in transforaminal epidural steroid injections (TFESIs) for the treatment of lumbar radiculopathy., Objectives: The primary goal of this study was to compare the proportion of patients who received injections of particulate steroids and required zero repeat injections within 12 months of their initial injection to the proportion of patients who received injections of nonparticulate steroids and also required zero repeat injections, as well as to compare the number of patients in the particulate cohort who required one or more repeat injections within 12 months of their initial injection to the number of patients in the nonparticulate cohort who required the same. The secondary goal was to evaluate the proportion of patients ultimately requiring surgery., Study Design: This is a single-center, IRB-approved, retrospective study evaluating the safety and effectiveness of nonparticulate as compared to particulate steroid medications when used in TFESIs as minimally invasive treatments for chronic lumbar radiculopathy., Setting: This study captured data (n = 1717) over a 4-year time frame (01/15/2018 to 01/15/2022)., Methods: The following data were collected from each patient's chart: age, gender, BMI, race, date of initial injection, number of repeat injections at the same lumbosacral level and on the same side within 12 months of the initial injection, and lumbar surgery date (if applicable). Inclusion criteria included: 1) having chronic low back pain of radicular etiology; 2) being at least 18 years old; 3) having experienced the failure of conservative therapy after 12 weeks (including physical therapy and/or medications); 4) having positive physical exam findings supporting nerve impingement (straight leg raise, slump test); and 5) showing lumbar MRI evidence of nerve impingement from disc herniation. Exclusion criteria included: 1) having received prior lumbar surgery at any level (L1-S1); 2) having been given prior TFESIs fewer than 6 months prior to initial injection; 3) having contracted a systemic infection at the proposed injection site; 4) undergoing active cancer treatment; and 5) having gotten any other spine injections., Results: A significantly greater proportion of patients in the nonparticulate steroid cohort received 0 repeat injections (87.5% vs 71.4%, P < 0.001). The particulate steroid cohort demonstrated a significantly greater proportion of patients who received repeat injections within 12 months after the initial injections (12.5% vs 29.6%, P < 0.001). There were no significant differences among patients requiring surgery between the 2 cohorts. Other outcome measures included the identification of risk factors significantly associated with repeat injections. There was a statistically significant weak positive correlation between age and repeat injections (Pearson corr = 0.102; P < 0.001) and a weak negative correlation between ethnicity/race and repeat injections (point-biserial corr = -0.093; P < 0.001).  No adverse events were reported., Limitations: Not all clinicians included in this study used each of the 3 steroid types, and all clinicians used either particulate or nonparticulate steroids exclusively., Conclusions: Our study demonstrates that the clinical outcomes associated with TFESIs of nonparticulate steroids are superior to those associated with TFESIs of particulate steroids when either variety of medication is used to treat lumbar radiculopathy. This is the first study to include a clinically useful predictive model using information on laterality, age, and steroid type.

The emulsifying ability of SA01-OmpA (outer membrane protein A from Acinetobacter sp. SA01) was found to be constrained by challenges like low production efficiency and high costs associated with protein recovery from E. coli inclusion bodies, as described in our previous study. The present study sought to benefit from the advantages of the targeted truncating of SA01-OmpA protein, taking into account the reduced propensity of protein expression as inclusion bodies and cytotoxicity. Here, the structure and activity relationship of two truncated recombinant forms of SA01-OmpA protein was unraveled through a hybrid approach based on experimental data and computational methodologies, representing an innovative bioemulsifier with advantageous emulsifying activity. The recombinant truncated SA01-OmpA variants were cloned and heterologously expressed in E. coli host cells and subsequently purified. The results showed increased emulsifying activity of N-terminally truncated SA01-OmpA (NT-OmpA) compared to full-length SA01-OmpA. Molecular dynamics (MD) simulations analysis demonstrated a direct correlation between the C-terminally truncated SA01-OmpA (CT-OmpA) and its expression as inclusion bodies. Analysis of the structure-activity relationship of truncated variants of SA01-OmpA revealed that, compared to the full-length protein, deletion of the β-barrel portion from the N-terminal of SA01-OmpA increased the emulsifying activity of NT-OmpA while lowering its expression as inclusion bodies. Contrary to the full-length protein, the N-terminally truncated SA01-OmpA was not as cytotoxic, according to the MTT assay, FCM analysis, and AO/EB staining. The findings of this extensive study advance our knowledge of SA01-OmpA at the molecular level as well as the design and development of efficient bioemulsifiers.IMPORTANCEPrevious research (Shahryari et al. 2021, mSystems 6: e01175-20) introduced and characterized the SA01-OmpA protein as a multifaceted protein with a variety of functions, including maintaining cellular homeostasis under oxidative stress conditions, biofilm formation, outer membrane vesicles (OMV) biogenesis, and beneficial emulsifying capacity. By truncating the SA01-OmpA protein, the current study presents a unique method for developing protein-type bioemulsifiers. The findings indicate that the N-terminally truncated SA01-OmpA (NT-OmpA) has the potential to fully replace full-length SA01-OmpA as a novel bioemulsifier with significant emulsifying activity. This study opens up a new frontier in bioemulsifiers, shedding light on a possible relationship between the structure and activity of SA01-OmpA truncated forms., Competing Interests: The authors declare no conflict of interest.

Homeostatic adaptation to systemic iron overload involves transcriptional induction of bone morphogenetic protein 6 (BMP6) in liver sinusoidal endothelial cells (LSECs). BMP6 is then secreted to activate signaling of the iron hormone hepcidin (HAMP) in neighboring hepatocytes. To explore the mechanism of iron sensing by LSECs, we generated TfrcTek-Cre mice with endothelial cell-specific ablation of transferrin receptor 1 (Tfr1). We also used control Tfrcfl/fl mice to characterize the LSEC-specific molecular responses to iron using single-cell transcriptomics. TfrcTek-Cre animals tended to have modestly increased liver iron content (LIC) compared with Tfrcfl/fl controls but expressed physiological Bmp6 and Hamp messenger RNA (mRNA). Despite a transient inability to upregulate Bmp6, they eventually respond to iron challenges with Bmp6 and Hamp induction, yet occasionally to levels slightly lower relative to LIC. High dietary iron intake triggered the accumulation of serum nontransferrin bound iron (NTBI), which significantly correlated with liver Bmp6 and Hamp mRNA levels and elicited more profound alterations in the LSEC transcriptome than holo-transferrin injection. This culminated in the robust induction of Bmp6 and other nuclear factor erythroid 2-related factor 2 (Nrf2) target genes, as well as Myc target genes involved in ribosomal biogenesis and protein synthesis. LSECs and midzonal hepatocytes were the most responsive liver cells to iron challenges and exhibited the highest expression of Bmp6 and Hamp mRNAs, respectively. Our data suggest that during systemic iron overload, LSECs internalize NTBI, which promotes oxidative stress and thereby transcriptionally induces Bmp6 via Nrf2. Tfr1 appears to contribute to iron sensing by LSECs, mostly under low iron conditions., (© 2023 by The American Society of Hematology.)

The purpose of this evaluation is to describe COVID-19 vaccine hesitancy among a sample of youth aged 12-15 and inform efforts to increase vaccination uptake among youth populations. We used data collected in May 2021 through a health education program for 9 th graders (N = 345). We used Spearman correlations and chi-square tests to assess the statistical significance of bivariate relationships. Less than half of students (42%) reported they are not hesitant at all about getting a COVID-19 vaccine. The remainder reported they were "a little hesitant" (22%), "somewhat hesitant" (21%), or "very hesitant" (15%). There were no statistically significant differences across age, gender, race/ethnicity, parental education, self-reported grades, or hours playing video games during school days. There was a statistically significant relationship between COVID-19 vaccine hesitancy and hours of TV watched during school days. The prevalence of COVID-19 vaccine hesitancy in this sample is high, but more research is needed to estimate its prevalence for youth at the state or national level. Correlates of COVID-19 vaccine hesitancy among adult populations may not match those found in youth populations. Research which recognizes youth as agentic rather than passive participants in decision-making opens opportunities for developing age-appropriate health communication and interventions for vaccination.

Background: Self-efficacy and fear of re-injury have been documented as factors related to an athlete's ability to return-to-sport after anterior cruciate ligament (ACL) reconstruction. The purpose of this study was to compare psychological readiness between athletes injured in their primary mode of sport versus those injured outside of their primary sport following ACL reconstruction., Hypothesis: Athletes sustaining 'in-sport' injuries will demonstrate poorer psychological readiness when compared their matched counterparts injured outside of their primary sport., Study Design: Case-Control Study., Methods: A single-surgeon database of 638 patients following ACL reconstruction was used to conduct a matched case-control analysis. Psychological readiness was examined 16-weeks postoperatively using the ACL-Return to Sport after Injury (ACL-RSI) questionnaire with subgroup analyses for the 'emotional', 'confidence' and 'injury-risk' subscales. Subject matching was performed for baseline patient and surgical demographics. All statistical comparisons were performed using a one-way (group) analysis variance (ANOVA) at a significance level of α = .05., Results: Ninety-two matched patients (49 'in-sport' injuries, 43 'out-of-sport' injuries) were included in the final analysis. The 'in-sport' group exhibited significantly lower total ACL-RSI scores (55.3 ±12.9 versus 60.8 ±11.6, t = 2.747, P < .001) when compared to the 'out-of-sport' group. Subscale comparisons indicated lower 'emotional' (P < .016) and higher 'injury risk' (P < .001) psychological constructs for 'in-sport' athletes versus 'out-of-sport' athletes. No differences were found between groups for the 'confidence' subscale (P = .987)., Conclusions: Athletes sustaining 'in-sport' ACL injuries demonstrated poorer psychological readiness when compared to athletes injured outside their primary sport when in preparation for return-to-sport activities following ACL reconstruction., Clinical Relevance: Clinicians should consider the potential impact of mode of injury on psychological readiness when returning athletes to sport after ACL reconstruction., Competing Interests: Dr. Walter Lowe, MD is a paid consultant for DonJoy Inc. & Arthrex Inc. Neither DonJoy Inc. or Arthrex Inc had involvement with any phase of this study.

Pre-exposure prophylaxis (PrEP) has emerged as a new HIV prevention strategy. A series of demonstration projects were conducted to explore the use of PrEP outside of clinical trial settings. Learning from the failures in community consultation and involvement in early oral tenofovir trials, these PrEP projects attempted to better engage communities and create spaces for community involvement in the planning and roll out of these projects. We briefly describe the community engagement strategies employed by seven Bill & Melinda Gates Foundation-funded PrEP demonstration projects and the lessons these projects offer for community engagement in PrEP implementation., Competing Interests: No competing interests were disclosed., (Copyright: © 2019 Reza-Paul S et al.)

Transferrin receptor 1 (Tfr1) mediates uptake of circulating transferrin-bound iron to developing erythroid cells and other cell types. Its critical physiological function is highlighted by the embryonic lethal phenotype of Tfr1-knockout (Tfrc -/- ) mice and the pathologies of several tissue-specific knockouts. We generated Tfrc Alb-Cre mice bearing hepatocyte-specific ablation of Tfr1 to explore implications in hepatocellular and systemic iron homeostasis. Tfrc Alb-Cre mice are viable and do not display any apparent liver pathology. Nevertheless, their liver iron content (LIC) is lower compared with that of control Tfrc fl/fl littermates as a result of the reduced capacity of Tfr1-deficient hepatocytes to internalize iron from transferrin. Even though liver Hamp messenger RNA (mRNA) and serum hepcidin levels do not differ between Tfrc Alb-Cre and Tfrc fl/fl mice, Hamp/LIC and hepcidin/LIC ratios are significantly higher in the former. Importantly, this is accompanied by modest hypoferremia and microcytosis, and it predisposes Tfrc Alb-Cre mice to iron-deficiency anemia. Tfrc Alb-Cre mice appropriately regulate Hamp expression following dietary iron manipulations or holo-transferrin injection. Holo-transferrin also triggers proper induction of Hamp mRNA, ferritin, and Tfr2 in primary Tfrc Alb-Cre hepatocytes. We further show that these cells can acquire 59 Fe from 59 Fe-transferrin, presumably via Tfr2. We conclude that Tfr1 is redundant for basal hepatocellular iron supply but essential for fine-tuning hepcidin responses according to the iron load of hepatocytes. Our data are consistent with an inhibitory function of Tfr1 on iron signaling to hepcidin via its interaction with Hfe. Moreover, they highlight hepatocellular Tfr1 as a link between cellular and systemic iron-regulatory pathways., (© 2019 by The American Society of Hematology.)

Background: To establish the feasibility of the dosimetric compliance criteria of the RTOG 1308 trial through testing against Intensity Modulation Radiation Therapy (IMRT) and Passive Scattering Proton Therapy (PSPT) plans., Methods: Twenty-six lung IMRT and 26 proton PSPT plans were included in the study. Dose Volume Histograms (DVHs) for targets and normal structures were analyzed. The quality of IMRT plans was assessed using a knowledge-based engineering tool., Results: Most of the RTOG 1308 dosimetric criteria were achieved. The deviation unacceptable rates were less than 10 % for most criteria; however, a deviation unacceptable rate of more than 20 % was computed for the planning target volume minimum dose compliance criterion. Dose parameters for the target volume were very close for the IMRT and PSPT plans. However, the PSPT plans led to lower dose values for normal structures. The dose parameters in which PSPT plans resulted in lower values than IMRT plans were: lung V5Gy (%) (34.4 in PSPT and 47.2 in IMRT); maximum spinal cord dose (31.7 Gy in PSPT and 43.5 Gy in IMRT); heart V5Gy (%) (19 in PSPT and 47 in IMRT); heart V30Gy (%) (11 in PSPT and 19 in IMRT); heart V45Gy (%) (7.8 in PSPT and 12.1 in IMRT); heart V50% (Gy) (7.1 in PSPT and 9.8 in IMRT) and mean heart dose (7.7 Gy in PSPT and 14.9 Gy in IMRT)., Conclusions: The revised RTOG 1308 dosimetric compliance criteria are feasible and achievable.

Introduction: The Corona virus disease (COVID-19) is a respiratory illness that is caused by SARS-CoV-2 virus. This virus was first reported in China in December 2019. It then spread to all countries and from March 11, 2020, the World Health Organization declared the COVID-19 outbreak a pandemic. In Uganda, the disease was first reported in March 2020 and COVID-19 vaccines became available by January 2021. Although COVID-19 vaccines were available in Uganda, uptake remained low. The aim of this study was to establish COVID-19 vaccine uptake awareness in a peri-urban setting in Entebbe City, Uganda. Methods: This was a cross-sectional study conducted among 127 men and 263 women who reside in Entebbe City, Uganda. Data was collected on socio-behavioral characteristics, knowledge, attitude, and practice (KAP) about COVID-19 vaccine using interviewer administered questionnaires. Uptake of COVID-19 vaccine was defined as the proportion of participants who had received at least one dose of the COVID-19 vaccine. We used descriptive statistics to estimate awareness of COVID-19 vaccines. The 'chi-square test' and 'modified Poisson regression' were used to assess variations in uptake of COVID-19 vaccines among respondents and their socio-demographics as well as other characteristics. Results: Ninety-nine percent (388 out of 390) of the study population were aware of at least one brand of COVID-19 vaccines in the country. Thirty-five percent (138 out of 390) knew that the vaccine immunity was achieved 14 days after the 2nd dose and 98.7% (385 out of 390) admitted that observing the standard operating procedure for COVID-19 infection prevention was necessary after vaccination. There was a gap in knowledge on vaccine safety reported by 74.6% (291 out of 390) participants. Some participants 37.2% (145 out of 390) had concerns about the vaccine. Of these, 57.9% (84 out of 145) believed that the vaccines were not helpful; and 30.3% (44 out of 145) feared serious side effects. Sixty-six percent (257 out of 390) believed that vaccines were not working and 79.0% (308 out of 390) admitted that vaccines were promoted for financial gain. At the time of performing the study, 36.2% and 22.3% had received the 1st and 2nd dose respectively. The main sources of information on COVID-19 vaccine were television (TV) and social media (p-value 0.001). In a multivariate model, COVID-19 vaccine acceptability was associated with salaried and self-employment (p-value 0.046). The other predicative factors were awareness of the COVID-19 vaccine (p-value <0.001) and having vaccine concerns (p-value 0.013). Conclusion: Uptake of COVID-19 vaccination in Entebbe community was low, partly attributed to knowledge gaps and concerns about vaccine safety and effectiveness. This highlights the need to enhance dissemination of information about COVID-19 vaccine. The lessons learnt in this study would be relevant for other emerging infections by informing vaccination implementation programs in similar settings. [ABSTRACT FROM AUTHOR]

This study reports an investigation into both isotropic and anisotropic permeability effects on gas production behavior during depressurization-induced natural gas hydrate dissociation at site NGHP-01-10D in the Krishna-Godavari basin. Numerical simulations were performed on a reservoir-scale model incorporating a single vertical well, examining different scenarios of permeability ratios (rrz). The investigation assessed gas and water production rates, cumulative production volumes, the gas-to-water ratio, and the spatial distribution of reservoir parameters throughout a production duration of 3 years. The findings indicate that permeability anisotropy has a substantial impact on hydrate dissociation and gas recovery. For rrz > 1, horizontal pressure propagation was promoted and gas production increased. For example, at t = 1100 days, the total gas production improved from 7.88 × 105 ST m3 for rrz = 1 to 55.9 × 105 ST m3 for rrz = 10. For rrz < 1, vertical pressure propagation resulted in higher water production with concomitantly lower rates of gas production rates. Spatial distribution analysis revealed that higher rrz values led to more extensive radial propagation of pressure drop, temperature decrease, gas saturation increase, and hydrate dissociation. The study concludes that higher horizontal permeability enhances depressurization effects, resulting in higher gas production rates and more favorable gas-to-water ratios. [ABSTRACT FROM AUTHOR]

The collection of the ancestral fruit cauchao (Amomyrtus luma) is part of the routines of women gatherers from the extreme south (44° South Latitude) in Chile. The traditional food knowledge of cauchao has not been documented, and there is no data on the nutritional composition. Women's experiences collecting cauchao can help understand the relationship between traditional food, herbal medicine, and local gatherers' communities. Thus, this research explores the traditional knowledge of food and the nutritional composition of cauchao. Mixed methods research was performed. A case study included in-depth interviews with 12 women gatherers and thematic analysis. The composition of macronutrients in cauchao was obtained by proximate chemical analyses and dietary fiber using the enzymatic-gravimetric method. Results showed that gathering for these women was more than just extracting natural resources; it was associated with family, food security, participation in different stages of the food system, and practices that could contribute towards sustainable food systems. Furthermore, cauchao fruit showed a high dietary fiber content, and women gatherers did not connect cauchao with dietary fiber. Since access to knowledge by small-scale food producers, especially women, is part of the Sustainable Development Goals (SDG#2.3), the approach of this research may help guide knowledge transfer among women gatherers. [ABSTRACT FROM AUTHOR]

Active and relic marine methane‐seep sites are widely distributed globally and are distinguished by distinctive geology, biogeochemistry, and ecosystems. The discovery of methane‐seep sites in the Krishna‐Godavari (K‐G) basin has created exciting new opportunities for methane‐seep research in the Bay of Bengal. In this study, we document the occurrence of authigenic carbonates, including micro‐crystalline aragonite crust (arg‐crusts) admixed with chemosynthetic shells and high‐magnesium carbonate tubular structures (HMC‐tube), from the methane‐seep site SSD‐045/4 in the K‐G basin. The δ13C values of HMC‐tubes (−54.5 to −46.2‰) and arg‐crusts (−57.6 to −34.8‰) indicate biogenic methane as the likely carbon source. Enhanced porewater alkalinity driving carbonate precipitation may be attributed to microbial‐mediated SO₄2−‐AOM processes. Additionally, δ13C values (−35.2 ± 8‰) of the residual organic matter within the carbonates suggest a contribution of methanotrophic bacterial biomass. The δ18Ocarb values of HMC and aragonite indicate methane hydrate degassing and crystallization pathways, respectively. Pelloid‐filled burrows suggest the reworking of shallow HMC deposit by burrowing organisms, whereas the polyphase cementations (aragonite and HMC) within burrows indicate early and burial diagenetic pathways. The wide range in ΣLREE/ΣHREE ratios and Ceanom values in arg‐crusts reflect micro‐spatial variations in redox conditions, likely due to cementation occurring in both open and closed diagenetic systems. In contrast, more constrained Ceanom values and ΣLREE/ΣHREE ratios in HMC tubes suggest persistent sulfidic conditions. Overall, these findings provide insights into the pathways of carbonate formation at the K‐G basin methane‐seep site, highlighting the complex interplay of microbial processes, fluid dynamics, and diagenetic alterations. Plain Language Summary: Methane cold‐seeps are regions on the seabed where methane (CH4) gas oozes out across the sediment‐water interface into the water column. Both active and inactive seepage sites are known across the oceans. Active methane seep sites expel significant quantities of methane into the seawater which influences the oceanic methane budget as well as the carbon cycle. In contrast, the preserved authigenic carbonate deposits and chemosynthetic fauna at the relic seep sites are archives of past seepage activities. The seep ecosystem comprises a variety of chemosynthetic and non‐chemosynthetic organisms, whereas the geological features include mounds, mud volcanoes, carbonate crusts, chimneys, etc. formed due to methane expulsion processes. Here, we investigate the origin of calcium carbonate structures formed in a cold seep region off the east coast of India. The carbonate structures include tubular‐shaped high magnesian carbonates (HMC) and crusts composed of aragonite minerals. These tubes and crusts archive biological and geological processes, including past variations in methane effusion and diffusion through the sediment. Tubular structures are formed by gas flow through the sediments as chimneys and by burrowing activities of benthic organisms. On the other hand, the aragonite crusts are formed where methane flow is high across the seabed. Key Points: Relics of methanogenic high magnesian calcite tubes and aragonite crust recovered from cold seep site K‐G basin east coast of IndiaHMC precipitation is confined to sulfidic conditions in contrast to a wider redox range for aragonite precipitationReworking of unconsolidated HMC produced the pelloid rich tubular structures, whereas aragonite crust formed at high CH4 flow conditions [ABSTRACT FROM AUTHOR]

This paper employs insights from earth science on the financial risk of project developments to present an economic theory of critical minerals. Our theory posits that back-ended critical mineral projects that have unaddressed technical and non-technical barriers, such as those involving lithium and cobalt, exhibit an additional risk for investors which we term the "back-ended risk premium". We show that the back-ended risk premium increases the cost of capital and, therefore, has the potential to reduce investment in the sector. We posit that the back-ended risk premium may also reduce the gains in productivity expected from artificial intelligence (AI) technologies in the mining sector. Progress in AI may, however, lessen the back-ended risk premium itself by shortening the duration of mining projects and the required rate of investment by reducing the associated risk. We conclude that the best way to reduce the costs associated with energy transition is for governments to invest heavily in AI mining technologies and research. Vespignani and Smyth present an economic theory of risk in critical minerals they term the "back-ended risk premium." They apply AI approaches to reduce this risk premium and lower costs in energy transition. [ABSTRACT FROM AUTHOR]

Background: Chickpea is an important pulse crop. The area, production and productivity of Kabuli chickpea are very low as compared to Desi type chickpea. While, worldwide chickpea production is predominated by Desi type (80%) compared to Kabuli type (20%). One of constraints limiting the Kabuli chickpea seed production is the fast seed deterioration process as, they possesses thin and fragile seed coat which makes it more susceptible to infestation of pulse beetle and storage fungi. In addition, the day by day increase in usage of chemical pesticides and increase in health awareness among the people and demand towards organic based products necessitate a new alternative method of seed storage than the routinely used storage methods. Modified atmosphere storage is an alternative method to avoid chemical fumigants, which are said to cause residual effect on seed material and development of resistance by storage pest against insecticides. Methods: The present investigation on modified atmosphere packaging (MAP) was carried out at the Department of Processing and Food Engineering, College of Agricultural Engineering, University of Agricultural Sciences, Raichur during March 2017. Further, its storage and seed quality assessment were conducted at Seed Quality and Research Laboratory of National Seed Project (Crops), Seed Unit, University of Agricultural Sciences, Dharwad during March 2017 to May 2018. Result: The results revealed that the Kabuli chickpea seeds stored in the gaseous atmosphere with the combination of CO2 (80%) +N2 (20%) + O2 (0%) [C2] have maintained the maximum germination (92%) followed by Vaccum Packaging [C2] by using 700 gauge polyethylene bag for 14 months under ambient conditions above the Indian Minimum Seed Certification Standards. [ABSTRACT FROM AUTHOR]

Background: Pulmonary arterial hypertension (PAH) is a life-threatening chronic cardiopulmonary disease. However, there is a paucity of studies that reflect the available biomarkers from separate gene expression profiles in PAH. Methods: The GSE131793 and GSE113439 datasets were combined for subsequent analyses, and batch effects were removed. Bioinformatic analysis was then performed to identify differentially expressed genes (DEGs). Weighted gene co-expression network analysis (WGCNA) and a protein-protein interaction (PPI) network analysis were then used to further filter the hub genes. Functional enrichment analysis of the intersection genes was performed using Gene Ontology (GO), Disease Ontology (DO), Kyoto encyclopedia of genes and genomes (KEGG) and gene set enrichment analysis (GSEA). The expression level and diagnostic value of hub gene expression in pulmonary arterial hypertension (PAH) patients were also analyzed in the validation datasets GSE53408 and GSE22356. In addition, target gene expression was validated in the lungs of a monocrotaline (MCT)-induced pulmonary hypertension (PH) rat model and in the serum of PAH patients. Results: A total of 914 differentially expressed genes (DEGs) were identified, with 722 upregulated and 192 downregulated genes. The key module relevant to PAH was selected using WGCNA. By combining the DEGs and the key module of WGCNA, 807 genes were selected. Furthermore, protein–protein interaction (PPI) network analysis identified HSP90AA1, CD8A, HIF1A, CXCL8, EPRS1, POLR2B, TFRC, and PTGS2 as hub genes. The GSE53408 and GSE22356 datasets were used to evaluate the expression of TFRC, which also showed robust diagnostic value. According to GSEA enrichment analysis, PAH-relevant biological functions and pathways were enriched in patients with high TFRC levels. Furthermore, TFRC expression was found to be upregulated in the lung tissues of our experimental PH rat model compared to those of the controls, and the same conclusion was reached in the serum of the PAH patients. Conclusions: According to our bioinformatics analysis, the observed increase of TFRC in the lung tissue of human PAH patients, as indicated by transcriptomic data, is consistent with the alterations observed in PAH patients and rodent models. These data suggest that TFRC may serve as a potential biomarker for PAH. [ABSTRACT FROM AUTHOR]

Vitamin D receptors are expressed in many organs and tissues, which suggests that vitamin D (VD) affects physiological functions beyond its role in maintaining bone health. Deficiency or inadequacy of 25(OH)VD is widespread globally. Population studies demonstrate that a positive association exists between a high incidence of VD deficiency and a high incidence of chronic diseases, including dementia, diabetes, and heart disease. However, many subjects have difficulty achieving the required circulating levels of 25(OH)VD even after high-dose VD supplementation, and randomized controlled clinical trials have reported limited therapeutic success post-VD supplementation. Thus, there is a discordance between the benefits of VD supplementation and the prevention of chronic diseases in those with VD deficiency. Why this dissociation exists is currently under debate and is of significant public interest. This review discusses the downregulation of VD-metabolizing genes needed to convert consumed VD into 25(OH)VD to enable its metabolic action exhibited by subjects with metabolic syndrome, obesity, and other chronic diseases. Research findings indicate a positive correlation between the levels of 25(OH)VD and glutathione (GSH) in both healthy and diabetic individuals. Cell culture and animal experiments reveal a novel mechanism through which the status of GSH can positively impact the expression of VD metabolism genes. This review highlights that for better success, VD deficiency needs to be corrected at multiple levels: (i) VD supplements and/or VD-rich foods need to be consumed to provide adequate VD, and (ii) the body needs to be able to upregulate VD-metabolizing genes to convert VD into 25(OH)VD and then to 1,25(OH)2VD to enhance its metabolic action. This review outlines the association between 25(OH)VD deficiency/inadequacy and decreased GSH levels, highlighting the positive impact of combined VD+LC supplementation on upregulating GSH, VD-metabolizing genes, and VDR. These effects have the potential to enhance 25(OH)VD levels and its therapeutic efficacy. [ABSTRACT FROM AUTHOR]

One such recent innovation in Sharia insurance in Indonesia is the introduction of waqf insurance products. In this study, we aim to explore the untapped potential of integrating waqf into Sharia insurance products, positioning it strategically within the insurance landscape of Indonesia. Employing a comprehensive sequential mixed methods approach, the study collected data through in-depth interviews with key stakeholders, including government officials, insurance companies, and nazhir (waqf managers). The qualitative interviews were complemented by quantitative surveys to provide a holistic understanding. A rigorous analysis was conducted, combining qualitative and quantitative techniques, such as weighting methods on the SWOT matrix. The findings resulted in a strategic formulation, highlighting the possibilities of waqf integration in the Indonesian insurance sector. The study reveals the promising trajectory of waqf insurance in Indonesia, positioning it in Quadrant I of the SWOT analysis. This implies that, with the collective support of all stakeholders, this Islamic social finance product has the potential to experience substantial growth, capitalizing on the existing opportunities. [ABSTRACT FROM AUTHOR]

Steroidogenic factor 1 (SF-1/Nr5a1) is an orphan nuclear receptor encoded by the Ftz-F1 gene and is required for gonad and adrenal development and regulation of hormone production within the reproductive and adrenal axes. To extend our understanding of Ftz-F1 and its role in SF-1 expression, we identified and characterized a yeast artificial chromosome (YAC) containing Ftz-F1. Within this YAC, Ftz-F1 is centrally located and flanked by genes encoding a second orphan nuclear receptor, germ cell nuclear factor, and proteasome (prosome, macropain) subunit beta type 7. Three lines of transgenic mice carrying the YAC were generated and in two lines (lines 7 and 14), RT-PCR and ribonuclease protection analysis showed that expression of transgenic SF-1 mimicked that of endogenous SF-1, both spatially and quantitatively. In the third line (line 15), pituitary and hypothalamic expression were absent. Comparison of the integrated transgenes revealed that line 15 was truncated at the end of intron 4 and revealed a region within the locus that is responsible for SF-1 expression in the pituitary and hypothalamus. The line 14 transgene was introduced into a mouse strain lacking functional SF-1. Examination of SF-1-deficient, transgene-positive mice revealed that the YAC was able to rescue adrenal and gonad development, which normally arrests in the SF-1-null embryos and showed that the 153-kb transgene integrated in line 14 is sufficient to properly direct SF-1 expression and support its biological activity. Thus, the study defines a region of Ftz-F1 that contains the requisite set of regulatory elements to direct SF-1 cell-specific expression and all temporal and quantitative changes need for its biological activity.

Grb2 is an adaptor molecule that couples membrane receptors such as the epidermal growth factor receptor (EGFR) to intracellular signaling pathways. To gain insight into the trafficking pathways followed by these molecules after activation by EGF, we visualized Grb2 and EGFR fused to GFP spectral variants in single live cells. In nonstimulated cells, Grb2-YFP was primarily localized diffusely in the cytoplasm, whereas EGFR-CFP was found on the plasma membrane and in endocytic structures localized in the perinuclear area. Within 1 minute of EGF stimulation, Grb2 redistributed to the plasma membrane where it bound EGFR-CFP in an SH2 dependent manner. The plasma membrane then began to dynamically ruffle, and Grb2-YFP and EGFR-CFP were found to internalize together in large macropinocytic structures. These structures were morphologically distinct from conventional, clathrin-derived endosomes and did not label with transferrin, AP-2 or clathrin heavy chain. Evidence that these structures did not require clathrin for internalization came from experiments showing that expression of the C-terminus of AP-180, which inhibited transferrin uptake, had no effect on EGF-induced internalization of EGFR. YFP-tagged Grb2 containing an inhibitory mutation in either N- or C-SH3 domain redistributed to the plasma membrane upon EGF stimulation, but the macropinocytic structures containing Grb2-YFP and EGFR-CFP did not translocate inward and appeared to remain tethered to the plasma membrane. This suggested that the Grb2 SH3 domain was responsible for coupling the membranes containing EGFR with downstream effectors involved in internalization of these membranes. Transferrin uptake was unaffected in the presence of all of the SH3 domain mutants, consistent with the EGF-stimulated EGFR internalization pathway being clathrin-independent. These results demonstrate a role for Grb2 in events associated with a macropinocytic internalization pathway for EGFR in activated cells.

The nonreceptor protein tyrosine kinase ZAP-70 is a critical enzyme required for successful T lymphocyte activation. After antigenic stimulation, ZAP-70 rapidly associates with T cell receptor (TCR) subunits. The kinetics of its translocation to the cell surface, the properties of its specific interaction with the TCRzeta chain expressed as a chimeric protein (TTzeta and Tzetazeta), and its mobility in different intracellular compartments were studied in individual live HeLa cells, using ZAP-70 and Tzetazeta fused to green fluorescent protein (ZAP-70 GFP and Tzetazeta-GFP, respectively). Time-lapse imaging using confocal microscopy indicated that the activation-induced redistribution of ZAP-70 to the plasma membrane, after a delayed onset, is of long duration. The presence of the TCRzeta chain is critical for the redistribution, which is enhanced when an active form of the protein tyrosine kinase Lck is coexpressed. Binding specificity to TTzeta was indicated using mutant ZAP-70 GFPs and a truncated zeta chimera. Photobleaching techniques revealed that ZAP-70 GFP has decreased mobility at the plasma membrane, in contrast to its rapid mobility in the cytosol and nucleus. Tzetazeta- GFP is relatively immobile, while peripherally located ZAP-70 in stimulated cells is less mobile than cytosolic ZAP-70 in unstimulated cells, a phenotype confirmed by determining the respective diffusion constants. Examination of the specific molecular association of signaling proteins using these approaches has provided new insights into the TCRzeta-ZAP-70 interaction and will be a powerful tool for continuing studies of lymphocyte activation.

The Golgi complex is a dynamic organelle engaged in both secretory and retrograde membrane traffic. Here, we use green fluorescent protein-Golgi protein chimeras to study Golgi morphology in vivo. In untreated cells, membrane tubules were a ubiquitous, prominent feature of the Golgi complex, serving both to interconnect adjacent Golgi elements and to carry membrane outward along microtubules after detaching from stable Golgi structures. Brefeldin A treatment, which reversibly disassembles the Golgi complex, accentuated tubule formation without tubule detachment. A tubule network extending throughout the cytoplasm was quickly generated and persisted for 5-10 min until rapidly emptying Golgi contents into the ER within 15-30 s. Both lipid and protein emptied from the Golgi at similar rapid rates, leaving no Golgi structure behind, indicating that Golgi membranes do not simply mix but are absorbed into the ER in BFA-treated cells. The directionality of redistribution implied Golgi membranes are at a higher free energy state than ER membranes. Analysis of its kinetics suggested a mechanism that is analogous to wetting or adsorptive phenomena in which a tension-driven membrane flow supplements diffusive transfer of Golgi membrane into the ER. Such nonselective, flow-assisted transport of Golgi membranes into ER suggests that mechanisms that regulate retrograde tubule formation and detachment from the Golgi complex are integral to the existence and maintenance of this organelle.

To investigate the cellular dynamics of ZAP-70, we have studied the distribution and regulation of its intracellular location using a ZAP-70 green fluorescent protein chimera. Initial experiments in epithelial cells indicated that ZAP-70 is diffusely located throughout the quiescent cell, and accumulates at the plasma membrane upon cellular activation, a phenotype enhanced by the coexpression of Lck and the initiation of ZAP-70 kinase activity. Subsequent studies in T cells confirmed this phenotype. Intriguingly, a large amount of ZAP-70, both chimeric and endogenous, resides in the nucleus of quiescent and activated cells. Nuclear ZAP-70 becomes tyrosine phosphorylated upon stimulation via the T cell receptor, indicating that it may have an important biologic function.

Food insecurity is a critical issue in the Americas, with severe impacts in the Caribbean, Mesoamerica, and South America, particularly affecting older adults in Indigenous and rural contexts where it intersects with poverty, gender, and ethnicity. This study aims to provide an in-depth understanding of the current research about food insecurity among older Indigenous adults in Latin America and the Caribbean. A comprehensive literature review was conducted, utilizing specific search queries and the population, intervention, comparison, and outcome (PICO) strategy across multiple databases to identify the pertinent studies. The findings indicate an increase in academic output on this topic since 2018, with significant emphasis on the interplay between climate change and food insecurity. The review highlights the importance of developing targeted food programs, reforming policies, and fostering collaboration between academia and local communities to implement practical interventions. Despite the growing body of literature, a notable research gap persists in rural areas of Latin America and the Caribbean. This study underscores the necessity of balancing the geographic distribution of research and emphasizes the preservation of cultural practices and the adaptation of public policies to support traditional food practices. It advocates for culturally sensitive interventions and interdisciplinary collaboration to formulate comprehensive strategies. The originality and value of this study lie in its focused analysis of older Indigenous adults, contributing crucial insights to the international literature on food security. [ABSTRACT FROM AUTHOR]

Background: The effect of substrate and strain on the nutritional and functional properties of mushroom flours and protein concentrates (PCs) has not thoroughly been investigated. Methods: The proteins of P. ostreatus flours (strains AMRL144 and 150) were isolated following alkaline extraction (pH 12) and isoelectric precipitation (pH 4) as it was determined by the solubility curves. The protein quality of the flours and PCs were evaluated by determining the protein solubility index (PSI) and their functional properties, such as water (WAC) and oil absorption capacity (OAC), foam capacity (FC), foam stability (FS) and emulsion stability (ES). The amino acid (AA) composition of the flours was determined by reversed-phase liquid chromatography after protein hydrolysis and o-phthalaldehyde derivatization. Results: The PSIs of the flours and PCs of P. ostreatus were comparable to those of soy protein flours and protein concentrates. The highest AA concentration was found for both strains when cultivated on the barley and oat straw (BOS) substrate, showing a similar trend as the protein content. A principal component analysis (PCA) indicated an impact of the strain on the functional properties. Conclusions: Both strains can produce high quality proteins especially when cultivated on wheat straw (WS). The FS was positively correlated with the P. ostreatus strain AMRL150 whereas the FC was positively correlated with AMRL144. [ABSTRACT FROM AUTHOR]

The ADP-ribosylation factors (ARFs) and ARF-like (ARL) GTPases serve as essential molecular switches governing a wide array of cellular processes. In this study, we used proximity-dependent biotin identification (BioID) to comprehensively map the interactome of 28 out of 29 ARF and ARL proteins in two cellular models. Through this approach, we identified ~3000 high-confidence proximal interactors, enabling us to assign subcellular localizations to the family members. Notably, we uncovered previously undefined localizations for ARL4D and ARL10. Clustering analyses further exposed the distinctiveness of the interactors identified with these two GTPases. We also reveal that the expression of the understudied member ARL14 is confined to the stomach and intestines. We identified phospholipase D1 (PLD1) and the ESCPE-1 complex, more precisely, SNX1, as proximity interactors. Functional assays demonstrated that ARL14 can activate PLD1 in cellulo and is involved in cargo trafficking via the ESCPE-1 complex. Overall, the BioID data generated in this study provide a valuable resource for dissecting the complexities of ARF and ARL spatial organization and signaling. [ABSTRACT FROM AUTHOR]

Background: School health education (SHE) serves as a primary pedagogical aspect of public health. This study aims to explore the curricula of preservice schoolteachers, examining whether graduate courses in Greek universities include SHE, how it is structured, and whether critical pedagogy principles are integrated. Methods: A corpus of n = 21 documents was compiled, encompassing all educational departments in Greek higher education, including Departments of Early Childhood Education and Care (n = 3), Departments of Preschool Education (n = 9), and Departments of Primary Education (n = 9). Results: Content analysis revealed the presence of SHE in 11 out of 21 educational departments. Thematic analysis uncovered significant variability in the curricula, with greater emphasis placed on health-related topics rather than the methodologies and values of SHE. Critical pedagogy principles were not explicitly evident in the curricula, while a persistent biomedical orientation left little room for the development of concepts related to social justice. Conclusions: This study represents the first of its kind in Greece and among the few internationally to examine preservice training for schoolteachers in SHE. The findings underscore the need for revisions to align with the key lessons learned from the major public health crisis of the COVID-19 pandemic. It is imperative to acknowledge that vulnerabilities have been exacerbated, and inequalities widened, necessitating a reassessment of current approaches to health education within teacher training programs. [ABSTRACT FROM AUTHOR]

Background: Psychological readiness is an important consideration for athletes and clinicians when making return to sport decisions following anterior cruciate ligament reconstruction (ACLR). To improve our understanding of the extent of deficits in psychological readiness, a systematic review is necessary. Objective: To investigate psychological readiness (measured via the Anterior Cruciate Ligament-Return to Sport after Injury scale (ACL-RSI)) over time after ACL tear and understand if time between injury and surgery, age, and sex are associated with ACL-RSI scores. Methods: Seven databases were searched from the earliest date available to March 22, 2022. Articles reporting ACL-RSI scores after ACL tear were included. Risk of bias was assessed using the ROBINS-I, RoB-2, and RoBANS tools based on the study design. Evidence certainty was assessed for each analysis. Random-effects meta-analyses pooled ACL-RSI scores, stratified by time post-injury and based on treatment approach (i.e., early ACLR, delayed ACLR, and unclear approach). Results: A total of 83 studies were included in this review (78% high risk of bias). Evidence certainty was 'weak' or 'limited' for all analyses. Overall, ACL-RSI scores were higher at 3 to 6 months post-ACLR (mean = 61.5 [95% confidence interval (CI) 58.6, 64.4], I2 = 94%) compared to pre-ACLR (mean = 44.4 [95% CI 38.2, 50.7], I2 = 98%), remained relatively stable, until they reached the highest point 2 to 5 years after ACLR (mean = 70.7 [95% CI 63.0, 78.5], I2 = 98%). Meta-regression suggests shorter time from injury to surgery, male sex, and older age were associated with higher ACL-RSI scores only 3 to 6 months post-ACLR (heterogeneity explained R2 = 47.6%), and this reduced 1–2 years after ACLR (heterogeneity explained R2 = 27.0%). Conclusion: Psychological readiness to return to sport appears to improve early after ACL injury, with little subsequent improvement until ≥ 2-years after ACLR. Longer time from injury to surgery, female sex and older age might be negatively related to ACL-RSI scores 12–24 months after ACLR. Due to the weak evidence quality rating and the considerable importance of psychological readiness for long-term outcomes after ACL injury, there is an urgent need for well-designed studies that maximize internal validity and identify additional prognostic factors for psychological readiness at times critical for return to sport decisions. Registration: Open Science Framework (OSF), https://osf.io/2tezs/. Key Points: Over 70% of studies measuring ACL-RSI scores were judged to have high risk of bias (i.e., low internal validity), leading to a certainty of evidence rating of weak for all analyses. ACL-RSI scores do not appear to increase during typical rehabilitation periods after anterior cruciate ligament reconstruction. Age, sex, and time from injury to surgery (i.e., treatment approach) appear prognostic for early ACL-RSI scores, but their prognostic ability diminishes for later ACL-RSI scores. [ABSTRACT FROM AUTHOR]

The potassium-chloride co-transporter 2, KCC2, is a neuron-specific ion transporter that plays a multifunctional role in neuronal development. In mature neurons, KCC2 maintains a low enough intracellular chloride concentration essential for inhibitory neurotransmission. During recent years, pathogenic variants in the KCC2 encoding gene SLC12A5 affecting the functionality or expression of the transporter protein have been described in several patients with epilepsy of infancy with migrating focal seizures (EIMFS), a devastating early-onset developmental and epileptic encephalopathy. In this study, we identified a novel recessively inherited SLC12A5 c.692G>A, p. (R231H) variant in a patient diagnosed with severe and drug-resistant EIMFS and profound intellectual disability. The functionality of the variant was assessed in vitro by means of gramicidin-perforated patch-clamp experiments and ammonium flux assay, both of which indicated a significant reduction in chloride extrusion. Based on surface immunolabeling, the variant showed a reduction in membrane expression. These findings implicate pathogenicity of the SLC12A5 variant that leads to impaired inhibitory neurotransmission, increasing probability for hyperexcitability and epileptogenesis. [ABSTRACT FROM AUTHOR]

Cellular senescence is a state of permanent growth arrest. It can be triggered by telomere shortening (replicative senescence) or prematurely induced by stresses such as DNA damage, oncogene overactivation, loss of tumor suppressor genes, oxidative stress, tissue factors, and others. Advances in techniques and experimental designs have provided new evidence about the biology of senescent cells (SnCs) and their importance in human health and disease. This review aims to describe the main aspects of SnCs phenotype focusing on alterations in subcellular compartments like plasma membrane, cytoskeleton, organelles, and nuclei. We also discuss the heterogeneity, dynamics, and plasticity of SnCs' phenotype, including the SASP, and pro‐survival mechanisms. We advance on the multiple layers of phenotypic heterogeneity of SnCs, such as the heterogeneity between inducers, tissues and within a population of SnCs, discussing the relevance of these aspects to human health and disease. We also raise the main challenges as well alternatives to overcome them. Ultimately, we present open questions and perspectives in understanding the phenotype of SnCs from the perspective of basic and applied questions. [ABSTRACT FROM AUTHOR]

During the Indian National Gas Hydrate Program (NGHP) Expedition 02, Logging-while-drilling (LWD) logs were acquired at three sites (NGHP-02-11, NGHP-02-12, and NGHP-02-13) across the Mahanadi Basin in area A. We applied rock physics theory to available sonic velocity logs to know the distribution of gas hydrate at site NGHP-02-11 and NGHP-02-13. Rock physics modeling using sonic velocity at well location shows that gas hydrate is distributed mainly within the depth intervals of 150e265 m and 100 e215 mbsf at site NGHP-02-11 and NGHP-02-13, respectively, with an average saturation of about 4% of the pore space and the maximum concentration of about 40% of the pore space at 250 m depth at site NGHP-02-11, and at site NGHP-02-13 an average saturation of about 2% of the pore space and the maximum concentration of about 20% of the pore space at 246 m depth, as gas hydrate is distributed mainly within 100e246 mbsf at this site. Saturation of gas hydrate estimated from the electrical resistivity method using density derived porosity and electrical resistivity logs from Archie's empirical formula shows high saturation compared to that from the sonic log. However, estimates of hydrate saturation based on sonic P-wave velocity may differ significantly from that based on resistivity, because gas and hydrate have higher resistivity than conductive pore fluid and sonic P-wave velocity shows strong effect on gas hydrate as a small amount of gas reduces the velocity significantly while increasing velocity due to the presence of hydrate. At site NGHP-02-11, gas hydrate saturation is in the range of 15% e30%, in two zones between 150-180 and 245e265 mbsf. Site NGHP-02-012 shows a gas hydrate saturation of 20%e30% in the zone between 100 and 207 mbsf. Site NGHP-02-13 shows a gas hydrate saturation up to 30% in the zone between 215 and 246 mbsf. Combined observations from rock physics modeling and Archie's approximation show the gas hydrate concentrations are relatively low (<4% of the pore space) at the sites of the Mahanadi Basin in the turbidite channel system. [ABSTRACT FROM AUTHOR]

Methane gas hydrate related bottom-simulating reflectors (BSRs) are imaged based on the in-line and cross-line multi-channel seismic (MCS) data from the Andaman Forearc Basin. The depth of the BSR depends on pressure and temperature and pore water salinity. With these assumptions, the BSR depth can be used to estimate the geothermal gradient (GTG) based on the availability of in-situ temperature measurements. This calculation is done assuming a 1D conductive model based on available in-situ temperature measurement at site NGHP-01-17 in the study area. However, in the presence of seafloor topography, the conductive temperature field in the subsurface is affected by lateral refraction of heat, which focuses heat in topographic lows and away from topographic highs. The 1D estimate of GTG in the Andaman Forearc Basin has been validated by drilling results from the NGHP-01 expedition. 2D analytic modeling to estimate the effects of topography is performed earlier along selected seismic profiles in the study area. The study extended to estimate the effect of topography in 3D using a numerical model. The corrected GTG data allow us to determine GTG values free of topographic effect. The difference between the estimated GTG and values corrected for the 3D topographic effect varies up to ~5 °C/km. These conclude that the topographic correction is relatively small compared to other uncertainties in the 1D model and that apparent GTG determined with the 1D model captures the major features, although the correction is needed prior to interpreting subtle features of the derived GTG maps. [ABSTRACT FROM AUTHOR]

Growth-factor-receptor-binding protein 2 (GRB2) is a non-enzymatic adaptor protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses, including signaling transduction and gene expression. GRB2 binds to numerous target molecules, thereby modulating a complex cell signaling network with diverse functions. The structural characteristics of GRB2 are essential for its functionality, as its multiple domains and interaction mechanisms underpin its role in cellular biology. The typical signaling pathway involving GRB2 is initiated by the ligand stimulation to its receptor tyrosine kinases (RTKs). The activation of RTKs leads to the recruitment of GRB2 through its SH2 domain to the phosphorylated tyrosine residues on the receptor. GRB2, in turn, binds to the Son of Sevenless (SOS) protein through its SH3 domain. This binding facilitates the activation of Ras, a small GTPase, which triggers a cascade of downstream signaling events, ultimately leading to cell proliferation, survival, and differentiation. Further research and exploration into the structure and function of GRB2 hold great potential for providing novel insights and strategies to enhance medical approaches for related diseases. In this review, we provide an outline of the proteins that engage with domains of GRB2, along with the function of different GRB2 domains in governing cellular signaling pathways. This furnishes essential points of current studies for the forthcoming advancement of therapeutic medications aimed at GRB2. [ABSTRACT FROM AUTHOR]

Objective: Frequent teacher turnover may damage the development of teachers and the regular operation of kindergartens. This original research presented kindergarten teachers' first, second, and third turnover rates and occurrence times. This research analyzed the relationship between socio-demographic variables and the varying frequency of kindergarten teacher turnover. These data were used to investigate the characteristics of first, second, and third kindergarten turnover. This research evaluated kindergarten teachers' occupational ambition, emotional attachment, and self-efficacy. Likewise, this research also analyzed the social context, organizational support, management mechanism, reward, and occupational stress of kindergarten. These data were used to determine the key factors affecting kindergarten teachers' turnover. Methods: This research recruited 1,118 kindergarten teachers (mean age = 31.67, sd = 5.02; 3.85% male, 96.14% female) from China. Based on the existing scales, this research developed the Questionnaire of Kindergarten Teachers' Turnover and Influencing Factors for the survey. Kindergarten teachers reported basic information and the impact factors of their first, second, and third turnover through online questionnaires. The Chi-square test was used to analyze the correlation between socio-demographic variables and different frequencies of kindergarten teacher turnover. The binary logistic regression explored the eight factors affecting kindergarten teachers' first, second, and third turnover. Results: The results showed that 43.65% of kindergarten teachers had resigned. In detail, 25.60% of kindergarten teachers resigned once, 10.64% of kindergarten teachers resigned twice, and 8.41% of kindergarten teachers resigned thrice. Gender and marital status were significantly correlated with the three frequencies of kindergarten teacher turnover. Occupational stress, reward, management mechanisms, and ambition consistently affected kindergarten teachers' first, second, and third turnover. Conclusion: The relevant management departments should pay attention to the high turnover rate of kindergarten teachers and put forward more strategies to improve their stability. Women and married can be favored in the recruitment of kindergarten teachers. It is crucial to reduce pressure and improve rewards for kindergarten teachers. Also, kindergartens should provide the space to display teachers' talents and improve management mechanisms. These results provide empirical support for proposing effective policies to promote the stability of kindergarten teachers' construction. [ABSTRACT FROM AUTHOR]

This paper examines the impact of gender diversity on financial reporting quality (accrual and real earnings management). We use a sample of 78 Egyptian listed companies over the period 2009–2021. The quality of financial reporting is measured using different models of earnings management (accrual and real earnings management). Accrual earnings management (AEM) is detected through four different models developed by modified Jones model, the Kasznik model, Kothari model, Raman and Shahrur model, while real earnings management (REM) is measured using six different model which are abnormal cash flows from operations (ABCFO), abnormal production costs (ABPROD), abnormal discretionary expenditures (ABDISEXP) and three aggregate proxies (RM1, RM2, RM3). Using the system generalized method of moments, companies with more gender diversity are more effective in reducing accrual earnings manipulation (AEM). The exception is the modified Jones model. Moreover, we find that gender diversity is positively and significantly correlated with financial reporting quality based on proxies of real earnings-based activity, except for RM2. The study found a non-significant and negative relationship between board diversity and RM2 as a proxy for REM. Overall, the empirical results based on accrual and real earnings management models (AEM and REM) support the notion that enterprises with more gender diversity on the board are more effective in controlling earnings manipulation practices. The predictions of corporate governance theories are confirmed. Policy makers should continue to promote and support gender diversity in leadership positions within organizations. This can be achieved through initiatives such as diversity quotas, mentoring programs, and leadership development opportunities for women. [ABSTRACT FROM AUTHOR]

The Golgi Apparatus (GA) is pivotal in vesicle sorting and protein modifications within cells. Traditionally, the GA has been described as a perinuclear organelle consisting of stacked cisternae forming a ribbon-like structure. Changes in the stacked structure or the canonical perinuclear localization of the GA have been referred to as "GA fragmentation", a term widely employed in the literature to describe changes in GA morphology and distribution. However, the precise meaning and function of GA fragmentation remain intricate. This review aims to demystify this enigmatic phenomenon, dissecting the diverse morphological changes observed and their potential contributions to cellular wound repair and regeneration. Through a comprehensive analysis of current research, we hope to pave the way for future advancements in GA research and their important role in physiological and pathological conditions. [ABSTRACT FROM AUTHOR]

We investigated the geochemistry of gas, pore fluid, and methane-derived authigenic carbonate (MDAC) from four sites in the southern Ulleung Basin, South Korea. In contrast to Sites 16GH-P1 and 16GH-P5, Sites 16GH-P3, and 16GH-P4 are characterized by acoustic chimney structures associated with gas flux. The composition of gas and isotopic signatures of methane (CH4) (C1/C2+ > 300, Ψ13CCH4 < -60‰, ΨDCH4 = -190‰) indicate microbial source CH4 at all sites. The upward migration of CH4 can affect the chemical and isotopic properties of pore fluid and gas-related byproducts (e.g., gas hydrate (GH) and MDAC) within the shallow sediments including the current sulfate-methane transition (SMT) (< 5 meters below seafloor). Although no GH was found, elevated Clconcentrations (maximum = 609 mM) with low dD and d18O values in Site 16GH-P4 pore fluids delineate the influence of massive GH formation in deeper sediment. In contrast, relatively constant Cl-, ΨD, and Ψ18O values in fluids from Sites 16GH-P1, 16GH-P3, and 16GH-P5 indicate a predominant origin from seawater. Pore fluids also exhibit higher concentrations of H4SiO4, B, Mg2+, and K+, along with increasing alkalinity compared to seawater. These observations suggest that marine silicate weathering alters fluid chemistry within the sediment, affecting element and carbon cycles. High alkalinity (up to 60 mM) and Mg2+/Ca2+ ratios (> 6) alongside decreasing Ca2+ and Sr2+ concentrations imply carbonate precipitation. MDACs with diverse morphologies, mainly composed of aragonite and magnesian calcite, and characterized by low carbon isotopic values (Ψ13CMDAC < -31.3‰), were found at Sites 16GH-P3 and 16GH-P4. Interestingly, d13CMDAC values at Site 16GH-P3 are clearly differentiated above and below the current SMT. High d13CMDAC values above the SMT (> -34.3‰) suggest the combined influence of seawater and CH4 migrating upward on MDAC precipitation, whereas low Ψ13CMDAC values below it (< -41.6‰) indicate a predominant impact of CH4 on MDAC formation. Additionally, the vertical variation of d18OMDAC values at Site 16GH-P4, compared to the theoretical values, reflects an association with GH dissociation and formation. Our findings improve the understanding of fluid, gas, and MDAC geochemistry in continental margin cold seeps, providing insights into global carbon and element cycles. [ABSTRACT FROM AUTHOR]

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Liquid–liquid phase separation (LLPS) is a novel principle for interpreting precise spatiotemporal coordination in living cells through biomolecular condensate (BMC) formation via dynamic aggregation. LLPS changes individual molecules into membrane-free, droplet-like BMCs with specific functions, which coordinate various cellular activities. The formation and regulation of LLPS are closely associated with oncogenesis, tumor progressions and metastasis, the specific roles and mechanisms of LLPS in tumors still need to be further investigated at present. In this review, we comprehensively summarize the conditions of LLPS and identify mechanisms involved in abnormal LLPS in cancer processes, including tumor growth, metastasis, and angiogenesis from the perspective of cancer hallmarks. We have also reviewed the clinical applications of LLPS in oncologic areas. This systematic summary of dysregulated LLPS from the different dimensions of cancer hallmarks will build a bridge for determining its specific functions to further guide basic research, finding strategies to intervene in LLPS, and developing relevant therapeutic approaches. [ABSTRACT FROM AUTHOR]

Aim To investigate the mechanism of perilipin 2 (PLIN2) increasing lipid accumulation in macrophages. Methods The experiments were divided into oxidized low density lipoprotein (ox-LDL) group, different PLIN2 expression groups, and different activity Rab18 groups, the levels of Rab18 and acyl-CoA long chain synthetase 3 (ACSL3) protein in high expression and silent expression of PLIN2 macrophages were measured, and the levels of PLIN2, Rab18, and ACSL3 protein expression in high expression PLIN2 macrophages with different activity Rab18 were measured. Western blot was used to detect protein expression levels, immunofluorescence was used to observe the localization of intracellular related proteins, and oil red O staining was used to observe intracellular lipid accumulation. Results The expression levels of Rab18 and ACSL3 in cells with high expression of PLIN2 were increased significantly (P<0. 05), and there was an intracellular phenomenon of co-localization of PLIN2 with Rab18 and ACSL3. The expression level of ACSL3 in high expression macrophages of PLIN2 after transfection with the Rab18 dominant mutant Q67L plasmid (Rab18 activity increased) was increased significantly (P<0. 05), and the number of intracellular lipid droplets was also increased significantly (P < 0. 05). Conclusion PLIN2 promotes macrophage lipid accumulation through Rab18 by up-regulating ACSL3. [ABSTRACT FROM AUTHOR]

Context: Salinomycin (SAL) is a chemotherapeutic drug with anti-osteosarcoma efficacy, but its hydrophobic properties have hindered its application. Nanoparticles have been widely used as drug carriers to improve the solubility of hydrophobic drugs. The dodecapeptide GE11 has been shown to have great binding affinity to the epidermal growth factor receptor (EGFR), which is highly overexpressed in osteosarcoma. Materials and Methods: We designed novel SAL-loaded GE11-conjugated polymer–lipid hybrid nanoparticles (GE11-NPs-SAL) to target osteosarcoma. The characterization and antitumor activity of GE11-NPs-SAL were evaluated both in vitro and in vivo. Results: The results showed that GE11-NPs-SAL had a size of ~100 nm with a high encapsulation efficacy of ~80%. Compared with the non-targeted nanoparticles, GE11-NPs-SAL showed increased internalization in osteosarcoma cells and improved therapeutic efficacy in osteosarcoma both in vitro and in vivo. Conclusions: GE11-NPs-SAL is a promising treatment for osteosarcoma. [ABSTRACT FROM AUTHOR]

Given the crucial role of vaccination in halting the COVID-19 pandemic, it is imperative to understand the factors that motivate adolescents to get vaccinated. We surveyed adolescents and their accompanying guardians scheduled to receive a COVID-19 vaccination (Comirnaty) in an urban region in Germany in mid-2021 regarding their motivation for getting vaccinated and collected data on their sociodemographic characteristics, medical history, vaccination status, and any history of COVID-19 infection in the family. We also queried information strategies related to the SARS-CoV-2 pandemic. Motivations for getting vaccinated were similar among adolescents and their parents. The primary reasons for vaccination were protection against SARS-CoV-2-related illness and gaining access to leisure facilities. This was not influenced by gender, health status, migration background, or the presence of chronic or acute diseases. The percentage of parents who had received SARS-CoV-2 immunization and the proportion of parents with a high level of education were higher among study participants than in the general population. Adolescents were especially willing to be vaccinated if they came from a better educational environment and had a high vaccination rate in the family. Emphasizing the importance of vaccination among all segments of the population and removing barriers to vaccines may lead to an ameliorated acceptance of COVID-19 vaccines. [ABSTRACT FROM AUTHOR]

Alopecia areata (AA) is an autoimmune disease that has a complex underlying immunopathogenesis characterized by nonscarring hair loss ranging from small bald patches to complete loss of scalp, face, and/or body hair. Although the etiopathogenesis of AA has not yet been fully characterized, immune privilege collapse at the hair follicle (HF) followed by T-cell receptor recognition of exposed HF autoantigens by autoreactive cytotoxic CD8+ T cells is now understood to play a central role. Few treatment options are available, with the Janus kinase (JAK) 1/2 inhibitor baricitinib (2022) and the selective JAK3/tyrosine kinase expressed in hepatocellular carcinoma (TEC) inhibitor ritlecitinib (2023) being the only US Food and Drug Administration--approved systemic medications thus far for severe AA. Several other treatments are used off-label with limited efficacy and/or suboptimal safety and tolerability. With an increased understanding of the T-cell--mediated autoimmune and inflammatory pathogenesis of AA, additional therapeutic pathways beyond JAK inhibition are currently under investigation for the development of AA therapies. This narrative review presents a detailed overview about the role of T cells and T-cell--signaling pathways in the pathogenesis of AA, with a focus on those pathways targeted by drugs in clinical development for the treatment of AA. A detailed summary of new drugs targeting these pathways with expert commentary on future directions for AA drug development and the importance of targeting multiple T-cell--signaling pathways is also provided in this review. [ABSTRACT FROM AUTHOR]

Although immunosenescence may result in increased morbidity and mortality, many mammals have evolved effective immune coping strategies to extend their lifespans. Thus, the immune systems of long‐lived mammals present unique models to study healthy longevity. To identify the molecular clues of anti‐immunosenescence, we first built high‐quality reference genome for a long‐lived myotis bat, and then compared three long‐lived mammals (i.e., bat, naked mole rat, and human) versus the short‐lived mammal, mouse, in splenic immune cells at single‐cell resolution. A close relationship between B:T cell ratio and immunosenescence was detected, as B:T cell ratio was much higher in mouse than long‐lived mammals and significantly increased during aging. Importantly, we identified several iron‐related genes that could resist immunosenescence changes, especially the iron chaperon, PCBP1, which was upregulated in long‐lived mammals but dramatically downregulated during aging in all splenic immune cell types. Supportively, immune cells of mouse spleens contained more free iron than those of bat spleens, suggesting higher level of ROS‐induced damage in mouse. PCBP1 downregulation during aging was also detected in hepatic but not pulmonary immune cells, which is consistent with the crucial roles of spleen and liver in organismal iron recycling. Furthermore, PCBP1 perturbation in immune cell lines would result in cellular iron dyshomeostasis and senescence. Finally, we identified two transcription factors that could regulate PCBP1 during aging. Together, our findings highlight the importance of iron homeostasis in splenic anti‐immunosenescence, and provide unique insight for improving human healthspan. [ABSTRACT FROM AUTHOR]

The liver plays a crucial role in maintaining systemic iron homeostasis through iron storage, sensing of systemic iron needs, and production of the iron-regulatory hormone hepcidin. While mice are commonly used as models for studying human iron homeostasis, their liver structure differs significantly from humans. Since the mouse liver is structured in six separated lobes, often, the analysis of a single defined lobe is preferred due to concerns over data reproducibility between experimental cohorts. In this study, we compared iron-related parameters in distinct liver lobes of C57BL/6 wild-type mice across different ages. We found that the non-heme iron levels, as well as the mRNA and protein expression of iron storage protein Ferritin and the iron importer Transferrin Receptor 1, were similar between liver lobes. Additionally, the mRNA expression of Hepcidin, as well as its regulators, Bmp2 and Bmp6, and iron importers Zip8 and Zip14 were comparable. Minor differences were observed in Ferroportin mRNA levels of 24-wk-old mice; however, this did not correlate with altered iron content. The findings in wild-type mice were reproduced in Hfe knock-out mice – a well-established genetic model of the most prevalent form of hemochromatosis. Overall, our results indicate that C57BL/6 mouse liver lobes can be used interchangeably for assessing iron content and expression of iron-related genes. Understanding if these findings are applicable to other mouse developmental stages, strains, or models of (iron-related) disorders will be key to promote reduction of experimental animal numbers and facilitate resource sharing among research groups studying liver iron homeostasis. NEW & NOTEWORTHY This study reveals that, despite being structurally separated, liver lobes from C57BL/6 wild-type and iron-overloaded mice can be used interchangeably for the evaluation of iron content and expression of iron-related genes. [ABSTRACT FROM AUTHOR]