Galectins and Immune Responses-Just How Do They Do Those Things They Do?

Galectins are a family of mammalian carbohydrate-binding proteins expressed by many cell types. Galectins can function intracellularly and can also be secreted to bind to cell surface glycoconjugate counterreceptors. Some galectins are made by immune cells, whereas other galectins are secreted by different cell types, such as endothelial or epithelial cells, and bind to immune cells to regulate immune responses. Galectin binding to a single glycan ligand is a low-affinity interaction, but the multivalency of galectins and the glycan ligands presented on cell surface glycoproteins results in high-avidity binding that can reversibly scaffold or cluster these glycoproteins. Galectin binding to a specific glycoprotein counterreceptor is regulated in part by the repertoire of glycosyltransferase enzymes (which make the glycan ligands) expressed by that cell, and the effect of galectin binding results from clustering or retention of specific glycoprotein counterreceptors bearing these specific ligands.

RASopathy mutations provide functional insight into the BRAF cysteine-rich domain and reveal the importance of autoinhibition in BRAF regulation.

BRAF is frequently mutated in human cancer and the RASopathy syndromes, with RASopathy mutations often observed in the cysteine-rich domain (CRD). Although the CRD participates in phosphatidylserine (PS) binding, the RAS-RAF interaction, and RAF autoinhibition, the impact of these activities on RAF function in normal and disease states is not well characterized. Here, we analyze a panel of CRD mutations and show that they increase BRAF activity by relieving autoinhibition and/or enhancing PS binding, with relief of autoinhibition being the major factor determining mutation severity. Further, we show that CRD-mediated autoinhibition prevents the constitutive plasma membrane localization of BRAF that causes increased RAS-dependent and RAS-independent function. Comparison of the BRAF- and CRAF-CRDs also indicates that the BRAF-CRD is a stronger mediator of autoinhibition and PS binding, and given the increased catalytic activity of BRAF, our studies reveal a more critical role for CRD-mediated autoinhibition in BRAF regulation.

Costimulatory capacity of CD137 mAbs on T cells depends on elaborate CRD structures but not on blocking ligand-receptor binding.

CD137 is mainly a costimulatory receptor of CD8+ T cells. Two representative CD137 antibodies, utomilumab, and urelumab, show different costimulatory capacities in clinical trials. Balancing the antitumor effect and systemic toxicity of T cells activated by CD137 signaling is a challenge that requires clinical consideration. In this study, a panel of specific anti-human CD137 monoclonal antibodies (mAbs) were prepared and their affinities, isotypes, CD137-CRD (cysteine-rich domain) binding regions, cross-reactivity to mouse and rhesus CD137, inhibition of ligand-receptor binding and costimulatory activities were analyzed. The results showed that anti-human CD137 mAbs had high cross-reactivity with rhesus CD137. MAbs fell into three clusters according to their different binding regions of the CD137 extracellular domain. They bound to CRDI+CRDII, CRDIII or CRDIV+STP. CRDIII-binding mAbs had the strongest blocking activity. Highly costimulatory CD137 mAbs showed stronger abilities to promote CD8+ T-cell proliferation. However, the costimulatory capacity of mAbs on T cells was not closely related to their ability to block CD137L-CD137 binding and may be controlled by more elaborate CRD conformational structures. This study provides additional information for the development of next-generation CD137 mAbs to meet clinical needs.

Effect of FTO genotype on exercise training and diet-indued weight loss in overweight and obese adults: a systematic review and meta-analysis.

Our meta-analysis, encompassing 30 studies with 46,976 subjects, aimed to explore the impact of fat mass and obesity-associated protein (FTO) genotypes on weight response to exercise and dietary interventions in overweight and obese adults. Electronic databases including PubMed and Google Scholar were searched from 2020 to September 2023 to identify relevant studies. Results revealed a significant reduction in body weight among individuals with the FTO risk allele following exercise and diet interventions (standardized mean difference [SMD] = - 0.619, 95% CI: - 1.137, - 0.100; p = .01). When examining FTO variants, both AA (SMD = - 0.148, 95% CI: - 0.282, - 0.014, p = .03, I2 = 24.96) and TA genotypes (SMD = - 0.674, 95% CI: - 1.162, - 0.186, p = .007, I2 = 91.12) showed significant weight reduction compared to the TT genotype. Moreover, individuals with the high-risk genotype AA + TT achieved greater weight loss compared to those with the normal-risk genotype TT (SMD = - 0.419, 95% CI: - 0.655, -0.183, p = .0001, I2 = 92.08) in the dominant genetic model. Subgroup analysis indicated that FTO risk allele carriers (AA + AT) with exercise interventions lasting six months and a body mass index of 25 - 29 experienced greater weight loss compared to TT carriers. These findings emphasize the importance of genetic considerations in weight management interventions and suggest personalized approaches for combating obesity. Further clinical trials are warranted to validate our study's findings.

Exploration of macrocyclic peptide binders to the extracellular CRD domain of human receptor tyrosine kinase-like orphan receptor 1 (ROR1).

Elevated levels of receptor tyrosine kinase-like orphan receptor 1 (RORl) expression are observed in multiple hematological and solid tumors, but not in most of the healthy adult tissues, identifying ROR1 as an attractive target for tumor-specific therapy. Herein we will describe the discovery of macrocyclic peptides as binders of the extracellular Cysteine-Rich Domain (CRD) of human ROR1 via mRNA in vitro selection technology using the PDPS platform, followed by exploration of sidechain SAR of parent macrocycle peptides, fluorescently labeled analogs, and a Peptide Drug Conjugate (PDC). The parent macrocyclic peptides represented by Compound 1 and Compound 14 displayed nanomolar cell-based binding to ROR1 and relatively good internalization in 786-O and MDA-MB-231 tumor cell lines. However, these peptides were not observed to induce apoptosis in Mia PaCa-2 cells, a model pancreatic tumor cell line with a relatively low level of cell surface expression of ROR1.

Effects of economic interventions on pediatric and adolescent HIV care outcomes: a systematic review.

Economic insecurity and poverty present major barriers to HIV care for young people. We conducted a systematic review of the current evidence for the effect of economic interventions on HIV care outcomes among pediatric populations encompassing young children, adolescents, and youth (ages 0-24). We conducted a search of PubMed MEDLINE, Cochrane, Embase, Scopus, CINAHL, and Global Health databases on October 12, 2022 using a search strategy curated by a medical librarian. Studies included economic interventions targeting participants <25 years in age which measured clinical HIV outcomes. Study characteristics, care outcomes, and quality were independently assessed, and findings were synthesized. Title/abstract screening was performed for 1934 unique records. Thirteen studies met inclusion criteria, reporting on nine distinct interventions. Economic interventions included incentives (n = 5), savings and lending programs (n = 3), and government cash transfers (n = 1). Study designs included three randomized controlled trials, an observational cohort study, a matched retrospective cohort study, and pilot intervention studies. While evidence is very limited, some promising findings were observed supporting retention and viral suppression, particularly for those with suboptimal care engagement or with detectable viral load. There is a need to further study and optimize economic interventions for children and adolescents living with HIV.

Largemouth bass galectin, MsGal-9: Mediating various functions as a pattern recognition receptor and a potential damage-associated molecular pattern.

Galectins are lectins that bind to ß-galactose and are widely expressed in immune system tissues, playing pivotal roles in innate immunity through their conserved carbohydrate-recognition domains (CRDs). In this present investigation, a tandem-repeat galectin was discovered in the largemouth bass, Micropterus salmoides (designated as MsGal-9). The open reading frame of MsGal-9 encodes two CRDs, each containing two consensus motifs that are essential for ligand binding. MsGal-9 is expressed in various tissues of the largemouth bass, with particularly high expression levels in the liver and spleen. The full-length form of MsGal-9, as well as the N-terminal (MsGal-9-N) and C-terminal (MsGal-9-C) CRDs, were individually recombined. Their ability for nonself recognition was studied. The three recombinant proteins were able to bind to glucan (GLU), peptidoglycan (PGN), and lipopolysaccharide (LPS), with MsGal-9 displaying the highest binding activity. Furthermore, rMsGal-9-N exhibited higher binding activity towards GLU in comparison to rMsGal-9-C. Further investigations revealed that the full-length rMsGal-9 could significantly bind to Gram-positive bacteria, Gram-negative bacteria, and fungi, while rMsGal-9-C specifically bound to Escherichia coli. However, rMsGal-9-N did not exhibit significant binding activity towards any microbes. These findings indicate that MsGal-9 requires both CRDs to cooperate in order to fulfill its nonself recognition function. All three recombinant proteins demonstrated agglutination activity towards various microbes, with MsGal-9 and MsGal-9-N displaying a similar broad binding spectrum, while MsGal-9-C agglutinated three types of bacteria. Moreover, both MsGal-9 and MsGal-9-N were capable of coagulating largemouth bass red blood cells, whereas MsGal-9-C lacked this ability. However, MsGal-9-C played a significant role in enhancing the encapsulation of leukocytes in comparison to MsGal-9-N. All three proteins acted as potential damage-associated molecular patterns (DAMPs), inducing apoptosis in leukocytes.

Food-Pollen Cross-Reactivity and its Molecular Diagnosis in China.

PURPOSE OF REVIEW: Plant-derived foods are one of the most common causative sources of food allergy in China, with a significant relationship to pollinosis. This review aims to provide a comprehensive overview of this food-pollen allergy syndrome and its molecular allergen diagnosis to better understand the cross-reactive basis. RECENT FINDINGS: Food-pollen cross-reactivity has been mainly reported in Northern China, Artemisia pollen is the major related inhalant source, followed by tree pollen (Betula), while grass pollen plays a minor role. Pollen allergy is relatively low in Southern China, with allergies to grass pollen being more important than weed and tree pollens. Rosaceae fruits and legume seeds stand out as major related allergenic foods. Non-specific lipid transfer protein (nsLTP) has been found to be the most clinically relevant cross-reacting allergenic component, able to induce severe reactions. PR-10, profilin, defensin, chitinase, and gibberellin-regulated proteins are other important cross-reactive allergen molecules. Artemisia pollen can induce allergenic cross-reactions with a wide range of plant-derived foods in China, and spring tree pollens (Betula) are also important. nsLTP found in both pollen and plant-derived food is considered the most significant allergen in food pollen cross-reactivity. Component-resolved diagnosis with potential allergenic proteins is recommended to improve diagnostic accuracy and predict the potential risk of causing allergic symptoms.

Formation of low-pressure reaction textures during near-isothermal exhumation of hot orogenic crust (Bohemian Massif, Austria).

Two types of aluminous paragneiss from the Loosdorf complex (Bohemian Massif, NE Austria) contain coarse-grained granulite assemblages and retrograde reaction textures that are investigated to constrain the post-peak history of the Gföhl unit in the southern Bohemian Massif. Both types have a peak assemblage garnet-biotite-sillimanite-plagioclase-K-feldspar-quartz-granitic melt ± kyanite ± ilmenite ± rutile, recording peak metamorphic conditions of ∼0.9-1.1 GPa and ∼780-820°C estimated by isochemical phase equilibrium modelling. The first sample type (Ysper paragneiss) developed (i) cordierite coronae around garnet and (ii) cordierite-spinel and cordierite-quartz reaction textures at former garnet-sillimanite interfaces. Calculated chemical potential relationships indicate that the textures formed in the course of a post-peak near-isothermal decompression path reaching ∼0.4 GPa. Texture formation follows a two-step process. Initially, cordierite coronae grow between garnet and sillimanite. As these coronae thicken, they facilitate the development of local compositional domains, leading to the formation of cordierite-spinel and cordierite-quartz symplectites. The second sample type (Pielach paragneiss) exhibits only discontinuous cordierite coronae around garnet porphyroblasts but lacks symplectites. The formation of cordierite there also indicates near-isothermal decompression to 0.4-0.5 GPa and 750-800°C. This relatively hot decompression path is explained by the contemporaneous exhumation of a large HP-UHT granulite body now underlying the Loosdorf complex. The timing of regional metamorphism in the granulites and the southern Bohemian Massif in general is well constrained and has its peak at ∼340 Ma. Monazite from Loosdorf paragneiss samples yield a slightly younger age of ∼335 Ma. Although the ages overlap within error, they are interpreted to reflect near-isothermal decompression and exhumation resulting in the formation of the observed reaction textures.

The effects of music-based interventions on behavioural and psychological symptoms of people living with dementia: a systematic review and network meta-analysis protocol.

OBJECTIVES: People living with dementia often experience behavioural and psychological symptoms of dementia (BPSD), which severely affect their well-being during the course of the disease. Particularly for BPSD outcomes, there is a high demand for increasing the evidence-based knowledge of non-pharmacological approaches, such as music-based interventions. Although previous reviews emphasize the potential effects of music-based interventions in people with dementia, they cover a wide range of different interventions and outcomes. METHOD: Therefore, this systematic review (SR) and network meta-analysis (NMA) aims to not only investigate the efficacy of music-based interventions on BPSD, but also to compare the impact of different types of music-based interventions on outcomes. Preferred reporting items for SR and meta-analysis protocols (PRISMA-P) and the PRISMA NMA extension were followed. Several databases will be searched from inception to the date the search will be performed, for relevant randomized or non-randomized controlled trials comparing a music-based intervention with treatment as usual, active controls, or another music-based intervention. Multivariate pairwise meta-analyses will be conducted for each outcome. NMA based on a frequentist random-effects model will be used to estimate the comparative effects of each type of music-based intervention and related components across outcomes. Heterogeneity will be investigated by meta-regression models. CONCLUSION: Based on our knowledge, this may be the first SR and NMA study to compare the efficacy of different types of music-based interventions. In addition, combined with our multivariate analysis approach, it will allow us to identify potential effect modifiers in music-based intervention for treating BPSD.

Effectiveness of oral motor appliances on oral motor function and speech in children: a systematic review.

BACKGROUND: Different oral motor appliances have been used in connection with speech therapy to improve oral motor function and speech development, but no consensus has been reached on the effectiveness of the appliances. The objective was to systematically review the effectiveness of oral motor appliances on oral motor function and speech in children with speech sound disorders (SSDs) or oral motor dysfunctions. METHODS: A systematic search was conducted up to February 2023 in the PubMed, Scopus, and Cochrane databases. Inclusion criteria were prospective randomized or case-control clinical trials investigating the effect of intraoral appliances on orofacial function and/or speech. The risk of bias was evaluated by the Cochrane Collaboration's Robins-I tool. RESULTS: Nine publications of three individual studies met the inclusion and search criteria. Six of the publications were conducted in children with Down Syndrome (DS) and three publications were conducted in children with Cerebral Palsy (CP). No meta-analysis was made due to the limitations of the publications. Selected studies reported some beneficial effects of intraoral appliances on oral motor function in children with DS and CP, although the evidence is low. Due to the study design in selected studies and confounding factors, the overall risk of bias was categorized as moderate or high. DISCUSSION: Intraoral appliances may improve oral motor function in children with DS and CP. Due to lack of studies this review limited to children with DS and CP. The initial question concerning SSDs was not answered. Well-designed RCTs with larger sample sizes are needed, especially among non-syndromic children with SSDs. The level of evidence was considered very low.

Nurse-led physical health interventions for people with mental illness: an integrative review of international literature.

BACKGROUND: People experiencing mental illness receive physical healthcare from nurses in a variety of settings including acute inpatient, secure extended care, forensic, and community services. While nurse-led clinical practice addressing sub-optimal consumer physical health is salient, a detailed understanding and description of the contribution by nurses to physical health interventions in people experiencing mental illness is not clearly articulated in the literature. AIMS: The aim of this integrative review is to describe the state of knowledge on nurse-led physical health intervention for consumers, focusing on nursing roles, nursing assessment, and intervention settings. METHODS: A systematic search of six databases using Medical Subject Headings from 2001 and 2022 inclusive was conducted. The Mixed Methods Appraisal Tool (MMAT) was utilised for quality appraisal. RESULTS: Seventy-four studies were identified as "nurse-led". Interventions were most common among community settings (n = 34, 46%). Nurses performed varied roles, often concurrently, including the collection of 341 physical health outcomes, and multiple roles with 225 distinct nursing actions identified across the included studies. A nurse as lead author was common among the included studies (n = 46, 62%). However, nurses were not always recognised for their efforts or contributions in authorship. CONCLUSIONS: There is potential gap in role recognition that should be considered when designing and reporting nurse-led physical health interventions.

Efficacy and acceptability of anti-inflammatory eicosapentaenoic acid for cognitive function in Alzheimer's dementia: A network meta-analysis of randomized, placebo-controlled trials with omega-3 fatty acids and FDA-approved pharmacotherapy.

Alzheimer's dementia (AD) is a major contributor to global disability, and effective therapies to modify disease progression are currently lacking. The neuro-inflammatory theory is a potential etiology underlying this neurodegenerative disease. Previous randomized, controlled trials (RCTs) have provided inconclusive results regarding efficacy of omega-3 polyunsaturated fatty acids (PUFAs) regimens, which might provide anti-inflammatory benefits in the management of AD, in improving cognitive function among participants with AD. The objective of this frequentist-model based network meta-analysis (NMA) was to evaluate the potential advantages of omega-3 PUFAs and currently FDA-approved medications for AD on overall cognitive function in AD individuals. The primary outcomes were: (1) changes in cognitive function, and (2) acceptability, which refers to all-cause discontinuation. Additionally, secondary outcomes included quality of life, behavioral disturbances and safety/tolerability, which was assessed through the frequency of any reported adverse event. This NMA included 52 RCTs (6 with omega-3 PUFAs and 46 with FDA-approved medications) involving 21,111 participants. The results showed that long-term high-dose (1500-2000 mg/day) of eicosapentaenoic acid (EPA)-dominant omega-3 PUFAs augmented with anti-oxidants had the highest potential for cognitive improvement among all investigated treatments [standardized mean difference = 3.00, 95% confidence intervals (95 %CIs) = 1.84-4.16]. Compared to placebo, omega-3 PUFAs had similar acceptability [odds ratio (OR) = 0.46, 95 %CIs = 0.04 to 5.87] and safety profiles (OR = 1.24, 95 %CIs = 0.66 to 2.33)o. These findings support the potential neurotherapeutic effects of high dosage EPA-dominant omega-3 PUFAs for the amelioration of cognitive decline in patients with AD. Future large-scale, long-term RCTs should focus on different dosages of EPA-dominant omega-3 PUFAs regimens on improving cognitive dysfunction in patients with AD at different levels of inflammatory status and psychopathology.

Incidental complex repetitive discharges on needle electromyography.

INTRODUCTION/AIMS: Complex repetitive discharges (CRDs) are spontaneous electromyography (EMG) waveforms often associated with chronic neurogenic or myopathic diseases, but incidentally identified CRDs have also been described. In this study we describe the distribution and possible significance of incidentally seen CRDs in otherwise normal electrodiagnostic studies. METHODS: A retrospective chart review was performed of all patients with CRDs incidentally documented on otherwise normal electrodiagnostic studies at Mayo Clinic from January 2013 through December 2020. Each patient's clinical symptoms, referral reason, electrodiagnostic report, and imaging studies were analyzed using descriptive statistics. RESULTS: Ninety-four patients (86 females; mean age, 62 years; range, 20 to 86 years) and 107 CRDs were studied. The most common neuromuscular reasons for electrodiagnostic referrals included radiculopathy, peripheral neuropathy, and myopathy. Mean symptom duration was 43 months (range, 1 to 312 months). Eighty-five patients had a CRD identified in one muscle (range, in all patients, one to five muscles). CRDs were identified most frequently in tensor fasciae latae (n = 21), biceps brachii (n = 16), and gluteus maximus (n = 9). Of the 58 patients in whom imaging was available, 46 (79%) had abnormalities that corresponded to the myotome in which the CRDs were visualized, most commonly L5 (n = 19) and C6 (n = 12). Of these 46 patients, 28 (61%) were referred for radicular or limb pain. DISCUSSION: CRDs can be incidentally noted on otherwise normal electrodiagnostic studies, most commonly in L5 and C6 myotomes. The mechanism of CRDs in the absence of electrodiagnostic features of axon loss or remodeling is unknown.

Efficacy of six exercise-based interventions for individuals undergoing hemodialysis: a network meta-analysis of randomized clinical trials.

BACKGROUND: Evidence comparing different exercise modalities in individuals undergoing hemodialysis remains incipient. Our aim was to conduct a systematic review and network meta-analysis of randomized clinical trials to compare and synthesize the efficacy of five different intradialytic exercise modalities and home-based training in this population. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: Studies were searched in PubMed/MEDLINE, Cochrane Library, Embase, Cinahl, and Scopus from their inception to 19 September 2022. We used traditional random-effects models and Bayesian network meta-analysis models. The risk of bias was assessed using the RoB v.2.0 tool, and the assessment of confidence in the results through the Confidence in Network Meta-Analysis (CINeMA) tool. RESULTS: Seventy-eight studies involving 3326 participants were included. Our network meta-analysis showed that combined training was the intervention with the best performance to increase VO2 peak [mean difference (MD) = 3.94 ml/kg/min; 95% credible interval (CrI), 2.38 to 5.76] and to reduce diastolic blood pressure (MD = -5.19 mmHg; 95%CrI, -9.35 to -0.96) compared to the usual care group. Inspiratory muscle training was the intervention that most improved the 6-minute walk test distance (MD = 70.97 m; 95%CrI, 18.09 to 129.87). C-reactive protein decreased in resistance training (MD = -2.6 mg/l; 95%CrI, -4.97 to -0.33) and aerobic training (MD = -1.4 mg/l; 95%CrI, -3.15 to -0.06). Kt/V improved in aerobic training (MD = 0.11; 95%CrI, 0.02 to 0.18), and SF-36 physical functioning outcomes improved in resistance training (MD = 10.66 points; 95%Crl, 1.91 to 20.22). No intradialytic exercise modality was superior to others or comparable with home-based training in improving the evaluated outcomes. Subgroup analysis revealed that exercise interventions >12 weeks improved functional capacity more than interventions ≤12 weeks, and that combined training reduces diastolic blood pressure only after 12 weeks of follow-up. Furthermore, our results suggest that moderate or moderate-to-vigorous intensity training leads to more pronounced improvements in functional capacity, whereas mild or mild-to-moderate intensity training does not have the same effect. In this review, most of the included studies were assessed as having some concern, which resulted in a low to very low level of confidence in the overall findings. CONCLUSIONS: Both intradialytic training and home-based training can promote benefits for individuals undergoing hemodialysis, with no evidence of the superiority of either training modality over the other.

Hysterectomy and sexual function: a systematic review and meta-analysis.

BACKGROUND: Sexual function after hysterectomy can be a concern for patients, and research remains inconclusive about changes in sexual function associated with hysterectomy. AIM: We meta-analyzed studies on change in sexual function from pre- to posthysterectomy and the role of total vs subtotal hysterectomy and concomitant bilateral salpingo-oophorectomy (BSO) in differences in such change. METHODS: We searched PubMed, Embase, and Cochrane databases from inception to January 2022. Two reviewers screened and included studies if they were published in a peer-reviewed journal and reported on sexual function pre- and posthysterectomy for benign nonprolapse indication. Methodological quality was assessed with the STROBE checklist. We used random effects multilevel models to meta-analyze standardized mean differences in pre- to postoperative sexual function and the posthysterectomy Female Sexual Function Index mean across study groups in R (RStudio). OUTCOMES: Outcomes included overall sexual function, dyspareunia, desire, arousal, lubrication, and orgasm. RESULTS: Thirty-two articles were analyzed: 8 randomized controlled trials, 20 prospective studies, 2 retrospective studies, 1 cross-sectional study, and 1 secondary analysis, comprising a total of 4054 patients. Each study provided data for at least 1 outcome. Study quality was moderate, and effect sizes showed large between-study heterogeneity. Hysterectomy was not associated with significant change in overall sexual function irrespective of surgical route, with patients tending to report potentially remaining sexual dysfunction posthysterectomy. Cervix removal was not significantly associated with differences in magnitude of change. Hysterectomy without BSO was associated with significantly stronger improvement in lubrication and orgasm than hysterectomy with BSO, which was not the case for desire, arousal or overall sexual function. However, these significant differences were not replicated within studies that directly compared cases with and without BSO. CLINICAL IMPLICATIONS: Clinicians should address remaining sexual dysfunction posthysterectomy, and BSO should not be considered if not medically required. STRENGTHS AND LIMITATIONS: We analyzed a comprehensive number of trials and studied clinically relevant factors that might relate to differences in change in sexual function. Conclusions need to be interpreted with caution since many studies showed moderate methodological quality and large effect size heterogeneity. CONCLUSION: Subtotal and total hysterectomy was not associated with significant change in overall sexual function irrespective of surgical route, with patients tending to report potentially remaining sexual dysfunction posthysterectomy. Hysterectomy without BSO was associated with significantly stronger improvement in lubrication and orgasm than hysterectomy with BSO. Future research on hysterectomy should analyze predictors of sexual function change trajectories, such as different indications.

Does intermittent fasting impact mental disorders? A systematic review with meta-analysis.

Accumulating evidence supports the benefits of intermittent fasting (IF) as a dietary strategy for cardiometabolic health and weight control. However, little is known about the potential implications of IF on mental disorders. The aim of this review was to synthesize evidence regarding the effects of IF on mental disorders (depression, anxiety, and mood state) in the general population. We conducted a systematic search in five databases from inception to January 2022. Randomized and nonrandomized clinical trials (RCTs/nonRCTs) were included. A random effects method was used to pool standardized mean differences (SMDs) and 95% CIs. A total of 14 studies involving 562 individuals were included, of which 8 were RCTs and 6 were nonRCTs. IF showed a moderate and positive effect on depression scores when compared to control groups (SMD: 0.41; 95%CI: 0.05 to 0.76; I2=45%; n = 4). Conversely, within-group analyses did not show any significant effect of IF on anxiety (SMD: 0.10; 95%CI: -0.09 to 0.30; I2=0%; n = 5) or mood state (SMD: 0.14; 95%CI: -0.09 to 0.37; I2=59%; n = 7). IF modalities did not negatively impact mental disorders in the general population. In fact, IF showed a positive influence on diminishing depression scores, and did not modify anxiety or mood.

Role of diet in osteoporosis incidence: Umbrella review of meta-analyses of prospective observational studies.

An umbrella review and meta-analysis were conducted to summarize evidence for the association between dietary factors and the incidence of osteoporosis in adults. Only systematic reviews or meta-analyses were eligible for this study. Two researchers independently performed reading, data extraction, and quality evaluation of the included literature. The outcomes included in this study were all associated with osteoporosis, including osteoporotic fractures and low bone density. A total of 54 studies were included in this study, with 83 adjusted hazard ratios on diet, dairy group (n = 13), alcohol (n = 2), tea (n = 6), coffee (n = 3), micronutrient (n = 31), dietary pattern (n = 21), and foods (n = 7) regarding the incidence of osteoporosis. Grades of Recommendations, Assessment, Development, and Evaluation (GRADE) quality assessment method was used in this study. The high, medium, low and very low quality studies accounted for 27.7, 41, 21.7 and 9.6% of this study, respectively. Based on the included literature studies in this umbrella review, it was found that dietary factors have a relevant impact on the incidences of human osteoporosis, appropriate consumption of dairy products, vegetables, fruits, and micronutrients, as well as reduced intake of alcohol and coffee, can reduce the risk of osteoporosis.

Dietary intake and biomarkers of linoleic acid and risk of prostate cancer in men: A systematic review and dose-response meta-analysis of prospective cohort studies.

Findings on the association of dietary intake and tissue biomarkers of linoleic acid (LA) with the risk of prostate cancer are conflicting. Also, no meta-analysis summarized available findings in this regard. Therefore, the current systematic review and dose-response meta-analysis were done to summarize the findings of prospective cohort studies that assessed dietary intake and tissue biomarkers of LA in relation to prostate cancer risk in adults. We conducted a systematic search using online databases, including PubMed, Scopus, and ISI Web of Science, to identify eligible articles published up to January 2023. We included prospective cohort studies that examined the associations of dietary intake and tissue biomarkers of LA with the risk of prostate cancer (total, advanced, and fatal prostate cancer). Summary relative risks (RR) and 95% confidence intervals (CI) were calculated for the highest versus lowest intakes/tissue levels of LA using a fixed-effects model. Also, linear and non-linear dose-response analyses were conducted. In total, 15 prospective cohort studies were included. These studies recruited a total sample size of 511,622 participants with an age range of ≥18 years. During the follow-up periods ranging from 5 to 21 years, 39,993 cases of prostate cancer, 5,929 cases of advanced prostate cancer, and 1,661 cases of fatal prostate cancer were detected. In the meta-analysis, we found that higher tissue levels of LA were associated with a reduced risk of prostate cancer (RR: 0.86, 95% CI: 0.77-0.96) so that in the dose-response analysis, each 5% increase in levels of LA was associated with a 14% lower risk of prostate cancer. Such a significant association was not seen for advanced prostate cancer (RR: 0.86, 95% CI: 0.65-1.13). Also, we found no significant association between dietary intake of LA and risk of total (RR:1.00, 95% CI: 0.97-1.04), advanced (RR: 0.98, 95% CI: 0.90-1.07), and fatal prostate cancer (RR: 0.97, 95% CI: 0.83-1.13). Our findings support the protective association between tissue levels of LA and the risk of prostate cancer in men.

Multivalent assembly of KRAS with the RAS-binding and cysteine-rich domains of CRAF on the membrane.

Membrane anchoring of farnesylated KRAS is critical for activation of RAF kinases, yet our understanding of how these proteins interact on the membrane is limited to isolated domains. The RAS-binding domain (RBD) and cysteine-rich domain (CRD) of RAF engage KRAS and the plasma membrane, unleashing the kinase domain from autoinhibition. Due to experimental challenges, structural insight into this tripartite KRAS:RBD-CRD:membrane complex has relied on molecular dynamics simulations. Here, we report NMR studies of the KRAS:CRAF RBD-CRD complex. We found that the nucleotide-dependent KRAS-RBD interaction results in transient electrostatic interactions between KRAS and CRD, and we mapped the membrane interfaces of the CRD, RBD-CRD, and the KRAS:RBD-CRD complex. RBD-CRD exhibits dynamic interactions with the membrane through the canonical CRD lipid-binding site (CRD ß7-8), as well as an alternative interface comprising ß6 and the C terminus of CRD and ß2 of RBD. Upon complex formation with KRAS, two distinct states were observed by NMR: State A was stabilized by membrane association of CRD ß7-8 and KRAS α4-α5 while state B involved the C terminus of CRD, ß3-5 of RBD, and part of KRAS α5. Notably, α4-α5, which has been proposed to mediate KRAS dimerization, is accessible only in state B. A cancer-associated mutation on the state B membrane interface of CRAF RBD (E125K) stabilized state B and enhanced kinase activity and cellular MAPK signaling. These studies revealed a dynamic picture of the assembly of the KRAS-CRAF complex via multivalent and dynamic interactions between KRAS, CRAF RBD-CRD, and the membrane.