Liraglutide Improves PCOS Symptoms in Rats by Targeting FDX1.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a gynecological endocrine disorder characterized by ovulatory disorders, hyperandrogenemia, and polycystic changes in the ovaries. FDX1 is a ferredoxin-reducing protein on human mitochondria that plays an important role in steroid anabolism. Liraglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), has recently emerged as a potential therapeutic agent for PCOS. Recent studies have suggested that FDX1 may be associated with the development of PCOS. This study aims to explore the pivotal role of FDX1 in the amelioration of PCOS through liraglutide intervention. MATERIALS AND METHODS: A PCOS rat model was induced via subcutaneous DHEA injections. Following successful model establishment, the rats were treated with liraglutide combined with metformin, or with each drug individually, over a six-week period. After 6 weeks of treatment, we assessed changes in body weight, fasting blood glucose, sex hormone levels, estrous cycle regularity, ovarian morphology, FDX1 expression in ovarian tissue, and ovarian ROS levels. RESULTS: PCOS rats exhibited significant increases in body weight and fasting blood glucose levels, disrupted estrous cycles, and polycystic ovarian morphology. FDX1 expression was notably reduced in the ovarian tissues of PCOS rats. Treatment with liraglutide, both alone and in combination with metformin, led to improvements in body weight, fasting blood glucose, sex hormone balance, estrous cycle regularity, ovarian morphology, and ovarian ROS levels. Notably, FDX1 expression was significantly restored in all treatment groups, with the most substantial increase observed in the liraglutide-treated group. CONCLUSION: This study suggests that FDX1 could serve as a potential biomarker for elucidating the underlying mechanisms of liraglutide's therapeutic effects in PCOS management.

Does Walking Have an Association with Osteoarthritis? A Two-Sample Mendelian Randomization Analysis.

Objective: Osteoarthritis (OA) is one of the major disabling human diseases. The related studies indicate a potential correlation between walking and OA. However, there is still a lack of evidence in genetics to support the correlation between walking and OA. Therefore, this study aimed to explore the relationship between walking and OA at the genetic level. Methods: The publicly available Genome Wide Association Study (GWAS) data were used, with inverse variance weighting (IVW, the random-effects model) as the main analysis method, whereas MR-Egger, Weighted median, Simple mode, and Weighted mode as the secondary analysis methods. In addition, Cochran's Q test, pleiotropy test, and MR-Egger intercept test were conducted to examine the heterogeneity and pleiotropy of the outcome. Results: In the MR analysis, IVW results showed a negative correlation between types of physical activity in last 4 weeks: Walking for pleasure (not as a means of transport) and OA (KOA or HOA) (odds ratio (OR) = 0.3224, 95% confidence interval (CI): 0.1261 to 0.8243), and the difference was of statistical significance (P = 0.0181). Moreover, IVW results also revealed a negative correlation between types of physical activity in last 4 weeks: Walking for pleasure (not as a means of transport) and KOA (OR = 0.1396, 95% CI: 0.0484 to 0.4026), and the difference was statistically significant (P = 0.0003). However, IVW results did not demonstrate any statistical significance types of physical activity in last 4 weeks: Walking for pleasure (not as a means of transport) and HOA (OR = 1.2075, 95% CI: 0.1978 to 7.3727, P = 0.8381). Conclusion: From genetic studies, types of physical activity in last 4 weeks: Walking for pleasure (not as a means of transport) is negatively correlated with knee osteoarthritis (KOA), but there is no clear evidence supporting its correlation with hip osteoarthritis (HOA).

Prevalence and factors associated with knee osteoarthritis among middle-aged and elderly individuals in rural Tianjin: a population-based cross-sectional study.

BACKGROUND: The prevalence of osteoarthritis has been investigated in many countries and regions. Considering the wide differences in ethnicity, socioeconomic status, environmental factors, and lifestyle patterns, our study aimed to report the prevalence of knee osteoarthritis (KOA) and its associated factors in rural areas of Tianjin. METHODS: This population-based cross-sectional study was conducted between June and August 2020. KOA was diagnosed according to the 1995 American College of Rheumatology criteria. Information on participants' age, years of education, BMI, smoking and drinking status, sleep quality, and frequency of walking were collected. Multivariate logistic regression analysis was used to analyze factors influencing KOA. RESULTS: This study included 3924 participants (1950 male and 1974 female); the mean age of all participants was 58.53 years. In total, 404 patients were diagnosed with KOA, and the overall prevalence of KOA was 10.3%. The prevalence of KOA was higher in women than in men (14.1% vs. 6.5%). The risk of KOA in women was 1.764 times higher than that in men. The risk of KOA increased following the increasement of age. There was higher risk of KOA in participants who walked frequently than in participants who walked infrequently (OR = 1.572); in participants with overweight than in participants with normal weight (OR = 1.509), in participants with average sleep quality (OR = 1.677) and those with perceived poor sleep quality (OR = 1.978), respectively, than participants with satisfactory sleep quality, and in postmenopausal women than in non-menopausal women (OR = 4.12). The risk of KOA in participants with an elementary level was lower (0.619 times) than participants with illiteracy. In addition, the results of gender subgroup analysis showed that in male, age, obesity, frequent walking and sleep quality were independent factors associated with KOA; while in female, age, BMI, education level, sleep quality, frequent walking and whether menopausal were independent factors associated with KOA (P < 0.05). CONCLUSION: The results of our population-based cross-sectional study showed that sex, age, educational level, BMI, sleep quality, and frequent walking were independent influencing factors for KOA, and the influencing factors for KOA differed between the sexes. In order to reduce the disease burden of KOA and the harm to the health of middle-aged and elderly people, the risk factors related to the control of KOA should be identified as much as possible. TRIAL REGISTRATION: ChiCTR2100050140.

Differential expression of microRNA in the serum of patients with polycystic ovary syndrome with insulin resistance.

Background: Polycystic ovary syndrome (PCOS) is the most common reproductive endocrine disease in women of childbearing age, and insulin resistance is an important etiological mechanism in PCOS. This study revealed the microRNA (miRNA) expression profile of PCOS with insulin resistance and explored the potential biological functions of differentially expressed miRNA. Methods: A total of 76 patients with PCOS and 30 normal healthy women were recruited in the gynecological clinic of the Second Hospital of Tianjin Medical University. We divided the patients with PCOS into a group with insulin resistance (n=46) and a group without insulin resistance (n=30). Peripheral venous serum samples from each group were used for deep sequencing to identify differentially expressed miRNAs. Hierarchical clustering heat maps were used to show differences in miRNA expression. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and target gene network databases were used to explore the potential target genes of differentially expressed miRNAs and to analyze their specific biological functions. Results: A case-control analysis found that the levels of body mass index (BMI), prolactin (PRL), total testosterone (T), fasting blood glucose (FBG), and fasting insulin (INS) in patients with PCOS were higher than those in healthy controls. High BMI, high blood sugar, and hyperinsulinemia were more significant in the PCOS with insulin resistance group than without insulin resistance group. Among the patients with PCOS, miR-122-5p was found to have more significant differences in the PCOS with insulin resistance group. GO and KEGG pathway analysis showed that the identified miRNAs were involved in the regulation of different biological processes, such as signal transduction, negative regulation of GTPase activity, chloride channel complex. The predicted target genes were related to the citrate cycle (TCA cycle) and the biosynthesis of mucin-type O-glycans. Conclusions: Our research demonstrated the use of miRNAs as new biomarkers for the diagnosis, treatment and presented a new strategy to lessen the symptoms of PCOS with insulin resistance.

A Pooled Sequencing Approach Identifies a Candidate Meiotic Driver in Drosophila.

Meiotic drive occurs when a selfish element increases its transmission frequency above the Mendelian ratio by hijacking the asymmetric divisions of female meiosis. Meiotic drive causes genomic conflict and potentially has a major impact on genome evolution, but only a few drive loci of large effect have been described. New methods to reliably detect meiotic drive are therefore needed, particularly for discovering moderate-strength drivers that are likely to be more prevalent in natural populations than strong drivers. Here, we report an efficient method that uses sequencing of large pools of backcross (BC1) progeny to test for deviations from Mendelian segregation genome-wide with single-nucleotide polymorphisms (SNPs) that distinguish the parental strains. We show that meiotic drive can be detected by a characteristic pattern of decay in distortion of SNP frequencies, caused by recombination unlinking the driver from distal loci. We further show that control crosses allow allele-frequency distortion caused by meiotic drive to be distinguished from distortion resulting from developmental effects. We used this approach to test whether chromosomes with extreme telomere-length differences segregate at Mendelian ratios, as telomeric regions are a potential hotspot for meiotic drive due to their roles in meiotic segregation and multiple observations of high rates of telomere sequence evolution. Using four different pairings of long and short telomere strains, we find no evidence that extreme telomere-length variation causes meiotic drive in Drosophila However, we identify one candidate meiotic driver in a centromere-linked region that shows an ∼8% increase in transmission frequency, corresponding to a ∼54:46 segregation ratio. Our results show that candidate meiotic drivers of moderate strength can be readily detected and localized in pools of BC1 progeny.

A screen for F1 hybrid male rescue reveals no major-effect hybrid lethality loci in the Drosophila melanogaster autosomal genome.

Hybrid sons between Drosophila melanogaster females and D. simulans males die as 3rd instar larvae. Two genes, D. melanogaster Hybrid male rescue (Hmr) on the X chromosome, and D. simulans Lethal hybrid rescue (Lhr) on chromosome II, interact to cause this lethality. Loss-of-function mutations in either gene suppress lethality, but several pieces of evidence suggest that additional factors are required for hybrid lethality. Here we screen the D. melanogaster autosomal genome by using the Bloomington Stock Center Deficiency kit to search for additional regions that can rescue hybrid male lethality. Our screen is designed to identify putative hybrid incompatibility (HI) genes similar to Hmr and Lhr which, when removed, are dominant suppressors of lethality. After screening 89% of the autosomal genome, we found no regions that rescue males to the adult stage. We did, however, identify several regions that rescue up to 13% of males to the pharate adult stage. This weak rescue suggests the presence of multiple minor-effect HI loci, but we were unable to map these loci to high resolution, presumably because weak rescue can be masked by genetic background effects. We attempted to test one candidate, the dosage compensation gene male specific lethal-3 (msl-3), by using RNA interference with short hairpin microRNA constructs targeted specifically against D. simulans msl-3 but failed to achieve knockdown, in part due to off-target effects. We conclude that the D. melanogaster autosomal genome likely does not contain additional major-effect HI loci. We also show that Hmr is insufficient to fully account for the lethality associated with the D. melanogaster X chromosome, suggesting that additional X-linked genes contribute to hybrid lethality.

The Hmr and Lhr hybrid incompatibility genes suppress a broad range of heterochromatic repeats.

Hybrid incompatibilities (HIs) cause reproductive isolation between species and thus contribute to speciation. Several HI genes encode adaptively evolving proteins that localize to or interact with heterochromatin, suggesting that HIs may result from co-evolution with rapidly evolving heterochromatic DNA. Little is known, however, about the intraspecific function of these HI genes, the specific sequences they interact with, or the evolutionary forces that drive their divergence. The genes Hmr and Lhr genetically interact to cause hybrid lethality between Drosophila melanogaster and D. simulans, yet mutations in both genes are viable. Here, we report that Hmr and Lhr encode proteins that form a heterochromatic complex with Heterochromatin Protein 1 (HP1a). Using RNA-Seq analyses we discovered that Hmr and Lhr are required to repress transcripts from satellite DNAs and many families of transposable elements (TEs). By comparing Hmr and Lhr function between D. melanogaster and D. simulans we identify several satellite DNAs and TEs that are differentially regulated between the species. Hmr and Lhr mutations also cause massive overexpression of telomeric TEs and significant telomere lengthening. Hmr and Lhr therefore regulate three types of heterochromatic sequences that are responsible for the significant differences in genome size and structure between D. melanogaster and D. simulans and have high potential to cause genetic conflicts with host fitness. We further find that many TEs are overexpressed in hybrids but that those specifically mis-expressed in lethal hybrids do not closely correlate with Hmr function. Our results therefore argue that adaptive divergence of heterochromatin proteins in response to repetitive DNAs is an important underlying force driving the evolution of hybrid incompatibility genes, but that hybrid lethality likely results from novel epistatic genetic interactions that are distinct to the hybrid background.

[Biomechanical research of less invasive stabilization system and dynamic condylar screw in fixing subtrochanteric fractures of femur].

OBJECTIVE: To compare the biomechanical characteristics of the less invasive stabilization system (LISS) and the dynamic condylar screw (DCS) in the fixation of subtrochanteric fractures of the femur so as to provide theoretical basis for choosing internal fixator in clinical application. METHODS: Twelve cadaveric human femurs (35-50 years old) were selected with similar proximal femur, excluding deformities, fractures, and other lesions. The twelve femur specimens were randomly divided into 2 groups, 6 specimens per group. An 1 cm gap of osteotomy model was made in the proximal femur up to 1 cm below the lesser trochanter to simulate a comminuted subtrochanteric fracture of femur, and the distal end was embedded with denture acrylic and liquid for denture acrylic. Fracture was fixed by LISS in group A, and was fixed by DCS in group B. The specimens were fixed on Instron-8874 servo-hydraulic mechanical testing machine in a single-leg standing position, and the axial compression test and dynamic fatigue test were carried out to compare the compressive strength and the strain distribution at both sides of the fracture line. RESULTS: Axial compression test: the strain values of the 2 strain gauges in group A were significantly smaller than those in group B (P < 0.01); the vertical down displacement of the femoral head in group A was significantly smaller than that in group B (P < 0.01) under the same load; when the load was 600 N, the axial rigidity of group A was (209.06 +/- 18.63) N/mm, which was significantly higher than that of group B [(65.79 +/- 7.26) N/mm] (t = 3.787, P = 0.004). Dynamic fatigue test: the vertical down displacement of the femoral head in group A was significantly smaller than that in group B in the same cyclic loading cycle (P < 0.01); when the vertical down displacement of the femoral head was 0.5 mm, the force and the cyclic loading cycles in group A were significantly larger than those in group B (P < 0.01). CONCLUSION: LISS, which has good mechanical stability, can meet the requirements for subtrochanteric fracture of femur fixation in biomechanics and anatomical structures. It can be proven that the LISS internal fixator is firmer than the DCS internal fixator by biomechanical comparison.

[Case-control study on the treatment of pain in patients with knee osteoarthritis by Pizhen].

OBJECTIVE: To evaluate and analyze mechanism of Pizhen for the treatment of pain in patients with knee osteoarthritis. METHODS: Eighty-five patients (85 knees) were divided into two groups according to random number table method. Among 35 patients in the experimental group, 6 patients were male and 29 patients were female, 1 patient lost follow-up, the average age was (56.65 +/- 4.89) years, and the patients were treated with Pizhen. Among 50 patients in the control group,there were 6 males and 44 females, the average age was (57.54 +/- 4.91) years, and the patients were treated with intra-articular injection with sodium hyaluronate. The VAS score and the data of algometer from the most obvious tenderness around the knee were used to evaluate the clinical effects. RESULTS: There were significant differences of scores in the experimental group before and after treatment (P<0.01). There were significant differences of scores in the control group before and after treatment (P<0.01). After treatment, there were no statistical differences of VAS score and the data of algometer between experimental and control groups ( P>0.01). There was negative correlation between VAS score and the data of algometer. CONCLUSION: The Pizhen is an effective method to treat pain in patients with knee osteoarthritis by relaxing tendon of soft tissue around pain point of knee joint, and relaxing compress and stimulation of nerves.

A role for Acp29AB, a predicted seminal fluid lectin, in female sperm storage in Drosophila melanogaster.

Females of many animal species store sperm for taxon-specific periods of time, ranging from a few hours to years. Female sperm storage has important reproductive and evolutionary consequences, yet relatively little is known of its molecular basis. Here, we report the isolation of a loss-of-function mutation of the Drosophila melanogaster Acp29AB gene, which encodes a seminal fluid protein that is transferred from males to females during mating. Using this mutant, we show that Acp29AB is required for the normal maintenance of sperm in storage. Consistent with this role, Acp29AB localizes to female sperm storage organs following mating, although it does not appear to associate tightly with sperm. Acp29AB is a predicted lectin, suggesting that sugar-protein interactions may be important for D. melanogaster sperm storage, much as they are in many mammals. Previous association studies have found an effect of Acp29AB genotype on a male's sperm competitive ability; our findings suggest that effects on sperm storage may underlie these differences in sperm competition. Moreover, Acp29AB's effects on sperm storage and sperm competition may explain previously documented evidence for positive selection on the Acp29AB locus.

Phylogeny of eusocial Lasioglossum reveals multiple losses of eusociality within a primitively eusocial clade of bees (Hymenoptera: Halictidae).

We performed a phylogenetic analysis of the species, species groups, and subgenera within the predominantly eusocial lineage of Lasioglossum (the Hemihalictus series) based on three protein coding genes: mitochondrial cytochrome oxidase I, nuclear elongation factor 1alpha and long-wavelength rhodopsin. The entire data set consisted of 3421 aligned nucleotide sites, 854 of which were parsimony informative. Analyses by equal weights parsimony, maximum likelihood, and Bayesian methods yielded good resolution among the 53 taxa/populations, with strong bootstrap support and high posterior probabilities for most nodes. There was no significant incongruence among genes, and parsimony, maximum likelihood, and Bayesian methods yielded congruent results. We mapped social behavior onto the resulting tree for 42 of the taxa/populations to infer the likely history of social evolution within Lasioglossum. Our results indicate that eusociality had a single origin within Lasioglossum. Within the predominantly eusocial clade, however, there have been multiple (six) reversals from eusociality to solitary nesting, social polymorphism, or social parasitism, suggesting that these reversals may be more common in primitively eusocial Hymenoptera than previously anticipated. Our results support the view that eusociality is hard to evolve but easily lost. This conclusion is potentially important for understanding the early evolution of the advanced eusocial insects, such as ants, termites, and corbiculate bees.