Intermittent blood flow restriction with low-load resistance training for older adults with knee osteoarthritis: a randomized, controlled, non-inferiority trial protocol.

BACKGROUND: Knee osteoarthritis (KOA) is a chronic musculoskeletal disorder characterized by pain and functional impairment. Blood flow restriction (BFR) with low-load resistance training (LLRT) demonstrates a similar improvement in clinical outcomes to high-load resistance training (HLRT) in treating KOA. It has not been established whether intermittent blood flow restriction (iBFR) with LLRT can lead to clinical outcomes that are comparable to those produced by continuous blood flow restriction (cBFR) with LLRT and HLRT. The aim of the proposed study is to evaluate the efficacy of iBFR with LLRT on pain, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), muscle strength, muscle mass, physical function, perceptions of discomfort and effort, and adherence in KOA patients. METHODS: This is a three-arm, non-inferiority, randomized controlled trial utilizing blinded assessors. Two hundred thirteen participants will be randomly allocated to one of the following three groups: iBFR group-receiving 4 months of LLRT with iBFR, twice weekly (n = 71); cBFR group-receiving 4 months of LLRT with cBFR, twice weekly (n = 71); or HLRT group-receiving 4 months of HLRT without BFR, twice weekly (n = 71). The primary outcome is pain. The secondary outcomes include the WOMAC, muscle strength, muscle mass, physical function, perceptions of discomfort and effort, and adherence. Pain and WOMAC will be measured at the baseline and 4 and 12 months after randomizations. Muscle strength, muscle mass, and physical function will be measured at the baseline and 4 months after randomizations. The perceptions of discomfort and effort will be measured during the first and final sessions. DISCUSSION: BFR with LLRT has a similar improvement in clinical outcomes as HLRT. However, cBFR may cause elevated ratings of perceived exertion and local discomfort, compromising patient tolerability and treatment adherence. If iBFR with LLRT could produce improvement in clinical outcomes analogous to those of HLRT and iBFR with LLRT, it could be considered an alternative approach for treating patients with KOA. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2300072820. Registered on June 26, 2023.

Deciphering the Therapeutic Role of Lactate in Combating Disuse-Induced Muscle Atrophy: An NMR-Based Metabolomic Study in Mice.

Disuse muscle atrophy (DMA) is a significant healthcare challenge characterized by progressive loss of muscle mass and function resulting from prolonged inactivity. The development of effective strategies for muscle recovery is essential. In this study, we established a DMA mouse model through hindlimb suspension to evaluate the therapeutic potential of lactate in alleviating the detrimental effects on the gastrocnemius muscle. Using NMR-based metabolomic analysis, we investigated the metabolic changes in DMA-injured gastrocnemius muscles compared to controls and evaluated the beneficial effects of lactate treatment. Our results show that lactate significantly reduced muscle mass loss and improved muscle function by downregulating Murf1 expression, decreasing protein ubiquitination and hydrolysis, and increasing myosin heavy chain levels. Crucially, lactate corrected perturbations in four key metabolic pathways in the DMA gastrocnemius: the biosynthesis of phenylalanine, tyrosine, and tryptophan; phenylalanine metabolism; histidine metabolism; and arginine and proline metabolism. In addition to phenylalanine-related pathways, lactate also plays a role in regulating branched-chain amino acid metabolism and energy metabolism. Notably, lactate treatment normalized the levels of eight essential metabolites in DMA mice, underscoring its potential as a therapeutic agent against the consequences of prolonged inactivity and muscle wasting. This study not only advances our understanding of the therapeutic benefits of lactate but also provides a foundation for novel treatment approaches aimed at metabolic restoration and muscle recovery in conditions of muscle wasting.

Parental exposure to Cypermethrin causes intergenerational toxicity in zebrafish offspring.

Cypermethrin (CYP), a synthetic pyrethroid pesticide, has been detected in agriculture and aquaculture. However, there is limited knowledge about the transgenerational impacts. This study aimed to investigate the developmental toxicity of CYP on F1 larvae offspring of adult zebrafish exposed to various CYP concentrations (5, 10, and 20 µg/L) for 28 days. The results indicated that CYP accumulated in parental zebrafish, and CYP was below the limit of quantification in offspring. Paternal exposure impacted the hatching rate and heart rate of the F1 generation. Furthermore, CYP significantly impacted the development of swim bladders in progeny and dysregulated the genes relevant to swim bladder development. The neutrophil migrated to the swim bladder. The mRNA levels of the inflammatory factors were also significantly elevated. According to network toxicology, PI3-AKT may be the signaling pathway for CYP-influenced bladder development. Subsequent molecular docking and Western blot analysis showed CYP affected the PI3-AKT signaling pathway. Notably, MK-2206, a specific Akt inhibitor, rescued the CYP-induced damage of swim bladder development in offspring. The present study highlights the potential risks of CYP on the development of offspring and lasting impact in aquatic environments.

Spatiotemporal multi-omics: exploring molecular landscapes in aging and regenerative medicine.

Aging and regeneration represent complex biological phenomena that have long captivated the scientific community. To fully comprehend these processes, it is essential to investigate molecular dynamics through a lens that encompasses both spatial and temporal dimensions. Conventional omics methodologies, such as genomics and transcriptomics, have been instrumental in identifying critical molecular facets of aging and regeneration. However, these methods are somewhat limited, constrained by their spatial resolution and their lack of capacity to dynamically represent tissue alterations. The advent of emerging spatiotemporal multi-omics approaches, encompassing transcriptomics, proteomics, metabolomics, and epigenomics, furnishes comprehensive insights into these intricate molecular dynamics. These sophisticated techniques facilitate accurate delineation of molecular patterns across an array of cells, tissues, and organs, thereby offering an in-depth understanding of the fundamental mechanisms at play. This review meticulously examines the significance of spatiotemporal multi-omics in the realms of aging and regeneration research. It underscores how these methodologies augment our comprehension of molecular dynamics, cellular interactions, and signaling pathways. Initially, the review delineates the foundational principles underpinning these methods, followed by an evaluation of their recent applications within the field. The review ultimately concludes by addressing the prevailing challenges and projecting future advancements in the field. Indubitably, spatiotemporal multi-omics are instrumental in deciphering the complexities inherent in aging and regeneration, thus charting a course toward potential therapeutic innovations.

OsSRF8 interacts with OsINP1 and OsDAF1 to regulate pollen aperture formation in rice.

In higher plants, mature male gametophytes have distinct apertures. After pollination, pollen grains germinate, and a pollen tube grows from the aperture to deliver sperm cells to the embryo sac, completing fertilization. In rice, the pollen aperture has a single-pore structure with a collar-like annulus and a plug-like operculum. A crucial step in aperture development is the formation of aperture plasma membrane protrusion (APMP) at the distal polar region of the microspore during the late tetrad stage. Previous studies identified OsINP1 and OsDAF1 as essential regulators of APMP and pollen aperture formation in rice, but their precise molecular mechanisms remain unclear. We demonstrate that the Poaceae-specific OsSRF8 gene, encoding a STRUBBELIG-receptor family 8 protein, is essential for pollen aperture formation in Oryza sativa. Mutants lacking functional OsSRF8 exhibit defects in APMP and pollen aperture formation, like loss-of-function OsINP1 mutants. OsSRF8 is specifically expressed during early anther development and initially diffusely distributed in the microsporocytes. At the tetrad stage, OsSRF8 is recruited by OsINP1 to the pre-aperture region through direct protein-protein interaction, promoting APMP formation. The OsSRF8-OsINP1 complex then recruits OsDAF1 to the APMP site to co-regulate annulus formation. Our findings provide insights into the mechanisms controlling pollen aperture formation in cereal species.

The RNA binding protein EHD6 recruits the m6A reader YTH07 and sequesters OsCOL4 mRNA into phase-separated ribonucleoprotein condensates to promote rice flowering.

N6-Methyladenosine (m6A) is one of the most abundant modifications of eukaryotic mRNA, but its comprehensive biological functionality remains further exploration. In this study, we identified and characterized a new flowering-promoting gene, EARLY HEADING DATE6 (EHD6), in rice. EHD6 encodes an RNA recognition motif (RRM)-containing RNA binding protein that is localized in the non-membranous cytoplasm ribonucleoprotein (RNP) granules and can bind both m6A-modified RNA and unmodified RNA indiscriminately. We found that EHD6 can physically interact with YTH07, a YTH (YT521-B homology) domain-containing m6A reader. We showed that their interaction enhances the binding of an m6A-modified RNA and triggers relocation of a portion of YTH07 from the cytoplasm into RNP granules through phase-separated condensation. Within these condensates, the mRNA of a rice flowering repressor, CONSTANS-like 4 (OsCOL4), becomes sequestered, leading to a reduction in its protein abundance and thus accelerated flowering through the Early heading date 1 pathway. Taken together, these results not only shed new light on the molecular mechanism of efficient m6A recognition by the collaboration between an RNA binding protein and YTH family m6A reader, but also uncover the potential for m6A-mediated translation regulation through phase-separated ribonucleoprotein condensation in rice.

Seroprevalence of the novel swine acute diarrhea syndrome coronavirus in China assessed by enzyme-linked immunosorbent assay.

The endemic outbreak of SADS-CoV has resulted in economic losses and potentially threatened the safety of China's pig industry. The molecular epidemiology of SADS-CoV in pig herds has been investigated in many provinces in China. However, there are no data over a long-time span, and there is a lack of extensive serological surveys to assess the prevalence of SADS-CoV in Chinese swine herds since the discovery of SADS-CoV. In this study, an indirect anti-SADS-CoV IgG enzyme-linked immunosorbent assay (ELISA) based on the SADS-CoV S1 protein was established to investigate the seroprevalence of SADS-CoV in Chinese swine herds. Cross-reactivity assays, indirect immunofluorescence, and western blotting assays showed that the developed ELISA had excellent SADS-CoV specificity. In total, 12,978 pig serum samples from 29 provinces/municipalities/autonomous regions in China were tested from 2022 to 2023. The results showed that the general seroprevalence of SADS-CoV in China was 59.97%, with seroprevalence ranging from 16.7% to 77.12% in different provinces and from 42.61% to 68.45% in different months. SADS-CoV is widely prevalent in China, and its seroprevalence was higher in Northeast China, North China, and Central China than in other regions. Among the four seasons, the prevalence of SADS-CoV was the highest in spring and the lowest in autumn. The results of this study provide the general seroprevalence profile of SADS-CoV in China, facilitating the understanding of the prevalence of SADS-CoV in pigs. More importantly, this study is beneficial in formulating preventive and control measures for SADS-CoV and may provide directions for vaccine development.

GITR exacerbates lysophosphatidylcholine-induced macrophage pyroptosis in sepsis via posttranslational regulation of NLRP3.

The NLRP3 inflammasome functions as an inflammatory driver, but its relationship with lipid metabolic changes in early sepsis remains unclear. Here, we found that GITR expression in monocytes/macrophages was induced by lysophosphatidylcholine (LPC) and was positively correlated with the severity of sepsis. GITR is a costimulatory molecule that is mainly expressed on T cells, but its function in macrophages is largely unknown. Our in vitro data showed that GITR enhanced LPC uptake by macrophages and specifically enhanced NLRP3 inflammasome-mediated macrophage pyroptosis. Furthermore, in vivo studies using either cecal ligation and puncture (CLP) or LPS-induced sepsis models demonstrated that LPC exacerbated sepsis severity/lethality, while conditional knockout of GITR in myeloid cells or NLRP3/caspase-1/IL-1ß deficiency attenuated sepsis severity/lethality. Mechanistically, GITR specifically enhanced inflammasome activation by regulating the posttranslational modification (PTM) of NLRP3. GITR competes with NLRP3 for binding to the E3 ligase MARCH7 and recruits MARCH7 to induce deacetylase SIRT2 degradation, leading to decreasing ubiquitination but increasing acetylation of NLRP3. Overall, these findings revealed a novel role of macrophage-derived GITR in regulating the PTM of NLRP3 and systemic inflammatory injury, suggesting that GITR may be a potential therapeutic target for sepsis and other inflammatory diseases. GITR exacerbates LPC-induced macrophage pyroptosis in sepsis via posttranslational regulation of NLRP3. According to the model, LPC levels increase during the early stage of sepsis, inducing GITR expression on macrophages. GITR not only competes with NLRP3 for binding to the E3 ligase MARCH7 but also recruits MARCH7 to induce the degradation of the deacetylase SIRT2, leading to decreasing ubiquitination but increasing acetylation of NLRP3 and therefore exacerbating LPC-induced NLRP3 inflammasome activation, macrophage pyroptosis and systemic inflammatory injury.

The Relationship Between Fracture and Mortality in a Chinese Maintenance Hemodialysis Patients Cohort.

Background: Patients on maintenance hemodialysis have an increased risk of fracture. However, the relationship between fracture and poor prognosis is not clear. Methods: A total of 182 maintenance hemodialysis patients were enrolled in the study. The relationship between fracture and poor prognosis (cardiovascular events, stroke, malignancy and 5-year all-cause mortality) were analyzed. Results: 21 of 182 patients had a history of fracture at the time of enrollment. 26 patients had a new fracture after enrollment. A total of 57 fractures occurred in 47 patients, the most common fracture site was the rib. Patients with fracture group had a higher proportion of elderly and female, higher serum phosphorus and B-type natriuretic peptide and lower hemoglobin, albumin, and potassium compared with those without fracture. Age (OR=3.809, 95% CI: 1.064-8.966, p=0.038), hemoglobin (OR=0.961, 95% CI: 0.925-0.997, p=0.035), and serum phosphorus (OR=3.325, 95% CI:1.104-10.019, p=0.033) were the independent risk factors of new fractures in MHD patients. The incidence of malignancy and 5-year all-cause mortality in patients with fracture was higher than those without fracture (p<0.05). But there was no significant difference in the incidence of acute myocardial infarction or stroke. Conclusion: 25.8% of maintenance hemodialysis patients had at least one fracture, with rib fractures accounting for the highest proportion. Age, hemoglobin and serum phosphorus were the independent risk factors of new fractures. The incidence of malignancy and 5-year all-cause mortality in patients with fracture was higher than those without fracture, but there was no significant difference in the incidence of acute myocardial infarction and stroke.

To determine the incidence of fractures in hemodialysis patients, we conducted this single center, prospective observational study. 182 patients were enrolled. We also recorded the 5-year incidence of acute myocardial infarction(AMI), stroke, malignancy, and mortality. Our results showed that the incidence of fracture in hemodialysis patients was 25.8%. The most common fracture site was the rib. There were significant statistical differences in age, gender, hemoglobin, serum albumin, B-type natriuretic peptide, potassium and phosphorus between patients with and without fractures. Logistic regression analysis suggested that advanced age, anaemia and hyperphosphatemia were independent risk factors for new fractures in hemodialysis patients. We followed 182 patients for 5 years and recorded the incidence of stroke, AMI and malignancy. The rates of AMI and stroke did not differ significantly between the two groups. However, the incidence of malignancy in patients with fractures is significantly higher than that in patients without fractures. In our study, a total of 74 patients died, including 24 deaths in the fracture group and 50 deaths in the non-fracture group. The main causes of death in 74 cases were cardiovascular events. Our study provides some insight into the association between fractures and poor outcomes in hemodialysis patients.

Public attitudes toward medical waste: Experiences from 141 countries.

BACKGROUND: Medical Waste (MW), conceptualized as waste generated in the diagnosis, treatment, or immunization of human beings or animals, posing massive threat to public health. Environment-friendly public attitudes promotes the shaping of pro-environmental behavior. However, the public attitudes of MW and the potential determinants remained scarce. The present study aims to reveal globally public attitudes towards MW and captured the determinants. METHODS: We integrated the crawler technology with sentiment analysis to captured the public attitudes toward MW across 141 specific countries from 3,789,764 related tweets. Multiple cross-national databases were integrated to assess characteristics including risk, resistance, environment, and development. The spatial regression model was taken to counterbalence the potential statistical bias. RESULTS: Overall, the global public attitudes towards MW were positive, and varied significantly across countries. Resilience (ß = 0.78, SD = 0.14, P < 0.01) and development (ß = 1.66, SD = 0.13, P < 0.01) posed positive influence on public attitudes towards MW, meanwhile, risk (ß = -0.1, SD = 0.12, P > 0.05) and environment (ß = 0.09, SD = 0.09, P > 0.05) were irrelated to the shaping of positive MW public attitudes. Several positive moderating influences was also captured. Additionally, the cross-national disparities of the determiants were also captured, more specific, public attitudes towards MW in extremely poor areas were more likely to be negatively affected by risks, resilience and development. CONCLUSIONS: This study focused mainly on the public attitudes as well as captured the potential determinants. Public attitudes towards MW were generally positive, but there were large cross-national disparities. Stakeholders would need to designate targeted strategies to enhance public satisfaction with MW management.

Ventricular Netrin-1 deficiency leads to defective pyramidal decussation and mirror movement in mice.

The corticospinal tract (CST) is the principal neural pathway responsible for conducting voluntary movement in the vertebrate nervous system. Netrin-1 is a well-known guidance molecule for midline crossing of commissural axons during embryonic development. Families with inherited Netrin-1 mutations display congenital mirror movements (CMM), which are associated with malformations of pyramidal decussation in most cases. Here, we investigated the role of Netrin-1 in CST formation by generating conditional knockout (CKO) mice using a Gfap-driven Cre line. A large proportion of CST axons spread laterally in the ventral medulla oblongata, failed to decussate and descended in the ipsilateral spinal white matter of Ntn1Gfap CKO mice. Netrin-1 mRNA was expressed in the ventral ventricular zone (VZ) and midline, while Netrin-1 protein was transported by radial glial cells to the ventral medulla, through which CST axons pass. The level of transported Netrin-1 protein was significantly reduced in Ntn1Gfap CKO mice. In addition, Ntn1Gfap CKO mice displayed increased symmetric movements. Our findings indicate that VZ-derived Netrin-1 deletion leads to an abnormal trajectory of the CST in the spinal cord due to the failure of CST midline crossing and provides novel evidence supporting the idea that the Netrin-1 signalling pathway is involved in the pathogenesis of CMM.

Increased prevalence of vertebrobasilar dolichoectasia in Parkinson's disease and its effect on white matter microstructure and network.

This study aimed to investigate the prevalence of vertebrobasilar dolichoectasia (VBD) in Parkinson's disease (PD) patients and analyze its role in gray matter changes, white matter (WM) microstructure and network alterations in PD. This is a cross-sectional study including 341 PD patients. Prevalence of VBD in these PD patients was compared with general population. Diffusion tensor imaging and T1-weighted imaging analysis were performed among 174 PD patients with or without VBD. Voxel-based morphometry analysis was used to estimate gray matter volume changes. Tract-based spatial statistics and region of interest-based analysis were used to evaluate WM microstructure changes. WM network analysis was also performed. Significantly higher prevalence of VBD in PD patients was identified compared with general population. Lower fractional anisotropy and higher diffusivity, without significant gray matter involvement, were found in PD patients with VBD in widespread areas. Decreased global and local efficiency, increased hierarchy, decreased degree centrality at left Rolandic operculum, increased betweenness centrality at left postcentral gyrus and decreased average connectivity strength between and within several modules were identified in PD patients with VBD. VBD is more prevalent in PD patients than general population. Widespread impairments in WM microstructure and WM network involving various motor and nonmotor PD symptom-related areas are more prominent in PD patients with VBD compared with PD patients without VBD.

Hot Carrier Trapping and It's Influence to the Carrier Diffusion in CsPbBr3 Perovskite Film Revealed by Transient Absorption Microscopy.

The defects in perovskite film can cause charge carrier trapping which shortens carrier lifetime and diffusion length. So defects passivation has become promising for the perovskite studies. However, how defects disturb the carrier transport and how the passivating affects the carrier transport in CsPbBr3 are still unclear. Here the carrier dynamics and diffusion processes of CsPbBr3 and LiBr passivated CsPbBr3 films are investigated by using transient absorption spectroscopy and transient absorption microscopy. It's found that there is a fast hot carrier trapping process with the above bandgap excitation, and the hot carrier trapping would decrease the population of cold carriers which are diffusible, then lower the carrier diffusion constant. It's proved that LiBr can passivate the defect and lower the trapping probability of hot carriers, thus improve the carrier diffusion rate. The finding demonstrates the influence of hot carrier trapping to the carrier diffusion in CsPbBr3 film.

The structure of the archaeal nuclease RecJ2 implicates its catalytic mechanism and inability to interact with GINS.

Bacterial RecJ exhibits 5'→3' exonuclease activity that is specific to single-stranded DNA (ssDNA); however, archaeal RecJs show 5' or 3' exonuclease activity. The hyperthermophilic archaea Methanocaldococcus jannaschii encodes the 5'-exonuclease MjRecJ1 and the 3'-exonuclease MjRecJ2. In addition to nuclease activity, archaeal RecJ interacts with GINS, a structural subcomplex of the replicative DNA helicase complex. However, MjRecJ1 and MjRecJ2 do not interact with MjGINS. Here, we report the structural basis for the inability of the MjRecJ2 homologous dimer to interact with MjGINS and its efficient 3' hydrolysis polarity for short dinucleotides. Based on the crystal structure of MjRecJ2, we propose that the interaction surface of the MjRecJ2 dimer overlaps the potential interaction surface for MjGINS and blocks the formation of the MjRecJ2-GINS complex. Exposing the interaction surface of the MjRecJ2 dimer restores its interaction with MjGINS. The cocrystal structures of MjRecJ2 with substrate dideoxynucleotides or product dCMP/CMP show that MjRecJ2 has a short substrate binding patch, which is perpendicular to the longer patch of bacterial RecJ. Our results provide new insights into the function and diversification of archaeal RecJ/Cdc45 proteins.

The impact of square dancing on psychological well-being and life satisfaction among aging women.

As the most popular sport among middle-aged and elderly women in China, square dancing has both physical and psychological benefits for menopausal women. Previous studies have shown that square dance exercises can promote the physical health of older women, but there is a lack of research on the influence of middle-aged and elderly women on mental health and mediating variables. Therefore, this study starts with one of the important indicators of mental health-positive affects, aiming to explore the impact of square dance on the positive emotions of elderly women and further explore the mediating mechanisms involved. We send out The Physical Activity Rating Scale, the Positive and Negative Affect Scale, the Connor-Davidson Resilience Scale, and the Satisfaction With Life Scale to a total of 2311 middle-aged and elderly women. SPSS 23 software and PROCESS were used to perform regression analysis and establish mediation models. Modeling results show square dance exercises could positively predict positive affect through the chain mediating effect of psychological resilience and life satisfaction. The results of this study are of great significance for promoting the extensive participation of middle-aged and elderly women in sports and protecting their mental health.

H-Aggregation of Squaraine Dye as Generic Colorimetric Molecules to Detect Cu2.

An infrared squaraine dye was utilized to detect Cu2+ in solvents based on H-aggregates of squaraine dye. H-aggregates are a type of aggregation with enhanced photophysical properties compared to monomers. In the presence of a Ca2+ solution, F-Cl offers exceptional H-aggregators that can be transformed into monomers by adding Cu2+. Furthermore, this mode successfully demonstrated fluorescence changes in HeLa cells cultured in vitro after the addition of Ca2+ or Cu2+. A highly specific detection of Cu2+ was achieved using this transformation mode.