Distinct virtual histology of grey matter atrophy in four neuroinflammatory diseases.

Gray matter (GM) atrophies were observed in multiple sclerosis, neuromyelitis optica spectrum disorders (both anti-aquaporin-4 antibody-positive [AQP4+], and -negative [AQP4-] subtypes NMOSD), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). Revealing the pathogenesis of brain atrophy in these disorders would help their differential diagnosis and guide therapeutic strategies. To determine the neurobiological underpinnings of GM atrophies in multiple sclerosis, AQP4+ NMOSD, AQP4- NMOSD, and MOGAD, we conducted a virtual histology analysis that links T1-weighted image derived GM atrophy and gene expression using a multicenter cohort of 324 patients with multiple sclerosis, 197 patients with AQP4+ NMOSD, 75 patients with AQP4- NMOSD, 47 patients with MOGAD, and 2,169 healthy controls (HCs). First, interregional GM atrophy profiles across the cortical and subcortical regions were determined by Cohen's d between patients with multiple sclerosis, AQP4+ NMOSD, AQP4- NMOSD, MOGAD and HCs. Then, the GM atrophy profiles were spatially correlated with the gene expressions extracted from the Allen Human Brain Atlas, respectively. Finally, we explored the virtual histology of clinical feature relevant GM atrophy by subgroup analysis that stratified by physical disability, disease duration, number of relapses, lesion burden, and cognitive function. Multiple sclerosis showed severe widespread GM atrophy pattern, mainly involving subcortical nuclei and brainstem. AQP4+ NMOSD showed obvious widespread GM atrophy pattern, predominately located in occipital cortex as well as cerebellum. AQP4- NMOSD showed mild widespread GM atrophy pattern, mainly located in frontal and parietal cortices. MOGAD showed GM atrophy mainly involving the frontal and temporal cortices. High expression of genes specific to microglia, astrocytes, oligodendrocytes, and endothelial cells in multiple sclerosis, S1 pyramidal cells in AQP4+ NMOSD, as well as S1 and CA1 pyramidal cells in MOGAD had spatial correlations with GM atrophy profiles were observed, while no atrophy profile related gene expression was found in AQP4- NMOSD. Virtual histology of clinical feature relevant GM atrophy mainly pointed to the shared neuronal and endothelial cells among the four neuroinflammatory diseases. The unique underlying virtual histology patterns were microglia, astrocytes, and oligodendrocytes for multiple sclerosis; astrocytes for AQP4+ NMOSD; and oligodendrocytes for MOGAD. Neuronal and endothelial cells were shared potential targets across these neuroinflammatory diseases. These findings might help their differential diagnosis and optimal therapeutic strategies.

Impacts of the Zero-Markup Drug Policy on Hospitalization Expenses of Patients with Stroke in Western China: An Interrupted Time Series Analysis.

Background: In 2016, an innovative medical pricing reform called zero-markup drug policy (ZMDP) was implemented in selected pilot cities in China, which focuses on curbing the unreasonable growth of medical expenses. This study aimed to evaluate the impacts of ZMDP on medical expenditure of stroke in western China. Methods: The quantitative data of inpatients diagnosed with stroke was extracted from the medical insurance system in 7 tertiary public hospitals. An interrupted time series (ITS) was used to analyze the instantaneous level and long-term trend changes of hospitalization expenses per visit from January 2015 to November 2018. Results: A total of 22,407 stroke inpatients were extracted. The total hospitalization expense per visit had the highest proportion of 20,000 CNY and above (33.66%). After the ZMDP, the median total hospitalization expense and western medicine expense per visit decreased by 631.74 CNY and 966.35 CNY, respectively (P <0.001). Before the policy, the total hospitalization expense, traditional Chinese medicine (TCM) expense, examination expense, treatment expense, laboratory expense and surgical expense per visit showed upward trends (P<0.05), while the anesthesia expense per visit showed a downward trend (P<0.001). When the policy was implemented, the anesthesia expense per visit instantaneously increased by 91.70% (P<0.001). After the policy, the total hospitalization expense, western medicine expense, TCM expense, treatment expense and surgical expense per visit changed from upward trends to downward trends (P<0.05). The anesthesia expense per visit changed from a downward trend to an upward trend (P<0.001), and the examination expense per visit maintained an upward trend (P=0.005). Conclusion: The economic burden of stroke inpatients decreased significantly with the implementation of the ZMDP, especially for the drug expenses. The medical service expenses increased significantly, reflecting the improvement in the value of medical staff's technical labor. However, the unexpected increase in the examination expenses was likely to be associated with the unreasonable medical compensation mechanism.

Dimethyl sulfoxide as a gas phase charge-reducing agent for the determination of PEGylated proteins' intact mass.

Determination of PEGylated proteins' intact mass by mass spectrometry is challenging due to the molecules' large size, excessive charges, and instrument limitations. Previous efforts have been reported. However, signal variability, ion coalescence, and a generally low degree of robustness have been observed. In this work, we have explored the capabilities of post-column infusion of dimethyl sulfoxide (DMSO) following reversed-phase liquid chromatography-mass spectrometry (RP-LCMS) to determine PEG-filgrastim' intact mass, and to characterize its PEG moiety. The method was optimized around reproducibility (six preparations, and three injection replicates) with an in-house prepared PEG-filgrastim standard. The method showed a mass accuracy of ≤1.2 Da. The average molecular weight (MWEO=483) was 40 147.9 Da. The number average molecular weight (Mn) and the weight average molecular weight (Mw) were observed to be 40 101.1 and 40 113.9 Da, respectively, both with an RSD of 0.03%. The molecular weight distribution of ethylene oxide (EO), the polydispersity index (PDI), was 1.0003 for all preparations with a minimum and maximum number of EO units of 448 ± 2 and 516 ± 2, respectively. The method was finally applied to commercially available Neulasta® lots where the Mn and Mw were 39 995.8 and 40 008.8 Da, respectively, both with an RSD of 0.1%. The minimum and maximum EO units across the lots were observed to be 444.5 ± 1.5 and 514 ± 3, respectively. The PDI for all Neulasta® lots was 1.0003. This study provides an insightful characterization of Neulasta® and describes a robust LC-MS methodology for the characterization of the PEGylated proteins.

Spinal cord and brain atrophy patterns in neuromyelitis optica spectrum disorder and multiple sclerosis.

BACKGROUND: Spinal cord and brain atrophy are common in neuromyelitis optica spectrum disorder (NMOSD) and relapsing-remitting multiple sclerosis (RRMS) but harbor distinct patterns accounting for disability and cognitive impairment. METHODS: This study included 209 NMOSD and 304 RRMS patients and 436 healthy controls. Non-negative matrix factorization was used to parse differences in spinal cord and brain atrophy at subject level into distinct patterns based on structural MRI. The weights of patterns were obtained using a linear regression model and associated with Expanded Disability Status Scale (EDSS) and cognitive scores. Additionally, patients were divided into cognitive impairment (CI) and cognitive preservation (CP) groups. RESULTS: Three patterns were observed in NMOSD: (1) Spinal Cord-Deep Grey Matter (SC-DGM) pattern was associated with high EDSS scores and decline of visuospatial memory function; (2) Frontal-Temporal pattern was associated with decline of language learning function; and (3) Cerebellum-Brainstem pattern had no observed association. Patients with CI had higher weights of SC-DGM pattern than CP group. Three patterns were observed in RRMS: (1) DGM pattern was associated with high EDSS scores, decreased information processing speed, and decreased language learning and visuospatial memory functions; (2) Frontal-Temporal pattern was associated with overall cognitive decline; and (3) Occipital pattern had no observed association. Patients with CI trended to have higher weights of DGM and Frontal-Temporal patterns than CP group. CONCLUSION: This study estimated the heterogeneity of spinal cord and brain atrophy patterns in NMOSD and RRMS patients at individual level, and evaluated the clinical relevance of these patterns, which may contribute to stratifying participants for targeted therapy.

Characterization of PEGylation sites in Neulasta and a biosimilar candidate with a combined fragmentation strategy in mass spectrometry analysis.

In the development of biosimilar products to Neulasta, it is essential to determine the intact molecular mass and confirm precise PEGylation sites. In this study, we applied a combination of techniques, including post-column addition of triethylamine in reversed-phase liquid chromatography-mass spectrometry (RPLC-MS) to determine the intact molecular mass, and in-source fragmentation (ISF) and higher-energy collision dissociation-tandem mass spectrometry (HCD-MS/MS) to identify the PEGylation site. Our results show that both the pegfilgrastim biosimilar candidate and Neulasta lots are mono-PEGylated at the N-terminal end. Furthermore, we show that the combined ISF and HCD-MS/MS method can be used for identifying the PEGylation sites in the diPEGylated variant of pegfilgrastim. The diPEGylated variant has modification sites at the N-terminal end and a lysine at position 35 in the protein sequence.

Comparative analysis of Herceptin N-Linked glycosylation by HILIC-FLD and LC-MS/MS methods.

Monoclonal antibodies like Herceptin play a pivotal role in modern therapeutics, with their glycosylation patterns significantly influencing their bioactivity. To characterize the N-glycan profile and their relative abundance in Herceptin, we employed two analytical methods: hydrophilic interaction chromatography with fluorescence detection (HILIC-FLD) for released glycans and liquid chromatography tandem mass spectrometry (LC-MS/MS) for glycopeptides. Our analysis included 21 European Union (EU)-Herceptin lots and 14 United States (US)-Herceptin lots. HILIC-FLD detected 25 glycan species, including positional isomers, revealing comparable chromatographic profiles for both EU and US lots. On the other hand, LC-MS/MS identified 26 glycoforms within the glycopeptide EEQYNSTYR. Both methods showed that a subset of glycans dominated the total abundance. Notably, EU-Herceptin lots with an expiration date of October 2022 exhibited increased levels of afucosylated and high mannose N-glycans. Our statistical comparisons showed that the difference in quantitative results between HILIC-FLD and LC-MS/MS is significant, indicating that the absolute quantitative values depend on the choice of the analytical method. However, despite these differences, both methods demonstrated a strong correlation in relative glycan proportions. This study contributes to the comprehensive analysis of Herceptin's glycosylation, offering insights into the influence of analytical methods on glycan quantification and providing valuable information for the biopharmaceutical industry.

Study on the prediction method of grasshopper occurrence risk in Inner Mongolia based on the maximum entropy model during the growing period.

Grasshoppers represent a significant biological challenge in Inner Mongolia's grasslands, severely affecting the region's animal husbandry. Thus, dynamic monitoring of grasshopper infestation risk is crucial for sustainable livestock farming. This study employed the Maxent model, along with remote sensing data, to forecast Oedaleus decorus asiaticus occurrence during the growing season, using grasshopper suitability habitats as a base. The Maxent model's predictive accuracy was high, with an AUC of 0.966. The most influential environmental variables for grasshopper distribution were suitable habitat data (34.27%), the temperature-vegetation dryness index during the spawning period (18.81%), and various other meteorological and vegetation factors. The risk index model was applied to calculate the grasshopper distribution across different risk levels for the years 2019-2022. The data indicated that the level 1 risk area primarily spans central, eastern, and southwestern Inner Mongolia. By examining the variable weights, the primary drivers of risk level fluctuation from 2019 to 2022 were identified as accumulated precipitation and land surface temperature anomalies during the overwintering period. This study offers valuable insights for future O. decorus asiaticus monitoring in Inner Mongolia.

The combination of IL-2 nanoparticles and Palbociclib enhances the anti-tumor immune response for colon cancer therapy.

Immunotherapy of tumors plays a pivotal role in the current treatment of cancer. While interleukin 2 (IL-2) demonstrated its efficacy as an immunotherapeutic drug in the early days, its short blood circulation time poses challenges in maintaining effective therapeutic concentrations. Additionally, IL-2's activation of regulatory T cells can counteract its anti-cancer effects. Therefore, the primary goal of this study was to formulate IL-2-carrying nanoparticles via boron-nitrogen coordination between methoxy poly (ethylene glycol) block poly-[(N-2-hydroxyethyl)-aspartamide]phenylboronic acid (mPEG-b-PHEA-PBA, P-PBA) and poly (L-lysine) (PLL). These nanoparticles are intended to be used in combination with CDK4/6 inhibitors to address the short blood circulation time of IL-2, reduce its immunosuppressive effects, and enhance the overall immune response. The envisaged outcome is a sustained and potent therapeutic effect, offering a novel and promising combination therapy strategy for tumor immunotherapy.

Network of Soil Fungi and the Microfauna Community under Diverse Anthropic Disturbances under Chrysopogon zizanioides Planting in the Reservoir.

The reservoir coastal zone is the transitional zone between the terrestrial ecosystem and the aquatic ecosystem. Soil is an essential part of the terrestrial ecosystem and vital for life on Earth. To understand the composition and diversity of the soil eukaryotic microbial community under the background of artificial planting of Chrysopogon zizanioides in various habitats after reservoir construction, including the original habitat (OH), the hydro-fluctuation belt (HB), and the road slope (RS), and to analyze the interaction between the main groups of eukaryotic microorganisms, this study conducted 18S rDNA amplification high-throughput sequencing of the soil eukaryotic microbial community. The study found that the dominant phylum of eukaryotic microorganisms in the three habitats was consistent, but there were significant differences in the community and diversity of eukaryotic microorganisms in the three habitats. The differences in fungal communities between sample sites were greater than those of soil microfauna. Correlation analysis showed that nitrogen, phosphorus, and organic matter were significantly correlated with eukaryotic microbial diversity, with alkaline-hydrolyzed nitrogen and total phosphorus significantly correlated with fungal communities and pH and water content correlated with soil microfauna. Co-occurrence network analysis found that the interactions between fungi and the correlation between fungi and soil microfauna dominated the eukaryotic microbial community, and the interactions between eukaryotic microbes in different habitats were dominated by positive correlations. After the construction of the reservoir, the newly formed hydro-fluctuation belt reduced the types of interrelationships between fungi and microfauna compared to the original habitat. The road slope provided protection of the supporting project for the reservoir construction, although there was also planted vegetation. Eukaryotic microbes declined significantly due to the damage to and loss of the organic layer, and the decline in microfauna was the most significant, resulting in a simple structure of the soil food web, which affects the function and stability of the soil ecosystem.

The Impact of high-performance work system perceived by medical staff on job satisfaction: the mediating role of self-efficacy.

As the mainstay of healthcare, the job satisfaction of medical staff deserves attention. This study aimed to explore the correlation between the perception of the high-performance work system (P-HPWS) and job satisfaction of medical staff in public hospitals and to further investigate the mediating effect of self-efficacy. From November 2019 to January 2020, a cross-sectional survey on working doctors and nurses was conducted in five tertiary public hospitals in China. A total of 520 participants were surveyed. The P-HPWS, job satisfaction, and self-efficacy were assessed using the 25-item self-administered scale, six-item job satisfaction questionnaire, and the General Self-Efficacy Scale, respectively. Linear regression and mediation effects models were used to identify the associations between primary variables. The results showed a significant positive correlation between P-HPWS and job satisfaction (P < 0.01), while self-efficacy played a mediating role between P-HPWS and job satisfaction. This finding reveals the benefits of improving employees' P-HPWS and self-efficacy on their job satisfaction, and that hospitals can improve their management systems by implementing and refining HPWS.

Survey on occupational injury among workers in a steel enterprise / 预防医学

Objective @#To investigate the prevalence of occupational injury and identify its influencing factors among workers in a steel enterprise in Gansu Province, so as to provide insights into prevention of occupational injury among steel workers. @*Methods@#Workers were sampled from a steel enterprise in Gansu Province using a cluster sampling method from January to March 2022, and participants' demographics, occupational history and occupational injury were collected using questionnaire surveys. The type of job and site and type of injury were analyzed among workers with occupational injuries, and factors affecting workers' occupational injuries were identified using a multivariable logistic regression model. @*Results@#A total of 12 089 questionnaires were allocated and 10 725 valid questionnaires were recovered, with an effective recovery rate of 88.71%. The respondents included 9 412 males (87.77%) and 1 312 females (12.23%), and had a median age of 36.00 (interquartile range, 15.00) years. Junior college and above was the predominant educational level (6 056 workers, 56.47%), and the respondents had a median length of service of 10 (interquartile range, 11) years. The prevalence of occupational injury was 5.25% among respondents. Overhaul worker was the main type of job (11.90%), and object strike was the predominant type of occupational injury (18.25%), while the lower limb was the predominant site of injury (27.82%). Multivariable logistic regression analysis identified men (OR=2.464, 95%CI: 1.580-3.843), age (30 to 39 years, OR=2.561, 95%CI: 1.643-3.993; 40 to 49 years, OR=5.197, 95%CI: 2.679-10.079; 50 years and older, OR=10.620, 95%CI: 6.788-16.615), exposure to high temperature (OR=1.400, 95%CI: 1.165-1.683), operating equipment failure (OR=1.291, 95%CI: 1.048-1.591), absence of personal safety protection equipment (OR=1.555, 95%CI: 1.064-2.273) and safety behavior scores (OR=0.967, 95%CI: 0.937-0.996) as factors affecting occupational injuries among workers in a steel enterprise. @*Conclusions@#Men and overhaul workers are at a high risk of occupational injuries in this steel enterprise. Objectstrike is the predominant type of injury and lower limb is the main site of injury. The risk of occupational injuries is affected by gender, age, working environments, equipment status and safety behaviors.

Immunoswitch Nanomodulators Enable Active Targeting and Selective Proliferation of Regulatory T Cells for Multiple Sclerosis Therapy.

Interleukin-2 (IL-2) used in multiple sclerosis (MS) therapy modulates the balance between regulatory T (Treg) cells and effector T (Teff) cells. However, the off-target activation of Teff cells by IL-2 limits its clinical application. Therefore, a rapidly prepared immunoswitch nanomodulator termed aT-IL2C NPs was developed, which specifically recognized Treg cells with high TIGIT expression thanks to the presence of an anti-TIGIT and an IL-2/JES6-1 complex (IL2C) being delivered to Treg cells but not to Teff cells with low TIGIT expression. Then, IL2C released IL-2 due to the specific expression of the high-affinity IL-2 receptor on Treg cells, thus enabling the active targeting and selective proliferation of Treg cells. Moreover, the anti-TIGIT of aT-IL2C NPs selectively inhibited the proliferation of Teff cells while leaving the proliferation of Treg cells unaffected. In addition, since the IL-2 receptor on Teff cells had medium-affinity, the IL2C hardly released IL-2 to Teff cells, thus enabling the inhibition of Teff cell proliferation. The treatment of experimental autoimmune encephalomyelitis (EAE) mice with aT-IL2C NPs ameliorated the severity of the EAE and restored white matter integrity. Collectively, this work described a potential promising agent for effective MS therapy.

Effects of Yinzhihuang on Alleviating Cyclosporine A-Induced Cholestatic Liver Injury via Farnesoid X Receptor-Mediated Regulation of Transporters and Enzymes in Vitro and in Vivo.

Yinzhihuang (YZH), a traditional Chinese medicine prescription, was widely used to treat cholestasis. Cholestatic liver injury limited the use of the immunosuppressive drug cyclosporine A (CsA) in preventing organ rejection after solid organ transplantation. Clinical evidences suggested that YZH could enhance bile acids and bilirubin clearance, providing a potential therapeutic strategy against CsA-induced cholestasis. Nevertheless, it remains unclear whether YZH can effectively alleviate CsA-induced cholestatic liver injury, as well as the molecular mechanisms responsible for its hepatoprotective effects. The purpose of the present study was to investigate the hepatoprotective effects of YZH on CsA-induced cholestatic liver injury and explore its molecular mechanisms in vivo and vitro. The results demonstrated that YZH significantly improved the CsA-induced cholestatic liver injury and reduced the level of liver function markers in serum of Sprague-Dawley (SD) rats. Targeted protein and gene analysis indicated that YZH increased bile acids and bilirubin efflux into bile through the regulation of multidrug resistance-associated protein 2 (Mrp2), bile salt export pump (Bsep), sodium taurocholate cotransporting polypeptide (Ntcp) and organic anion transporting polypeptide 2 (Oatp2) transport systems, as well as upstream nuclear receptors farnesoid X receptor (Fxr). Moreover, YZH modulated enzymes involved in bile acids synthesis and bilirubin metabolism including Cyp family 7 subfamily A member 1 (Cyp7a1) and uridine 5'-diphosphate (UDP) glucuronosyltransferase family 1 member A1 (Ugt1a1). Furthermore, the active components geniposidic acid, baicalin and chlorogenic acid exerted regulated metabolic enzymes and transporters in LO2 cells. In conclusion, YZH may prevent CsA-induced cholestasis by regulating the transport systems, metabolic enzymes, and upstream nuclear receptors Fxr to restore bile acid and bilirubin homeostasis. These findings highlight the potential of YZH as a therapeutic intervention for CsA-induced cholestasis and open avenues for further research into its clinical applications.

Surface-Enhanced Raman Scattering-Based Surface Chemotaxonomy: Combining Bacteria Extracellular Matrices and Machine Learning for Rapid and Universal Species Identification.

Rapid, universal, and accurate identification of bacteria in their natural states is necessary for on-site environmental monitoring and fundamental microbial research. Surface-enhanced Raman scattering (SERS) spectroscopy emerges as an attractive tool due to its molecule-specific spectral fingerprinting and multiplexing capabilities, as well as portability and speed of readout. Here, we develop a SERS-based surface chemotaxonomy that uses bacterial extracellular matrices (ECMs) as proxy biosignatures to hierarchically classify bacteria based on their shared surface biochemical characteristics to eventually identify six distinct bacterial species at >98% classification accuracy. Corroborating with in silico simulations, we establish a three-way inter-relation between the bacteria identity, their ECM surface characteristics, and their SERS spectral fingerprints. The SERS spectra effectively capture multitiered surface biochemical insights including ensemble surface characteristics, e.g., charge and biochemical profiles, and molecular-level information, e.g., types and numbers of functional groups. Our surface chemotaxonomy thus offers an orthogonal taxonomic definition to traditional classification methods and is achieved without gene amplification, biochemical testing, or specific biomarker recognition, which holds great promise for point-of-need applications and microbial research.

The Effects of Silicone Tube Intubation During Endoscopic Dacryocystorhinostomy in Patients With Acute Dacryocystitis With Acquired Skin Fistulization.

OBJECTIVE: This study aimed to determine the silicone tube intubation requirement for endoscopic dacryocystorhinostomy (En-DCR) in patients with acute dacryocystitis (AD) with acquired skin fistulization. METHODS: Between September 2012 and October 2020, patients with AD and acquired skin fistulization undergoing En-DCR at the Eye Hospital of Wenzhou Medical University were randomized into treatment groups in which silicone tube intubation was carried out or not (groups A and B, respectively). All patients with skin fistulae present for 1+ months at En-DCR underwent fistulectomy. Operative success was assessed at 12 months post En-DCR in both treatment groups. Multiple logistic analyses were performed to assess for influencing factors on surgical success. RESULTS: This study evaluated 94 patients for whom complete postoperative data were available, including 45 in group A and 44 in group B. Overall, 15 patients underwent fistulectomy and En-DCR simultaneously (8 from group A; 7 from group B ). At 12-month follow-up, anatomic and functional success rates were higher for patients in group A (93.3%, 86.7%) relative to those in group B (77.3%, 68.2%) (P<0.05). Intranasal ostium obstruction caused lacrimal passage reconstruction failure in group A. In contrast, intranasal ostium and canalicular obstruction caused it in patients in group B. No significant variations in operation success rates across groups were seen when group B cases with canalicular obstruction were eliminated from the analyses (P=0.070, >0.05). Multiple logistic regression analysis showed operative success was significantly influenced by fistulectomy (OR: 1.641, P<0.05) and intubation (OR: -1.559, P<0.05). CONCLUSION: These findings imply that in patients with AD with skin fistulization undergoing En-DCR, intraoperative intubation is linked with a lower incidence of canalicular obstruction and positive outcomes. Accordingly, intraoperative intubation should be performed when operating on patients with AD with skin fistulization.

Male and female are not the same: a multicenter study of static and dynamic functional connectivity in relapse-remitting multiple sclerosis in China.

Background: Sex-related effects have been observed in relapsing-remitting multiple sclerosis (RRMS), but their impact on functional networks remains unclear. Objective: To investigate the sex-related differences in connectivity strength and time variability within large-scale networks in RRMS. Methods: This is a multi-center retrospective study. A total of 208 RRMS patients (135 females; 37.55 ± 11.47 years old) and 228 healthy controls (123 females; 36.94 ± 12.17 years old) were included. All participants underwent clinical and MRI assessments. Independent component analysis was used to extract resting-state networks (RSNs). We assessed the connectivity strength using spatial maps (SMs) and static functional network connectivity (sFNC), evaluated temporal properties and dynamic functional network connectivity (dFNC) patterns of RSNs using dFNC, and investigated their associations with structural damage or clinical variables. Results: For static connectivity, only male RRMS patients displayed decreased SMs in the attention network and reduced sFNC between the sensorimotor network and visual or frontoparietal networks compared with healthy controls [P<0.05, false discovery rate (FDR) corrected]. For dynamic connectivity, three recurring states were identified for all participants: State 1 (sparse connected state; 42%), State 2 (middle-high connected state; 36%), and State 3 (high connected state; 16%). dFNC analyses suggested that altered temporal properties and dFNC patterns only occurred in females: female patients showed a higher fractional time (P<0.001) and more dwell time in State 1 (P<0.001) with higher transitions (P=0.004) compared with healthy females. Receiver operating characteristic curves revealed that the fraction time and mean dwell time of State 1 could significantly distinguish female patients from controls (area under the curve: 0.838-0.896). In addition, female patients with RRMS also mainly showed decreased dFNC in all states, particularly within cognitive networks such as the default mode, frontoparietal, and visual networks compared with healthy females (P < 0.05, FDR corrected). Conclusion: Our results observed alterations in connectivity strength only in male patients and time variability in female patients, suggesting that sex-related effects may play an important role in the functional impairment and reorganization of RRMS.

Achieving Molecular Recognition of Structural Analogues in Surface-Enhanced Raman Spectroscopy: Inducing Charge and Geometry Complementarity to Mimic Molecular Docking.

Molecular recognition of complex isomeric biomolecules remains challenging in surface-enhanced Raman scattering (SERS) spectroscopy due to their small Raman cross-sections and/or poor surface affinities. To date, the use of molecular probes has achieved excellent molecular sensitivities but still suffers from poor spectral specificity. Here, we induce "charge and geometry complementarity" between probe and analyte as a key strategy to achieve high spectral specificity for effective SERS molecular recognition of structural analogues. We employ 4-mercaptopyridine (MPY) as the probe, and chondroitin sulfate (CS) disaccharides with isomeric sulfation patterns as our proof-of-concept study. Our experimental and in silico studies reveal that "charge and geometry complementarity" between MPY's binding pocket and the CS sulfation patterns drives the formation of site-specific, multidentate interactions at the respective CS isomerism sites, which "locks" each CS in its analogue-specific complex geometry, akin to molecular docking events. Leveraging the resultant spectral fingerprints, we achieve > 97 % classification accuracy for 4 CSs and 5 potential structural interferences, as well as attain multiplex CS quantification with < 3 % prediction error. These insights could enable practical SERS differentiation of biologically important isomers to meet the burgeoning demand for fast-responding applications across various fields such as biodiagnostics, food and environmental surveillance.

hoxa1a-Null Zebrafish as a Model for Studying HOXA1-Associated Heart Malformation in Bosley-Salih-Alorainy Syndrome.

Mutations in HOXA1 can lead to diseases such as Bosley-Salih-Alorainy syndrome, involving severe cardiovascular malformations. However, the role of HOXA1 in cardiac morphogenesis remains unclear. hoxa1a is a homologous gene to human HOXA1 in zebrafish. We used CRISPR to make hoxa1a-null zebrafish that exhibited multiple heart malformations. In situ hybridization and sections revealed the morphological changes in mutants: enlarged ventricle with thickened myocardium and increased trabeculae, intensified OFT and inadequate heart looping, with electrocardiography supporting these pathological changes. High-speed photography captured cardiac pumping and revealed a significant decrease in cardiac output. Furthermore, lacking hoxa1a led to posterior body abnormality that affected movement ability, corresponding with the motor development delay in patients. Upregulation of hox paralogues in hoxa1a-null fish implied a compensatory mechanism between hox genes. Accordingly, we successfully constructed a hoxa1a-null model with a cardiac disease pattern which occurred in human HOXA1-associated heart malformation. The study of hoxa1a in zebrafish can further promote the understanding of hox genes and related diseases.

[Effects of Fertilizer Application Strategy Adjustments on Nitrogen and Phosphorus Loss from Typical Crop Systems in Taihu Lake Region].

The intensity of crop farming fertilizer input is generally high in the Taihu Lake Region, with chemical fertilizer as the main form. Due to inappropriate fertilizer application, nitrogen and phosphorus loss have occurred, causing serious agricultural non-point source pollution. The Ministry of Agriculture and Rural Affairs of China has launched the "zero-growth action for chemical fertilizer use" and "replacement action with organic fertilizer" ("two actions" for short) campaigns since 2015. Local agricultural sectors adjusted fertilizer application strategies of crop farming to respond to the call of two actions. However, the current research is still focusing on reducing the total amount of fertilizer application and increasing the area of organic fertilizer application, which is mainly based on grain crops. The study of agricultural environment problems is still lacking, especially in vegetable, orchard, and tea systems. Therefore, a study was carried out in the typical agricultural area of Suzhou City Wuzhong District from 2019 to 2021. Based on the data of the amount of nitrogen and phosphorus removal by harvest crops and soil nitrogen and phosphorus residual in paddy, vegetable, orchard, and tea systems, the loss was estimated. The responses of nitrogen and phosphorus loss from typical crop systems to fertilizer application strategy adjustments were studied through analysis of different factors. The results showed that fertilizer application rate was the key to control nitrogen and phosphorus loss. Additionally, the suitable replacement ratio of organic fertilizer could further reduce the loss risk. It should be noted that the urgent demand for nutrients in crop growth should be considered to determine the timing of organic fertilizer application, and agricultural machinery should be used to assist organic fertilizer application to reduce labor output if possible. Fertilizer efficiency was the core of environmental friendliness and economic benefits of crop farming. Hence, improving fertilizer efficiency should be the guidance of fertilizer application strategy adjustment. Our suggestions on the adjustment of fertilizer application strategy in different crop systems in the study area are as follows:attention should be paid to the nitrogen, phosphorus, and potassium input ratio in paddy systems to further reduce nitrogen and phosphorus loss. Planting structure adjustment should be emphasized in vegetable systems to promote fertilizer efficiency. The strategy to satisfy both tea and orchard growth from a composite system perspective would help to build crop systems that meet the needs of green agricultural development.

Non-Pharmacological Interventions in Patients With Heart Failure With Reduced Ejection Fraction: A Systematic Review and Network Meta-Analysis.

OBJECTIVE: To determine the effectiveness of non-pharmacologic interventions and the additional benefits of their combination in patients with heart failure with reduced ejection fraction (HFrEF). DATA SOURCES: We searched PubMed, Embase, and the Cochrane Clinical Trials Register from the date of database inception to April 22, 2023. STUDY SELECTION: Randomized controlled trials involving non-pharmacologic interventions conducted in patients with HFrEF were included. DATA EXTRACTION: Data were extracted by 2 independent reviewers based on a pre-tested data extraction form. The quality of evidence was assessed using the Cochrane Risk of Bias tool and the Grading of Recommendations Assessment, Development, and Evaluation method. DATA SYNTHESIS: A total of 82 eligible studies (4574 participants) were included. We performed a random-effects model within a Bayesian framework to calculate weighted mean differences (WMDs) and 95% credibility intervals. High or moderate certainty evidence indicated that high-intensity aerobic interval training (HIAIT) was best on improving 6-minute walk distance (6MWD; 68.55 m [36.41, 100.47]) and left ventricular ejection fraction (6.28% [3.88, 8.77]), while high-intensity aerobic continuous training (HIACT) is best on improving peak oxygen consumption (Peak VO2; 3.48 mL/kg•min [2.84, 4.12]), quality of life (QOL; -17.26 [-29.99, -7.80]), resting heart rate (-8.20 bpm [-13.32, -3.05]), and N-terminal pro-B-type natriuretic peptide (-600.96 pg/mL [-902.93, -404.52]). Moderate certainty evidence supported the effectiveness of inspiratory muscle training to improve peak oxygen consumption and functional electrical stimulation to improve QOL. Moderate-intensity aerobic continuous training (MIACT) plus moderate-intensity resistance training (MIRT) had additional benefits in Peak VO2, 6MWD, and QOL. This review did not provide a comprehensive evaluation of adverse events. CONCLUSIONS: Both HIAIT and HIACT are the most effective single non-pharmacologic interventions for HFrEF. MIACT plus MIRT had additional benefits in improving peak oxygen consumption, 6MWD, and QOL.