Therapeutic Applications of Nanomedicine: Recent Developments and Future Perspectives.

The concept of nanomedicine has evolved significantly in recent decades, leveraging the unique phenomenon known as the enhanced permeability and retention (EPR) effect. This has facilitated major advancements in targeted drug delivery, imaging, and individualized therapy through the integration of nanotechnology principles into medicine. Numerous nanomedicines have been developed and applied for disease treatment, with a particular focus on cancer therapy. Recently, nanomedicine has been utilized in various advanced fields, including diagnosis, vaccines, immunotherapy, gene delivery, and tissue engineering. Multifunctional nanomedicines facilitate concurrent medication delivery, therapeutic monitoring, and imaging, allowing for immediate responses and personalized treatment plans. This review concerns the major advancement of nanomaterials and their potential applications in the biological and medical fields. Along with this, we also mention the various clinical translations of nanomedicine and the major challenges that nanomedicine is currently facing to overcome the clinical translation barrier.

Geochemical Characteristics of Trace Elements and Mineralization Model of the Ediacaran-Early Cambrian Phosphorites, South China.

As a nonrenewable resource, phosphate rock is an important support for the development and survival of the national economy. The regional distribution and output of phosphate rock in China are extremely uneven, and the amount of high-quality ore resources is relatively poor, which seriously restricts the development and utilization of phosphate rock resources in China. This paper briefly summarizes the distribution characteristics of phosphate rock resources and summarizes the characteristics and research progress of Ediacaran-early Cambrian phosphorus mineralization types, geological characteristics, and deposit genesis of the Yangtze platform in South China. The Ediacaran-early Cambrian sedimentary phosphorite deposits in China are mainly distributed in Yunnan, Guizhou, Hubei, Sichuan and Hunan provinces of the Yangtze platform, in which the early Cambrian phosphate deposits are also rich in rare earth elements, associated with uranium, nickel, molybdenum, vanadium, and other beneficial metal elements. The increase of atmospheric oxygen content at the Ediacaran-Cambrian boundary may have promoted the extensive oxygenation of the late Neoproterozoic oceans, so the Ediacaran-early Cambrian oceans generally showed a reductive environment, and there may be dynamic chemical stratification of the oxidation zone-sulfide zone-iron zone. Up to the early Cambrian, the redox stratified structure of Precambrian seawater may still be inherited, showing that the surface water is an oxidizing environment, changing to a reduction environment, and even wedge-shaped sulfide water is developed at the bottom of the deep basin. The main phosphorus sources are deep phosphorus-rich seawater, continental weathering, and deep hydrothermal activity of Ediacaran-early Cambrian marine sedimentary phosphorite deposits in South China. The genetic mechanisms of phosphorite deposits in the Yangtze platform in South China are mainly biogenic, upwelling phosphorus-forming theory, mechanical mineralization, and syn-sedimentary hot water mixed genesis. In the future, it is still necessary to further explore the internal relationship between phosphorus deposits and major geological events, the in situ analysis of microstructure of phosphate rock ores, and the genetic mechanism of phosphate deposits and the reconstruction of paleo-marine environment.

Association between body mass index and medication-overuse headache among individuals with migraine: a cross-sectional study.

INTRODUCTION: Medication-overuse headache (MOH) is a secondary chronic headache disorder that occurs in individuals with a pre-existing primary headache disorder, particularly migraine disorder. Obesity is often combined with chronic daily headaches and is considered a risk factor for the transformation of episodic headaches into chronic headaches. However, the association between obesity and MOH among individuals with migraine has rarely been studied. The present study explored the association between body mass index (BMI) and MOH in people living with migraine. METHODS: This cross-sectional study is a secondary analysis of data from the Survey of Fibromyalgia Comorbidity with Headache study. Migraine and MOH were diagnosed using the criteria of the International Classification of Headache Disorders, 3rd edition. BMI (kg/m2) is calculated by dividing the weight (kg) by the square of the height (m). Multivariable logistic regression analysis was used to evaluate the association between BMI and MOH. RESULTS: A total of 2,251 individuals with migraine were included, of whom 8.7% (195/2,251) had a concomitant MOH. Multivariable logistic regression analysis, adjusted for age, sex, education level, headache duration, pain intensity, headache family history, chronic migraine, depression, anxiety, insomnia, and fibromyalgia, demonstrated there was an association between BMI (odds ratio [OR], 1.05; 95% confidence interval [CI], 1.01-1.11; P = 0.031) and MOH. The results remained when the BMI was transformed into a category. Compared to individuals with Q2 (18.5 kg/m2 ≤ BMI ≤ 23.9 kg/m2), those with Q4 (BMI ≥ 28 kg/m2) had an adjusted OR for MOH of 1.81 (95% CI, 1.04-3.17; P = 0.037). In the subgroup analyses, BMI was associated with MOH among aged more than 50 years (OR, 1.13; 95%, 1.03-1.24), less than high school (OR, 1.08; 95%, 1.01-1.15), without depression (OR, 1.06; 95%, 1.01-1.12), and without anxiety (OR, 1.06; 95%, 1.01-1.12). An association between BMI and MOH was found in a sensitivity analysis that BMI was classified into four categories according to the World Health Organization guidelines. CONCLUSION: In this cross-sectional study, BMI was associated with MOH in Chinese individuals with migraine.

Simulation of Dispersion and Explosion Characteristics of LiFePO4 Lithium-Ion Battery Thermal Runaway Gases.

In recent years, as the installed scale of battery energy storage systems (BESS) continues to expand, energy storage system safety incidents have been a fast-growing trend, sparking widespread concern from all walks of life. During the thermal runaway (TR) process of lithium-ion batteries, a large amount of combustible gas is released. In this paper, the 105 Ah lithium iron phosphate battery TR test was conducted, and the flammable gas components released from the battery TR were detected. The simulation tests of the diffusion and explosion characteristics of lithium iron phosphate battery's (LFP) TR gases with different numbers and positions in the BESS were carried out using FLACS simulation software. It was found that the more batteries TR simultaneously, the shorter the time for the combustible gas concentration in the energy storage cabin to reach the explosion limit. When 48 batteries were in TR simultaneously in the energy storage cabin, the shortest time was 9.8 s, and the further the location of the fire is from the hatch, the largest explosion overpressure is generated to the hatch, up to 583 kPa. When the gas generated by the TR of 48 batteries explodes, the maximum explosion overpressure at 5 m outside the energy storage cabin hatch is more significant than 40 kPa, which will cause serious injury to humans. The causes of TR of batteries in prefabricated chambers are complex, and the location and amount of thermal runaway of batteries as well as the diffusion of combustible fumes can have different effects on the external environment. The research results can provide support for the safety design of BESS.

Rimegepant orally disintegrating tablet 75 mg for acute treatment of migraine in adults from China: a subgroup analysis of a double-blind, randomized, placebo-controlled, phase 3 clinical trial.

BACKGROUND: Rimegepant orally disintegrating tablet (ODT), an oral small-molecule calcitonin gene-related peptide receptor antagonist, is indicated for acute and preventive treatment of migraine in the United States and other countries. Previously, a large clinical trial assessed the efficacy and safety of rimegepant ODT 75 mg for the acute treatment of migraine in adults living in China or South Korea. A post hoc subgroup analysis of this trial was performed to evaluate the efficacy and safety of rimegepant for acute treatment of migraine in adults living in China. METHODS: Eligible participants were ≥ 18 years of age and had a ≥ 1-year history of migraine, with 2 to 8 attacks of moderate or severe pain intensity per month and < 15 headache days per month during the 3 months before screening. Participants self-administered rimegepant ODT 75 mg or matching placebo to treat a single migraine attack of moderate or severe pain intensity. The co-primary endpoints were pain freedom and freedom from the most bothersome symptom (MBS) at 2 h post-dose. Key secondary endpoints included pain relief at 2 h post-dose, ability to function normally at 2 h post-dose, use of rescue medication within 24 h post-dose, and sustained pain freedom from 2 to 24 h and 2 to 48 h post-dose. All p values were nominal. Safety was assessed via treatment-emergent adverse events (TEAEs), electrocardiograms, vital signs, and routine laboratory tests. RESULTS: Overall, 1075 participants (rimegepant, n = 538; placebo, n = 537) were included in the subgroup analysis. Rimegepant was more effective than placebo for the co-primary endpoints of pain freedom (18.2% vs. 10.6%, p = 0.0004) and freedom from the MBS (48.0% vs. 31.8%, p <  0.0001), as well as all key secondary endpoints. The incidence of TEAEs was comparable between the rimegepant (15.2%) and placebo (16.4%) groups. No signal of drug-induced liver injury was observed, and no study drug-related serious TEAEs were reported in the rimegepant group. CONCLUSIONS: A single dose of rimegepant 75 mg rimegepant was effective for the acute treatment of migraine in adults living in China, with safety and tolerability similar to placebo. TRIAL REGISTRATION: Clinicaltrials.gov NCT04574362 Date registered: 2020-10-05.

Artificial Intelligence-Driven Platform: Unveiling Critical Hepatic Molecular Alterations in Hepatocellular Carcinoma Development.

Since most Hepatocellular Carcinoma (HCC) typically arises as a consequence of long-term liver damage, the hepatic molecular characteristics are closely related to the occurrence of HCC. Gaining comprehensive information about the location, morphology, and hepatic molecular alterations related to HCC is essential for accurate diagnosis. However, there is a dearth of technological advancements capable of concurrently providing precise HCC diagnosis and discerning the accompanying hepatic molecular alterations. In this study, an integrated information system is developed for the pathological-level diagnosis of HCC and the revelation of critical molecular alterations in the liver. This system utilizes computed tomography/Surface-enhanced Raman scattering combined with an artificial intelligence strategy to establish connections between the occurrence of HCC and alterations in hepatic biomolecules. Employing artificial intelligence techniques, the SERS spectra from both healthy and HCC groups are successfully classified into two distinct categories with a remarkable accuracy rate of 91.38%. Based on molecular profiling, it is identified that the nucleotide-to-lipid signal ratio holds significant potential as a reliable indicator for the occurrence of HCC, thereby serving as a promising tool for prevention and therapeutic surveillance.

Urban-canopy airflow dynamics: A numerical investigation of drag forces and distribution for generic neighborhoods, and their relationships with breathability.

Thorough investigations of urban-canopy drag primarily stemming from pressure drag on building surfaces are necessary given the turbulent flows within complex urban areas. Moreover, a gap persists regarding the relationships between canopy drag and breathability. Therefore, this work delves into the canopy-layer airflow dynamics for generic urban neighborhoods by performing three-dimensional Reynolds-Averaged Navier-Stokes simulations. A total of 32 subcases are examined, encompassing uniform- and varying-height and diverse plan area densities (λp, categorized into groups of sparse: 0.0625/0.067, medium: 0.23/0.25, and dense: 0.53/0.56). Results for the drag distribution highlight the windward-row shelter effect for the medium and the dense, local shelter by taller buildings, and distinct shapes of sectional drag forces (F⁎Z). Local velocity and mean age of air are found strongly positively and negatively correlated to F⁎Z, respectively, with distinct slopes in relation to λp. For the uniform-height, the normalized bulk drag (F⁎bulk, referred to as drag coefficient in literature) peaks for the medium with wake-interference regime; F⁎bulk demonstrates a maximum increase of over two times with height variation; moreover, F⁎bulk for varying-height groups exhibits a marked increase from the sparse to the medium, while remaining comparable values for the dense. The frontal area averaged drag (FAf,ave) exhibits a decreasing trend against λp across all cases. Further, FAf,ave exhibits strong correlations with λp and porosity, and with bulk ventilation indices such as spatially averaged velocity, air change rate, and normalized net escape velocity. Throughout the 'suburban-urban-suburban' canopy, medium neighborhoods exerting larger drag cause greater streamwise outdoor pressure drops and flow reductions compared to the sparse. However, dense neighborhoods with lower drag exhibit even larger pressure losses, which should be carefully scrutinized. The findings can inform urban planners in designing more aerodynamically efficient neighborhoods and guide strategies for improving air quality within urban environments.

Profile of Chinese Cluster Headache Register Individual Study (CHRIS): Clinical characteristics, diagnosis and treatment status data of 816 patients in China.

BACKGROUND: The clinical profile of cluster headache may differ among different regions of the world, warranting interest in the data obtained from the initial Chinese Cluster Headache Register Individual Study (CHRIS) for better understanding. METHODS: We conducted a multicenter, prospective, longitudinal cohort study on cluster headache across all 31 provinces of China, aiming to gather clinical characteristics, treatment approaches, imaging, electrophysiological and biological samples. RESULTS: In total 816 patients were enrolled with a male-to-female ratio of 4.33:1. The mean age at consultation was 34.98 ± 9.91 years, and 24.89 ± 9.77 years at onset. Only 2.33% were diagnosed with chronic cluster headache, and 6.99% had a family history of the condition. The most common bout was one to two times per year (45.96%), lasting two weeks to one month (44.00%), and occurring frequently in spring (76.23%) and winter (73.04%). Of these, 68.50% experienced one to two attacks per day, with the majority lasting one to two hours (45.59%). The most common time for attacks was between 9 am and 12 pm (75.86%), followed by 1 am and 3 am (43.48%). Lacrimation (78.80%) was the most predominant autonomic symptom reported. Furthermore, 39.22% of patients experienced a delay of 10 years or more in receiving a correct diagnosis. Only 35.67% and 24.26% of patients received common acute and preventive treatments, respectively. CONCLUSION: Due to differences in ethnicity, genetics and lifestyle conditions, CHRIS has provided valuable baseline data from China. By establishing a dynamic cohort with comprehensive multidimensional data, it aims to advance the management system for cluster headache in China.

Short-distance vesicle transport via phase separation.

In addition to long-distance molecular motor-mediated transport, cellular vesicles also need to be moved at short distances with defined directions to meet functional needs in subcellular compartments but with unknown mechanisms. Such short-distance vesicle transport does not involve molecular motors. Here, we demonstrate, using synaptic vesicle (SV) transport as a paradigm, that phase separation of synaptic proteins with vesicles can facilitate regulated, directional vesicle transport between different presynaptic bouton sub-compartments. Specifically, a large coiled-coil scaffold protein Piccolo, in response to Ca2+ and via its C2A domain-mediated Ca2+ sensing, can extract SVs from the synapsin-clustered reserve pool condensate and deposit the extracted SVs onto the surface of the active zone protein condensate. We further show that the Trk-fused gene, TFG, also participates in COPII vesicle trafficking from ER to the ER-Golgi intermediate compartment via phase separation. Thus, phase separation may play a general role in short-distance, directional vesicle transport in cells.

Three-Dimensional Reconfigurable Optical Singularities in Bilayer Photonic Crystals.

Metasurfaces and photonic crystals have revolutionized classical and quantum manipulation of light and opened the door to studying various optical singularities related to phases and polarization states. However, traditional nanophotonic devices lack reconfigurability, hindering the dynamic switching and optimization of optical singularities. This paper delves into the underexplored concept of tunable bilayer photonic crystals (BPhCs), which offer rich interlayer coupling effects. Utilizing silicon nitride-based BPhCs, we demonstrate tunable bidirectional and unidirectional polarization singularities, along with spatiotemporal phase singularities. Leveraging these tunable singularities, we achieve dynamic modulation of bound-state-in-continuum states, unidirectional guided resonances, and both longitudinal and transverse orbital angular momentum. Our work paves the way for multidimensional control over polarization and phase, inspiring new directions in ultrafast optics, optoelectronics, and quantum optics.

A pilot study on a patient with refractory headache: Personalized deep brain stimulation through stereoelectroencephalography.

The integration of stereoelectroencephalography with therapeutic deep brain stimulation (DBS) holds immense promise as a viable approach for precise treatment of refractory disorders, yet it has not been explored in the domain of headache or pain management. Here, we implanted 14 electrodes in a patient with refractory migraine and integrated clinical assessment and electrophysiological data to investigate personalized targets for refractory headache treatment. Using statistical analyses and cross-validated machine-learning models, we identified high-frequency oscillations in the right nucleus accumbens as a critical headache-related biomarker. Through a systematic bipolar stimulation approach and blinded sham-controlled survey, combined with real-time electrophysiological data, we successfully identified the left dorsal anterior cingulate cortex as the optimal target for the best potential treatment. In this pilot study, the concept of the herein-proposed data-driven approach to optimizing precise and personalized treatment strategies for DBS may create a new frontier in the field of refractory headache and even pain disorders.

Levistilide A Exerts a Neuroprotective Effect by Suppressing Glucose Metabolism Reprogramming and Preventing Microglia Polarization Shift: Implications for Parkinson's Disease.

The microglia, displaying diverse phenotypes, play a significant regulatory role in the development, progression, and prognosis of Parkinson's disease. Research has established that glycolytic reprogramming serves as a critical regulator of inflammation initiation in pro-inflammatory macrophages. Furthermore, the modulation of glycolytic reprogramming has the potential to reverse the polarized state of these macrophages. Previous studies have shown that Levistilide A (LA), a phthalide component derived from Angelica sinensis, possesses a range of pharmacological effects, including anti-inflammatory, antioxidant, and neuroprotective properties. In our study, we have examined the impact of LA on inflammatory cytokines and glucose metabolism in microglia induced by lipopolysaccharide (LPS). Furthermore, we explored the effects of LA on the AMPK/mTOR pathway and assessed its neuroprotective potential both in vitro and in vivo. The findings revealed that LA notably diminished the expression of M1 pro-inflammatory factors induced by LPS in microglia, while leaving M2 anti-inflammatory factor expression unaltered. Additionally, it reduced ROS production and suppressed IκB-α phosphorylation levels as well as NF-κB p65 nuclear translocation. Notably, LA exhibited the ability to reverse microglial glucose metabolism reprogramming and modulate the phosphorylation levels of AMPK/mTOR. In vivo experiments further corroborated these findings, demonstrating that LA mitigated the death of TH-positive dopaminergic neurons and reduced microglia activation in the ventral SNpc brain region of the midbrain and the striatum. In summary, LA exhibited neuroprotective benefits by modulating the polarization state of microglia and altering glucose metabolism, highlighting its therapeutic potential.

[Network Meta-analysis of Chinese patent medicines in treatment of coronary heart disease complicated with heart failure].

The efficacy and safety of different Chinese patent medicines in the treatment of coronary heart disease complicated with heart failure were evaluated by network Meta-analysis. The randomized controlled trial(RCT) of Chinese patent medicines for coronary heart disease complicated with heart failure was retrieved from CNKI, Wanfang, VIP, SinoMed, PubMed, Web of Science, EMbase, and Cochrane Library with the time interval from inception to July 5, 2023. The quality of the included RCT was evaluated by the Cochrane's risk of bias assessment tool, and a network Meta-analysis was performed in Stata 16.0. Finally, a total of 82 RCTs were included, involving 9 298 patients and 11 Chinese patent medicines. Network Meta-analysis yielded the following results based on the surface under the cumulative ranking curve(SUCRA).(1)In terms of improving the clinical response rate, the top three interventions were Qishen Yiqi Dripping Pills + conventional western medicine, Zhenyuan Capsules + conventional western medicine, and Tongxinluo Capsules + conventional western medicine.(2) In terms of increasing left ventricular ejection fraction(LVEF), the top three interventions were Shexiang Baoxin Pills + conventional western medicine, Compound Danshen Dripping Pills + conventional western medicine, and Tongxinluo Capsules + conventional western medicine.(3) In terms of reducing left ventricular end-diastolic diameter(LVEDD), the top three interventions were Shexiang Tongxin Dripping Pills + conventional western medicine, Tongxinluo Capsules + conventional western medicine, and Shexiang Baoxin Pills + conventional western medicine.(4) In terms of reducing N-terminal pro-brain natriuretic peptide(NT-proBNP), the top three interventions were Shexiang Baoxin Pills + conventional western medicine, Qi-shen Yiqi Dripping Pills + conventional western medicine, and Compound Danshen Dripping Pills + conventional western medicine.(5) In terms of reducing hyper-sensitive C-reactive protein(hs-CRP), the top three interventions were Naoxintong Capsules + conventional western medicine, Shexiang Baoxin Pills + conventional western medicine, and Compound Danshen Dripping Pills + conventional western medicine.(6) In terms of increasing the distance of the six-minute walking trail(6MWT), the top three interventions were Zhen-yuan Capsules + conventional western medicine, Qili Qiangxin Capsules + conventional western medicine, and Qishen Yiqi Dripping Pills + conventional western medicine. The results showed that Chinese patent medicines combined with conventional western medicine can effectively improve the clinical response rate, LVEF, and 6MWT and reduce LVEDD, NT-proBNP, and hs-CRP. However, due to the overall low quality of the articles included and the few articles of some Chinese patent medicines, direct comparison between diffe-rent Chinese patent medicines remains to be carried out and the results need to be further verified.

Self-Powered Dual-Band Electrochromic Supercapacitor Devices for Smart Window Based on Ternary Dielectric Triboelectric Nanogenerator.

A dual-band electrochromic supercapacitor device (DESCD) can be driven by an external power supply to modulate solar radiation, which is a promising energy-saving strategy and has broad application prospects in smart windows. However, traditional power supplies, such as batteries, supercapacitors, etc., usually face limited lifetimes and potential environmental issues. Hence, we propose a self-powered DESCD based on TiO2/WO3 dual-band electrochromic material and a ternary dielectric rotating triboelectric nanogenerator (TDR-TENG). The TDR-TENG can convert mechanical energy from the environment into electrical energy to obtain a high output of 840 V, 23.9 µA, and 327 nC. The as-prepared TDR-TENG can drive the TiO2/WO3 film to store energy with a high dual-band modulation amplitude of 41.6% in the visible (VIS) region and 84% in the near-infrared (NIR) region, decreasing the indoor-outdoor light-heat interaction and thereby reducing the building energy consumption. The self-powered DESCD demonstrated in this study has multiple functions of energy harvesting, energy storage, and energy saving, providing a promising strategy for the development of self-powered smart windows.

Phosphorylation-dependent membraneless organelle fusion and fission illustrated by postsynaptic density assemblies.

Membraneless organelles formed by phase separation of proteins and nucleic acids play diverse cellular functions. Whether and, if yes, how membraneless organelles in ways analogous to membrane-based organelles also undergo regulated fusion and fission is unknown. Here, using a partially reconstituted mammalian postsynaptic density (PSD) condensate as a paradigm, we show that membraneless organelles can undergo phosphorylation-dependent fusion and fission. Without phosphorylation of the SAPAP guanylate kinase domain-binding repeats, the upper and lower layers of PSD protein mixtures form two immiscible sub-compartments in a phase-in-phase organization. Phosphorylation of SAPAP leads to fusion of the two sub-compartments into one condensate accompanied with an increased Stargazin density in the condensate. Dephosphorylation of SAPAP can reverse this event. Preventing SAPAP phosphorylation in vivo leads to increased separation of proteins from the lower and upper layers of PSD sub-compartments. Thus, analogous to membrane-based organelles, membraneless organelles can also undergo regulated fusion and fission.

Does sacubitril/valsartan work in children with heart failure?-a pilot study.

Background: Sacubitril/valsartan is an angiotensin receptor neprilysin antagonist (ARNI) approved for adult heart failure (HF). Its safety and efficacy in pediatric HF patients with cardiomyopathy or congenital heart disease are poorly understood. A pilot study was conducted to assess the clinical response, efficacy and safety of sacubitril/valsartan in this population at a tertiary care hospital in China. Methods: Clinical parameters of patients who received sacubitril/valsartan from January 2019 to March 2023 were retrospectively collected and analyzed. Children over 1 month with a left ventricular ejection fraction (LVEF) <45% were included. Clinical efficacy was evaluated by echocardiographic LVEF, N-terminal pro-brain natriuretic peptide (NT-proBNP), New York Heart Association (NYHA) HF classification, HF re-admission, and death or transplantation. The initial dose was either 0.2 mg/kg bid or 0.4 mg/kg bid, with a target dose of 2.3 mg/kg bid or 3.1 mg/kg bid. Results: Forty-five patients (60% male) with a median age of 7.86 years were enrolled. Among them, 23 had congenital heart disease and 22 had cardiomyopathies. The median maintenance dose was 0.76 mg/kg. The primary endpoint of LVEF up to 45% was reached by 24 patients (53.3%). The median NT-proBNP was significantly decreased from 5,501.5 pg/ml to 2,241.5 pg/ml (P < 0.001), more in congenital heart disease than in cardiomyopathies (P = 0.032). The NYHA HF class was improved or remained stable in 42 cases (93.3%). During a median follow-up of 1.23 years, 13 patients (28.9%) were re-hospitalized due to HF, and 9 patients (20%) died or underwent transplantation. Hypotension was the main adverse event, occurring in 8 patients. Conclusions: Sacubitril/valsartan may be effective in children with HF, but its safety and outcomes may differ depending on the etiology and anatomy of HF. Early post-operative congenital heart disease patients had less tolerance, more hypotension but better recovery and outcomes, while mid- and late- post-operative congenital heart disease patients and cardiomyopathy patients had less side effects but poorer clinical outcomes.

[Outcome indicators in clinical trials on traditional Chinese medicine treatment of microvascular angina].

This study reviewed the current status of the use of outcome indicators in randomized controlled trial(RCT) on traditional Chinese medicine(TCM) treatment of microvascular angina(MVA) and analyzed the existing problems and possible solutions, aiming to provide a basis for the design of high-quality RCT and the establishment of core outcome sets for MVA. CNKI, Wanfang, VIP, SinoMed, PubMed, EMbase, Cochrane Library, Web of Science, and 2 clinical trial registries were searched for the RCT on TCM treatment of MVA according to pre-defined criteria. The Cochrane's risk of bias assessment tool was used to evaluate the methodological quality of the included RCT and the use of outcome indicators was summarized. A total of 69 RCTs were included, from which 100 outcome indicators were extracted, with the frequency of 430. The extracted outcome indicators belonged to 8 domains: response rate, symptoms and signs, physical and chemical examinations, TCM efficacy, safety, quality of life, economic evaluation, and long-term prognosis. The indicators of physical and chemical examinations were the most(70 indicators with the frequency of 211), followed by those of response rate(7 indicators with the frequency of 73) and symptoms and signs(7 indicators with the frequency of 54). The outcome indicators with higher frequency were adverse reactions, angina attack frequency, clinical efficacy, endothelin-1, total duration of treadmill exercise, and hypersensitive C-reactive protein. The RCT on TCM treatment of MVA had the following problems: irregular reporting of adverse reactions, diverse indicators with low frequency, lack of attention to the application of endpoint indicators, insufficient use of TCM differentiation and efficacy indicators, non-standard evaluation criteria and failure to reflect the basic characteristics of TCM. A unified MVA syndrome differentiation standard should be established, on the basis of which an MVA treatment efficacy evaluation system and core outcome indicator set that highlights the characteristics of TCM with patient-reported outcomes as the starting point should be established to improve the clinical research and research value.

Ca2+-induced release of IQSEC2/BRAG1 autoinhibition under physiological and pathological conditions.

IQSEC2 (aka BRAG1) is a guanine nucleotide exchange factor (GEF) highly enriched in synapses. As a top neurodevelopmental disorder risk gene, numerous mutations are identified in Iqsec2 in patients with intellectual disabilities accompanied by other developmental, neurological, and psychiatric symptoms, though with poorly understood underlying molecular mechanisms. The atomic structures of IQSECs, together with biochemical analysis, presented in this study reveal an autoinhibition and Ca2+-dependent allosteric activation mechanism for all IQSECs and rationalize how each identified Iqsec2 mutation can alter the structure and function of the enzyme. Transgenic mice modeling two pathogenic variants of Iqsec2 (R359C and Q801P), with one activating and the other inhibiting the GEF activity of the enzyme, recapitulate distinct clinical phenotypes in patients. Our study demonstrates that different mutations on one gene such as Iqsec2 can have distinct neurological phenotypes and accordingly will require different therapeutic strategies.

A female case report of LGMD2B with compound heterozygous mutations of the DYSF gene and asymptomatic mutation of the X-linked DMD gene.

We report the case of a 31-year-old Chinese woman with a chief complaint of weakness in the lower limbs, which was diagnosed as limb-girdle muscular dystrophy 2B (LGMD2B) with compound heterozygous mutations of the DYSF gene. Meanwhile, this woman is an asymptomatic carrier with the mutation of the X-linked DMD gene. The electromyography, muscle MRI, and muscle biopsy indicated a chronic myogenic injury with dysferlin deletion. As a result of genetic testing, compound heterozygous G-to-T base substitution at position 5,497 in exon 49 of the DYSF gene, leading to a codon change from glutamic acid to termination codon at position 1,833, and a heterozygous C-to-G base change at position 4,638 + 8 in intron 42 of the DYSF gene with a consequence of splice, which has never been reported, were identified as candidate causative mutations. Unfortunately, DMD gene mutation c.3921+12A>G of the DMD gene on the X chromosome was also found in this patient. Finally, the patient was diagnosed as LGMD2B clinically and genetically. In the previous 2 years, the patient's lower limb weakness became slightly worse, resulting in even the total distance walked than before. Fortunately, during the follow-up, her son had not shown slowness or limitation of movement. Genetic testing by next-generation sequencing confirmed the final diagnosis of LGMD2B, and we identified the novel compound heterozygous variants in the DYSF gene, which is of great significance to the accurate diagnosis of genetically coded diseases. Much attention needs to be paid in clinics toward hereditary neuromuscular diseases with multiple pathogenic gene mutations. Genetic counseling and clinical follow-up should be the priorities in future, and promising treatments are also worth exploring.

Returning ryegrass to continuous cropping soil improves soil nutrients and soil microbiome, producing good-quality flue-cured tobacco.

The widespread and continuous cultivation of tobacco has led to soil degradation and reduced crop yields and quality. Green manure is an essential organic fertilizer that alleviates obstacles to continuous cultivation. However, the plant-soil microecological effects of green manure on flue-cured tobacco cultivation remain unclear. Thus, a positioning trail including two treatments, chemical fertilizer application only (treatment NPK) and chemical fertilizer application with turning ryegrass (treatment NPKG) was conducted, and the effect of ryegrass returning on the soil physicochemical properties, soil microbiome, crop yield, and quality of flue-cured tobacco in continuous cropping soil were investigated. Results showed that returning ryegrass to the field increased the thickness of soil humus layer from 13 cm to 15 cm, reduced the humus layer soil bulk density to 1.29 cm3/g. Ryegrass tilled and returned to the field increased soil organic matter content by 6.89-7.92%, increased rhizosphere soil available phosphorus content by 2.22-17.96%, and converted the soil non-exchangeable potassium into potassium that was available for plant absorption and utilization. Ryegrass tilling and returning to the field increased the potassium content of middle leaves of flue-cured tobacco by 7.69-10.07%, the increased potassium content in flue-cured tobacco was accompanied by increased total sugar, reducing sugar, and the ratio of reducing sugar to nicotine, which facilitated the harmonization of the chemical composition of cured tobacco leaves. Moreover, the increased number of markedly improved operational taxonomic units enhanced the complexity of the soil bacterial community and its compactness after ryegrass tillage and their return to the field. The available potassium, available phosphorus, total potassium content, pH, and sampling period of the rhizosphere soil had considerable effects on the rhizosphere microbial. Ryegrass tilling and returning to the field changed the soil microbiome, which increased the abundance of bulk soil Proteobacteria, rhizosphere soil Fibrobacterota, and microbes with anti-pathogen activity (Lysobacteria, Sphingomonas, Chaetomium, and Minimedusa); and reduced the abundance of pathogenic fungi Neocosmospore genus in the soil. In brief, ryegrass returned to the field, improved soil microecology and restored soil nutrients, and established a new dynamic balance of soil ecology, thereby improving the quality of cultivated land and the quality of flue-cured tobacco.