Design and Screening of Fluorescent Probes Based upon Hemicyanine Dyes for Monitoring Mitochondrial Viscosity in Living Cells.

Viscosity, at the subcellular level, plays a crucial role as a physicochemical factor affecting microenvironment homeostasis. Abnormal changes in mitochondrial viscosity often lead to various diseases in the organism. Based on the twisted intramolecular charge transfer mechanism, four hemicyanine dye fluorescent probes (HT-SA, HT-SA-S, HT-Bzh, and HT-NA) were designed and synthesized for viscosity response. The single bond between the nitrogen-containing heterocycle and the carbon-carbon double in the structure of the probe bond served as the viscosity response site. Finally, the probe HT-Bzh was screened as the optimal mitochondrial viscosity probe according to its responsiveness, targeting, and interference resistance. The fluorescence intensity of the probe HT-Bzh increased 22-fold when the viscosity was increased from 13.75 to 811.2 cP. In summary, all four viscosity probes we have developed can be used in different applications depending on the external environment, providing a valuable reference for the design of potential tools to address viscosity monitoring in biological systems.

Chromosome-level genome provides insight into the evolution and conservation of the threatened goral (Naemorhedus goral).

BACKGROUND: Gorals Naemorhedus resemble both goats and antelopes, which prompts much debate about the intragenus species delimitation and phylogenetic status of the genus Naemorhedus within the subfamily Caprinae. Their evolution is believed to be linked to the uplift of the Qinghai-Tibet Plateau (QTP). To better understand its phylogenetics, the genetic information is worth being resolved. RESULTS: Based on a sample from the eastern margin of QTP, we constructed the first reference genome for Himalayan goral Naemorhedus goral, using PacBio long-read sequencing and Hi-C technology. The 2.59 Gb assembled genome had a contig N50 of 3.70 Mb and scaffold N50 of 106.66 Mb, which anchored onto 28 pseudo chromosomes. A total of 20,145 protein-coding genes were predicted in the assembled genome, of which 99.93% were functionally annotated. Phylogenetically, the goral was closely related to muskox on the mitochondrial genome level and nested into the takin-muskox clade on the genome tree, rather than other so-called goat-antelopes. The cladogenetic event among muskox, takin and goral occurred sequentially during the late Miocene (~ 11 - 5 Mya), when the QTP experienced a third dramatic uplift with consequent profound changes in climate and environment. Several chromosome fusions and translocations were observed between goral and takin/muskox. The expanded gene families in the goral genome were mainly related to the metabolism of drugs and diseases, so as the positive selected genes. The Ne of goral continued to decrease since ~ 1 Mya during the Pleistocene with active glaciations. CONCLUSION: The high-quality goral genome provides insights into the evolution and valuable information for the conservation of this threatened group.

A ThT Derivative as Zn2+ Sensor Based on DNA G-quadruplex.

In this report, we developed a sensing strategy based on ThT-E (a ThT derivative) and DNA G-quadruplex for the label-free detection of Zn2+. In the absence of Zn2+, there was a fluorescence enhancement of ThT-E by interaction with human telomere sequence. On the addition of Zn2+, Zn2+ induced a more compact antiparallel G-quadruplex to release ThT-E, resulting in fluorescence quenching. The detection limit was 0.6996 µM, and the fluorescence intensity showed a good linear relationship with the concentration of Zn2+ in the range of 0-10 µM. This sensing strategy which only needs to mix two kinds of materials has the characteristics of label-feel, simple operation, short response time, economical and efficient.

Cut-off values of haemoglobin and clinical outcomes in incident peritoneal dialysis: the PDTAP study.

BACKGROUND: To explore the cut-off values of haemoglobin (Hb) on adverse clinical outcomes in incident peritoneal dialysis (PD) patients based on a national-level database. METHODS: The observational cohort study was from the Peritoneal Dialysis Telemedicine-assisted Platform (PDTAP) dataset. The primary outcomes were all-cause mortality, major adverse cardiovascular events (MACE) and modified MACE (MACE+). The secondary outcomes were the occurrences of hospitalization, first-episode peritonitis and permanent transfer to haemodialysis (HD). RESULTS: A total of 2591 PD patients were enrolled between June 2016 and April 2019 and followed up until December 2020. Baseline and time-averaged Hb <100 g/l were associated with all-cause mortality, MACE, MACE+ and hospitalizations. After multivariable adjustments, only time-averaged Hb <100 g/l significantly predicted a higher risk for all-cause mortality {hazard ratio [HR] 1.83 [95% confidence interval (CI) 1.19-281], P = .006}, MACE [HR 1.99 (95% CI 1.16-3.40), P = .012] and MACE+ [HR 1.77 (95% CI 1.15-2.73), P = .010] in the total cohort. No associations between Hb and hospitalizations, transfer to HD and first-episode peritonitis were observed. Among patients with Hb ≥100 g/l at baseline, younger age, female, use of iron supplementation, lower values of serum albumin and renal Kt/V independently predicted the incidence of Hb <100 g/l during the follow-up. CONCLUSION: This study provided real-world evidence on the cut-off value of Hb for predicting poorer outcomes through a nation-level prospective PD cohort.

MdbHLH93 confers drought tolerance by activating MdTyDC expression and promoting dopamine biosynthesis.

Dopamine and its biosynthesis-limiting enzyme tyrosine decarboxylase (TyDC) play a vital part in mediating plant growth and the response to drought stress. However, the underlying molecular mechanism remains poorly understood. Here, drought stress markedly induced the expression of Malus domestica bHLH93 (MdbHLH93), the apple basic helix-loop-helix transcription factor. Moreover, MdbHLH93 directly bound to the Malus domestica TyDC (MdTyDC) promoter and positively regulated its expression, which resulted in dopamine synthesis and enhanced drought tolerance. Furthermore, the additive effect of overexpressing MdbHLH93 and MdTyDC simultaneously promoted dopamine synthesis and drought tolerance in apples, while the interference of MdbHLH93 inhibited this effect, indicating that MdTyDC-regulated dopamine synthesis and drought tolerance were positively regulated by MdbHLH93. Taken together, these findings suggest the positive regulation of dopamine accumulation by MdbHLH93 through its transcriptional regulation of MdTyDC and show that increased dopamine content confers drought tolerance in apples.

Independent risk factors for depression in older adult patients receiving peritoneal dialysis for chronic kidney disease.

BACKGROUND: According to the trend of global population aging, the proportion of elderly patients with chronic kidney disease (CKD) is expected to increase. However, there are more than 20 million people in China with decompensated kidney function, of which 19.25% are elderly people. Therefore, special attention should be paid to the education years, sleep quality, anxiety status, comorbidities with diabetes, cardiovascular disease (CVD), and anemia as independent risk factors for depression in elderly CKD patients. This study explores the clinical mana-gement of elderly CKD patients that should address these risk factors to prevent depression and improve their prognosis. AIM: To investigate depression risk factors in older patients receiving peritoneal dialysis, aiding future prevention of depression in these patients. METHODS: This retrospective study included a primary study population of 170 patients with CKD who received peritoneal dialysis from January 2020 to December 2022. We assessed the patients' mental status using the Beck Depression Inventory Score-II (BDI-II), Self-Rating Anxiety Scale (SAS), Anxiety Inventory Score, and the Pittsburgh Sleep Quality Index (PSQI). Logistic regression was employed to identify depression independent risk factors among these patients. RESULTS: The non-depressed group had a significantly longer education period than the depressed group (P < 0.05). The depressed group exhibited significantly higher mental status scores than the non-depressed group (P < 0.001). Patients with diabetes mellitus (DM) or CVD had a higher probability of developing dep-ression. Patients with depression had significantly lower hemoglobin and albumin levels than patients without depression (P < 0.05). Spearman correlation analysis of BDI-II scale scores, measuring depression, indicated positive correlations with BDI-II and SAS scores as risk factors for depression in patients with CKD. In contrast, years of education, hemoglobin levels, and peritoneal Kt/V were negatively correlated, serving as protective factors against depression. An analysis of variance for influences with significant differences in the univariate analysis revealed that years of schooling, BDI-II, SAS, PSQI, DM, CVD, and hemoglobin levels independently influenced depression in older patients with CKD. CONCLUSION: Education, BDI-II, SAS, PSQI, DM, and CVD are independent risk factors for depression in older patients with CKD; therefore, post-treatment psychological monitoring of high-risk patients is crucial to prevent depression.

The effects of zinc sulfate on mycelial enzyme activity and metabolites of Pholiota adiposa.

The aim of this study was to investigate the effect of zinc sulphate on the activities of different enzymes and metabolites of Pholiota adiposa. In the experiment, we used the conventional enzyme activity assay to determine the changes of six indicators, including protein content, laccase activity, cellulase activity, amylase activity and polyphenol oxidase activity, under different concentrations of zinc sulphate treatment. The results showed that the activities of amylase, laccase, cellulase and peroxidase were Zn2+(200)>Zn2+(0)>Zn2+(400)>Zn2+(800).The activities of catalase and superoxide dismutase were Zn2+(200)>Zn2+(400)>Zn2+(800), and zinc sulfate could significantly affect the activity of polylipic squamase in a dose-dependent manner. Further correlation analysis showed that all six enzyme activities were significantly correlated with each other (P<001); the results of the statistical model test showed that the regression model constructed was statistically significant; overall the residuals met the conditions of normal distribution, and the corresponding points of different enzyme activities Q-Q' were more evenly distributed around y = x, and all fell in the 90% acceptance interval, thus the series was considered to obey normal distribution; the results of the principal The results of the principal component analysis showed that principal component 1 was positively correlated with amylase, laccase and cellulase. Principal component 2 was positively correlated with superoxide dismutase and catalase, and negatively correlated with peroxidase. The analysis of Metabonomic data revealed that zinc sulfate had a significant impact on the expression of metabolites in the mycelium. Moreover, varying concentrations of zinc sulfate exerted significant effects on the levels of amino acids, organic acids, and gluconic acid. This conclusion was confirmed by other experimental data. The results of the study provide a scientific reference for better research, development and utilization of Pholiota adiposa.

Diverse O-methyltransferases catalyze the biosynthesis of floral benzenoids that repel aphids from the flowers of waterlily Nymphaea prolifera.

Nymphaea is a key genus of the ANA grade (Amborellales, Nymphaeales, and Austrobaileyales) of basal flowering plants, which serve as a key model to study the early evolution of floral traits. In this study, we comprehensively investigated the emission, biosynthesis, and biological function of the floral scent in a night-blossoming waterlily Nymphaea prolifera. The headspace volatile collection combined with GC-MS analysis showed that the floral scent of N. prolifera is predominately comprised by methylated benzenoids including anisole, veratrole, guaiacol, and methoxyanisole. Moreover, the emission of these floral benzenoids in N. prolifera exhibited temporal and spatial pattern with circadian rhythm and tissue specificity. By creating and mining transcriptomes of N. prolifera flowers, 12 oxygen methyltransferases (NpOMTs) were functionally identified. By in vitro enzymatic assay, NpOMT3, 6, and 7 could produce anisole and NpOMT5, 7, 9, produce guaiacol, whereas NpOMT3, 6, 9, 11 catalyzed the formation of veratrole. Methoxyanisole was identified as the universal product of all NpOMTs. Expression patterns of NpOMTs provided implication for their roles in the production of the respective benzenoids. Phylogenetic analysis of OMTs suggested a Nymphaea-specific expansion of the OMT family, indicating the evolution of lineage-specific functions. In bioassays, anisole, veratrole, and guaiacol in the floral benzenoids were revealed to play the critical role in repelling waterlily aphids. Overall, this study indicates that the basal flowering plant N. prolifera has evolved a diversity and complexity of OMT genes for the biosynthesis of methylated benzenoids that can repel insects from feeding the flowers. These findings provide new insights into the evolutional mechanism and ecological significance of the floral scent from early-diverged flowering plants.

Yttrium-modified drinking water treatment residue for efficient phosphorus removal: efficacy, mechanism, and reproducibility.

The excessive presence of phosphate can cause eutrophication in water bodies. Yttrium has an extremely high affinity for phosphorus and is capable of forming stable complexes at low concentrations. Moreover, limitations in the resourcefulness of drinking water treatment residues were observed. In this study, a highly efficient phosphorus removal adsorbent (RJDWTR@Y) was prepared by calcination-alkali leaching-yttrium-loaded composite modification employing domestic drinking water treatment residue as raw material. And the effects of multiple factors on phosphate adsorption by RJDWTR@Y were examined. The results illustrated that the maximum adsorption capacity of the RJDWTR@Y for phosphate was 319.76 mg/g, with the chemical reaction of the multilayer as the predominant adsorption process. The adsorption mechanism is electrostatic gravitational force and the inner sphere complexation effect. RJDWTR@Y was effective against interference even at high concentrations of the coexisting anion. After five cycles, the desorption efficiency of phosphate was 75.11%. Filling the fixed bed with the material can efficiently remove phosphorus from the flowing liquid. The synthesis of RJDWTR@Y and the results of the study indicated that it has good application prospects. In addition to efficiently removing phosphorus, it can also recycle waste and achieve sustainability.

Effects of paricalcitol combined with hemodiafiltration on bone-metabolism-related indexes in patients with diabetic nephropathy and chronic renal failure.

BACKGROUND: Diabetic nephropathy (DN) is frequently seen in the development of diabetes mellitus, and its pathogenic factors are complicated. Its current treatment is controversial, and there is a lack of a relevant efficacy prediction model. AIM: To determine the effects of paricalcitol combined with hemodiafiltration on bone-metabolism-related indexes in patients with DN and chronic renal failure (CRF), and to construct an efficacy prediction model. METHODS: We retrospectively analyzed 422 patients with DN and CRF treated in Cangzhou Central Hospital between May 2020 and May 2022. We selected 94 patients who met the inclusion and exclusion criteria. Patients were assigned to a dialysis group (n = 45) and a joint group (n = 49) in relation to therapeutic regimen. The clinical efficacy of the two groups was compared after treatment. The changes in laboratory indexes after treatment were evaluated, and the two groups were compared for the incidence of adverse reactions. The predictive value of laboratory indexes on the clinical efficacy on patients was analyzed. RESULTS: The dialysis group showed a notably worse improvement in clinical efficacy than the joint group (P = 0.017). After treatment, the joint group showed notably lower serum levels of serum creatinine, uric acid (UA) and blood urea nitrogen (BUN) than the dialysis group (P < 0.05). After treatment, the joint group had lower serum levels of phosphorus, procollagen type I amino-terminal propeptide (PINP) and intact parathyroid hormone than the dialysis group, but a higher calcium level (P < 0.001). Both groups had a similar incidence of adverse reactions (P > 0.05). According to least absolute shrinkage and selection operator regression analysis, UA, BUN, phosphorus and PINP were related to treatment efficacy. According to further comparison, the non-improvement group had higher risk scores than the improvement group (P < 0.0001), and the area under the curve of the risk score in efficacy prediction was 0.945. CONCLUSION: For treatment of CRF and DN, combined paricalcitol and hemodiafiltration can deliver higher clinical efficacy and improve the bone metabolism of patients, with good safety.

Breast cancer pre-clinical screening using infrared thermography and artificial intelligence: a prospective, multicentre, diagnostic accuracy cohort study.

BACKGROUND: Given the limited access to breast cancer (BC) screening, the authors developed and validated a mobile phone-artificial intelligence-based infrared thermography (AI-IRT) system for BC screening. MATERIALS AND METHODS: This large prospective clinical trial assessed the diagnostic performance of the AI-IRT system. The authors constructed two datasets and two models, performed internal and external validation, and compared the diagnostic accuracy of the AI models and clinicians. Dataset A included 2100 patients recruited from 19 medical centres in nine regions of China. Dataset B was used for independent external validation and included 102 patients recruited from Langfang People's Hospital. RESULTS: The area under the receiver operating characteristic curve of the binary model for identifying low-risk and intermediate/high-risk patients was 0.9487 (95% CI: 0.9231-0.9744) internally and 0.9120 (95% CI: 0.8460-0.9790) externally. The accuracy of the binary model was higher than that of human readers (0.8627 vs. 0.8088, respectively). In addition, the binary model was better than the multinomial model and used different diagnostic thresholds based on BC risk to achieve specific goals. CONCLUSIONS: The accuracy of AI-IRT was high across populations with different demographic characteristics and less reliant on manual interpretations, demonstrating that this model can improve pre-clinical screening and increase screening rates.

M6A-mediated-upregulation of lncRNA BLACAT3 promotes bladder cancer angiogenesis and hematogenous metastasis through YBX3 nuclear shuttling and enhancing NCF2 transcription.

Lymphatic metastasis is recognized as the leading manner of metastasis in bladder cancer (BLCa), but hematogenous metastasis accounts for a majority of cancer-associated deaths. The past two decades have witnessed tremendous attention in long non-coding RNAs (lncRNAs), which are a new hope for the development of targeted drug therapy for metastatic cancers; however, the underlying mechanism of lncRNAs involved in BLCa hematogenous metastasis remains to be elucidated. Here, we identified BLCa-associated transcript 3 (BLACAT3), a lncRNA, which was aberrantly upregulated in BLCa and corelated with poor prognosis of patients with muscle-invasive bladder cancer. Methodologically, m6A epitranscriptomic microarray, RNA sequencing and mass spectrometry (MS) were used to screen the key molecules of the regulatory axis. Functional assays, animal models and clinical samples were used to explore the roles of BLACAT3 in BLCa in vitro and in vivo. Mechanistically, m6A modification contributes to BLACAT3 upregulation by stabilizing RNA structure. BLACAT3 recruits YBX3 to shuttle into the nucleus, synergistically enhances NCF2 transcription, and promotes BLCa angiogenesis and hematogenous metastasis by activating downstream NF-κB signaling. Our findings will develop prognosis prediction tools for BLCa patients and discover novel therapeutic biological targets for metastatic BLCa.

Room Temperature Anhydrous Suzuki-Miyaura Polymerization Enabled by C-S Bond Activation.

The Suzuki-Miyaura cross-coupling is one of the most important and powerful methods for constructing C-C bonds. However, the protodeboronation of arylboronic acids hinder the development of Suzuki-Miyaura coupling in the precise synthesis of conjugated polymers (CPs). Here, an anhydrous room temperature Suzuki-Miyaura cross-coupling reaction between (hetero)aryl boronic esters and aryl sulfides was explored, of which universality was exemplified by thirty small molecules and twelve CPs. Meanwhile, the mechanistic studies involving with capturing four coordinated borate intermediate revealed the direct transmetalation of boronic esters in the absence of H2 O suppressing the protodeboronation. Additionally, the room temperature reaction significantly reduced the homocoupling defects and enhanced the optoelectronic properties of the CPs. In all, this work provides a green protocol to synthesize alternating CPs.

"One stone, two birds": a mitochondria-targeted fluorescent probe for the detection of viscosity and HSO3- in living cells.

The material transport and physiological events of mitochondria need to be supported by a suitable microenvironment. For example, high viscosity will seriously hinder material exchange, and SO2, as the precursor of HSO3-, is an endogenous signal molecule that plays a key role in information transmission. It is very important to detect viscosity and HSO3- in mitochondria. Here, we developed a dual-responsive fluorescent probe (named Hcy-NT) to image the changes in mitochondrial viscosity and HSO3- in a "killing two birds with one stone" manner. Hcy-NT showed an OFF-ON fluorescence signal for the increase in cell viscosity induced by nystatin, while an ON-OFF fluorescence signal for intracellular and endogenous HSO3-. Its limits of detection for HSO3- were calculated by both absorption and fluorescence methods, which were 1.200 and 1.291 µM, respectively. This work provides a valuable tool for the study of viscosity and HSO3- related physiological processes and the diagnosis of potential diseases.

Design and Screening of Fluorescent Probes Based upon Hemicyanine Dyes to Sensitively Respond to HSO3- in Living Cells.

SO2, a gas signaling molecule, can be produced endogenously in mitochondria. Its hydrolysate, HSO3-, plays a key role in food preservation, cardiovascular relaxation, and other fields, suggesting that it is important to achieve its detection. Here, based on the Michael addition mechanism, four hemicyanine dye fluorescent probes (ETN, ETB, STB, and EIB) were designed and synthesized for responding to HSO3-. We evaluated the reaction ability of different probes with HSO3- and tried to explain the reasons for the significantly different response effects between probes and HSO3- according to the structure-activity relationship. The influence of different substituents of probes on the properties of mitochondria-targeting was also discussed. Finally, we screened out ETN as the optimal HSO3- probe due to its high sensitivity, rapid reactivity, and good mitochondria-targeting, and it could sensitively respond to HSO3- in living cells. The LODs of ETN for HSO3- were calculated by both absorption and fluorescence methods, respectively, which were 2.727 and 0.823 µM. Our work provided valuable references for designing strategies and potential tools for response to SO2 derivatives in biosystems.

Hydroxylamine facilitated catalytic degradation of methylene blue in a Fenton-like system for heat-treatment modified drinking water treatment residues.

Rational treatment of drinking water treatment residues (WTR) has become an environmental and social issue due to the risk of secondary contamination. WTR has been commonly used to prepare adsorbents because of its clay-like pore structure, but then requires further treatment. In this study, a Fenton-like system of H-WTR/HA/H2O2 was constructed to degrade organic pollutants in water. Specifically, WTR was modified by heat treatment to increase its adsorption active site, and to accelerate Fe(III)/Fe(II) cycling on the catalyst surface by the addition of hydroxylamine (HA). Moreover, the effects of pH, HA and H2O2 dosage on the degradation were discussed with methylene blue (MB) as the target pollutant. The mechanism of the action of HA was analyzed and the reactive oxygen species in the reaction system were determined. Combined with the reusability and stability experiments, the removal efficiency of MB remained 65.36% after 5 cycles. Consequently, this study may provide new insights into the resource utilization of WTR.

Three-dimensional femur morphology analysis for the optimal location of subtrochanteric osteotomy with an implanted Wagner cone stem in total hip arthroplasty for Crowe type IV developmental dysplasia of the hip.

BACKGROUND: This study aimed to accurately evaluate the matching of proximal and distal femoral segments and fitting of the femur-femoral stem in patients with Crowe type IV developmental dysplasia of the hip (DDH) who have undergone subtrochanteric osteotomy at different locations with an implanted Wagner cone stem to improve the rate of the bone union at the osteotomy site. METHODS: Three-dimensional femur morphology of 40 patients with Crowe type IV DDH was evaluated at each cross-section to determine the femoral cortical bone area. This study focused on five osteotomy lengths (2.5, 3, 3.5, 4, and 4.5 cm). The overlapped area between the proximal and distal cortical bone segments was defined as the contact area (S, mm2), and the contact area to distal cortical bone area ratio was defined as the coincidence rate (R). Three indicators were used to evaluate the matching and fitting of the osteotomy sites with the implanted Wagner cone stems: (1) higher S and R between the proximal and distal segments; (2) the effective fixation length of the femoral stem at the distal segments being at least 1.5 cm; and (3) osteotomy did not involve the isthmus. RESULTS: In all groups, S significantly decreased in the two proximal levels above the 0.5 cm level below the lesser trochanter (LT) compared with those below this level. In comparison, at osteotomy lengths from 2.5 to 4 cm, R significantly decreased in the three proximal levels. The optimal osteotomy levels ranged from 1.5 and 2.5 cm below the LT for an appropriately sized stem. CONCLUSIONS: Subtrochanteric osteotomy at the optimal level not only ensures fitting of the femur-femoral stem but also meets the requirements of a higher S and R to ensure adequate reduction and stabilization at the osteotomy site, which may contribute to the bone union. Although the optimal osteotomy level varies with the size of the femoral stem and the length of the subtrochanteric osteotomy, the optimal osteotomy levels for an appropriately sized Wagner cone femoral stem implantation range from 1.5 to 2.5 cm below the LT.

Study on the Efficacy of Sacubitril/Valsartan in Patients with Heart Failure with Preserved Ejection Fraction Undergoing Peritoneal Dialysis.

INTRODUCTION: Cardiovascular disease is the most common cause of death and morbidity in patients with end-stage renal disease. Sacubitril/valsartan (SAC/VAL) can reduce the risk of cardiovascular mortality among patients with heart failure (HF). The present study set out to evaluate the efficacy of SAC/VAL in the treatment of patients with HF with preserved ejection fraction (HFpEF) undergoing peritoneal dialysis (PD) (HFpEF&PD). METHODS: A total of 160 patients with HFpEF&PD were enrolled and randomly divided into the control group (N = 80) and SAC/VAL group (N = 80). The cardiac function efficacy, HF scoring efficacy, echocardiographic parameters, serological indicators, and 6-minute walking test were compared before and after treatment. RESULTS: After 6 months of treatment, the total number of patients who responded to treatment in the SAC/VAL group was higher than that of the control group in terms of cardiac function and HF scoring efficacy. After treatment, levels of early diastolic/late diastolic filling velocity and left ventricular ejection fraction were increased in both groups, while the levels of left atrial diameter, left ventricular end-diastolic diameter, left ventricular end-systolic diameter, inter-ventricular septal diameter, and left ventricular posterior wall diameter were decreased; the NT-proBNP levels were diminished in both groups, while hemoglobin levels and the 6-minute walk distance were increased; the systolic blood pressure, diastolic blood pressure, and 24-h ultrafiltration volume were lowered in all patients. The changes in these indexes in the SAC/VAL group were more obvious than those in the controls. CONCLUSION: SAC/VAL can significantly improve cardiac function in patients with HFpEF&PD.

SARS-CoV-2 RBD and Its Variants Can Induce Platelet Activation and Clearance: Implications for Antibody Therapy and Vaccinations against COVID-19.

The COVID-19 pandemic caused by SARS-CoV-2 virus is an ongoing global health burden. Severe cases of COVID-19 and the rare cases of COVID-19 vaccine-induced-thrombotic-thrombocytopenia (VITT) are both associated with thrombosis and thrombocytopenia; however, the underlying mechanisms remain inadequately understood. Both infection and vaccination utilize the spike protein receptor-binding domain (RBD) of SARS-CoV-2. We found that intravenous injection of recombinant RBD caused significant platelet clearance in mice. Further investigation revealed the RBD could bind platelets, cause platelet activation, and potentiate platelet aggregation, which was exacerbated in the Delta and Kappa variants. The RBD-platelet interaction was partially dependent on the ß3 integrin as binding was significantly reduced in ß3-/- mice. Furthermore, RBD binding to human and mouse platelets was significantly reduced with related αIIbß3 antagonists and mutation of the RGD (arginine-glycine-aspartate) integrin binding motif to RGE (arginine-glycine-glutamate). We developed anti-RBD polyclonal and several monoclonal antibodies (mAbs) and identified 4F2 and 4H12 for their potent dual inhibition of RBD-induced platelet activation, aggregation, and clearance in vivo, and SARS-CoV-2 infection and replication in Vero E6 cells. Our data show that the RBD can bind platelets partially though αIIbß3 and induce platelet activation and clearance, which may contribute to thrombosis and thrombocytopenia observed in COVID-19 and VITT. Our newly developed mAbs 4F2 and 4H12 have potential not only for diagnosis of SARS-CoV-2 virus antigen but also importantly for therapy against COVID-19.