Tryptophan-Doped Poly(vinyl alcohol) Films with Ultralong-Lifetime Room-Temperature Phosphorescence and Color-Tunable Afterglow Under Ambient Conditions.

The development of a persistent luminescence system with long-lived phosphorescence and color-tunable afterglow at room temperature represents a challenge, largely due to the intensive non-radiative deactivation pathway. In this study, an ultralong-lived room temperature phosphorescence (RTP) system has been achieved using a hydrogen-bonding strategy where poly(vinyl alcohol) (PVA) matrices were doped with tryptophan (Trp) derivatives. The PVA film doped with N-α-(9-Fluorenylmethoxycarbonyl)-L-tryptophan (Fmoc-L-Trp) exhibited a long-lived phosphorescence emission of up to 3859.70 ms, and a blue afterglow for a duration greater than 34 s, under ambient conditions. The introduction of two other fluorescent dyes (i. e., Rhodamine B and Basicred14) to the PVA film facilitates adjustment to the color of the afterglow from blue to orange, and pink, by a triplet-to-singlet Förster-resonance energy transfer (TS-FRET) process. These films have been successfully applied in silk-screen printing and in multicolor afterglow light-emitting diode (LED) arrays.

Structures of the ADGRG2-Gs complex in apo and ligand-bound forms.

Adhesion G protein-coupled receptors are elusive in terms of their structural information and ligands. Here, we solved the cryogenic-electron microscopy (cryo-EM) structure of apo-ADGRG2, an essential membrane receptor for maintaining male fertility, in complex with a Gs trimer. Whereas the formations of two kinks were determinants of the active state, identification of a potential ligand-binding pocket in ADGRG2 facilitated the screening and identification of dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate and deoxycorticosterone as potential ligands of ADGRG2. The cryo-EM structures of DHEA-ADGRG2-Gs provided interaction details for DHEA within the seven transmembrane domains of ADGRG2. Collectively, our data provide a structural basis for the activation and signaling of ADGRG2, as well as characterization of steroid hormones as ADGRG2 ligands, which might be used as useful tools for further functional studies of the orphan ADGRG2.

NAD+ affects differentially expressed genes-MBOAT2-SLC25A21-SOX6 in experimental autoimmune encephalomyelitis model.

BACKGROUND: Nicotinamide adenine dinucleotide (NAD+) plays a key role in neuroinflammation and neurodegeneration and provides anti-inflammatory and neuroprotective effects in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). AIM: In this study, we aimed to investigate whether NAD+ affects differentially expressed genes (DEGs) in splenocytes of EAE mice to reveal candidate genes for the pathogenesis of MS. METHODS: The EAE model was used to perform an intervention on NAD+ to investigate its potential as a protective agent in inflammation and demyelination. Transcriptome analysis of nerve tissue was carried out to gain better insights into NAD+ function. Effects of NAD+ on DEGs in the splenocytes of EAE mice were investigated to determine its anti-inflammatory effect. RESULTS: NAD+ in EAE mice showed the clinical score was significantly improved (EAE 3.190 ± 0.473 vs. NAD+ 2.049 ± 0.715). DEGs (MBOAT2, SLC25A21, and SOX6) between the EAE and the EAE + NAD+ groups showed that SOX6 was significantly improved after NAD+ treatment compared with the EAE group, and other indicators were improved but did not reach statistical significance. NAD+ exhibited clinical scores in EAE mice, and key inflammation was ameliorated in EAE mice spleen after NAD+ intervention, while transcriptome analysis between EAE and EAE + NAD+ groups showed several DEGs in the underlying mechanism. CONCLUSION: NAD+ on DEGs attenuates disease severity in EAE. Transcriptome analysis on nerve tissue reveals several protein targets in the underlying mechanisms. However, NAD+ does not significantly improve DEGs in the splenocytes of the EAE model.

MBOAT2, SLC25A21, and SOX6 show significant fold change in EAE mice, while SOX6 shows significantly lower expression in the EAE group and the EAE + NAD⁺ group compared with the Ctrl.NAD⁺ in the EAE model provides its protective role in inflammation and demyelination.NAD⁺ exhibits clinical scores in EAE mice.NAD⁺ does not significantly improve DEGs in splenocytes of the EAE.

Sustained-Compensated Interfacial Zincophilic Sites to Assist High-Capacity Aqueous Zn Metal Batteries.

Aqueous Zn metal batteries have attracted extensive attention due to their intrinsic advantages. However, zinc ions tend to deposit irregularly, seriously depleting the capacity and stability of the battery. The construction of zincophilic sites can effectively regulate the nucleation and growth of Zn, but there is a defect that these sites will be covered with gradual failure after long-term cycling. Here, in combination with the sustained-compensated strategy, interfacial zincophilic sites are continuously constructed, thus effectively avoiding the threat of dendrites and improving the electrochemical performance. Impressively, at 10 mA cm-2 and 5 mAh cm-2, the protected Zn metal exhibits excellent cycling stability over 2000 cycles in the Zn//Zn battery. Moreover, even the cathode mass loading is considerably high (35 mg cm-2), and the Zn//NVO full cell significantly outperforms with high areal capacity (up to 4 mAh cm-2). This novel strategy provides a direction for the development of high-capacity aqueous batteries.

Application of interpretable machine learning algorithms to predict acute kidney injury in patients with cerebral infarction in ICU.

BACKGROUND: Acute kidney injury (AKI) is not only a complication but also a serious threat to patients with cerebral infarction (CI). This study aimed to explore the application of interpretable machine learning algorithms in predicting AKI in patients with cerebral infarction. METHODS: The study included 3920 patients with CI admitted to the Intensive Care Unit and Emergency Medicine of the Central Hospital of Lishui City, Zhejiang Province. Nine machine learning techniques, including XGBoost, logistics, LightGBM, random forest (RF), AdaBoost, GaussianNB (GNB), Multi-Layer Perceptron (MLP), support vector machine (SVM), and k-nearest neighbors (KNN) classification, were used to develop a predictive model for AKI in these patients. SHapley Additive exPlanations (SHAP) analysis provided visual explanations for each patient. Finally, model effectiveness was assessed using metrics such as average precision (AP), sensitivity, specificity, accuracy, F1 score, precision-recall (PR) curve, calibration plot, and decision curve analysis (DCA). RESULTS: The XGBoost model performed better in the internal validation set and the external validation set, with an AUC of 0.940 and 0.887, respectively. The five most important variables in the model were, in order, glomerular filtration rate, low-density lipoprotein, total cholesterol, hemiplegia and serum kalium. CONCLUSION: This study demonstrates the potential of interpretable machine learning algorithms in predicting CI patients with AKI.

Realization of a Hopf Insulator in Circuit Systems.

Three-dimensional (3D) two-band Hopf insulators are a paradigmatic example of topological phases beyond the topological classifications based on powerful methods like K theory and symmetry indicators. Since this class of topological insulating phases was theoretically proposed in 2008, they have attracted significant interest owing to their conceptual novelty, connection to knot theory, and many fascinating physical properties. However, because their realization requires special forms of long-range spin-orbit coupling, they have not been achieved in any 3D system yet. Here, we report the first experimental realization of the long-sought-after Hopf insulator in a 3D circuit system. To implement the Hopf insulator, we construct basic pseudospin modules and connection modules that can realize 2×2-matrix elements and then design the circuit network according to a tight-binding Hopf insulator Hamiltonian constructed by the Hopf map. By simulating the band structure of the designed circuit network and calculating the Hopf invariant, we find that the circuit realizes a Hopf insulator with Hopf invariant equaling 4. Experimentally, we measure the band structure of a printed circuit board and find the observed properties of the bulk bands and topological surface states are in good agreement with the theoretical predictions, verifying the bulk-boundary correspondence of the Hopf insulator. Our scheme brings the experimental study of Hopf insulators to reality and opens the door to the implementation of more unexplored topological phases beyond the known topological classifications.

Patterned Nanoparticle Arrays Fabricated Using Liquid Film Rupture Self-Assembly.

Self-assembly is an important bottom-up fabrication approach based on accurate manipulation of solid-air-liquid interfaces to construct microscale structures using nanoscale materials. This approach plays a substantial role in the fabrication of microsensors, nanosensors, and actuators. Improving the controllability of self-assembly to realize large-scale regular micro/nano patterns is crucial for this approach's further development and wider applications. Herein, we propose a novel strategy for patterning nanoparticle arrays on soft substrates. This strategy is based on a unique process of liquid film rupture self-assembly that is convenient, precise, and cost-efficient for mass manufacturing. This approach involves two key steps. First, suspended liquid films comprising monolayer polystyrene (PS) spheres are realized via liquid-air interface self-assembly over prepatterned microstructures. Second, these suspended liquid films are ruptured in a controlled manner to induce the self-assembly of internal PS spheres around the morphological edges of the underlying microstructures. This nanoparticle array patterning method is comprehensively investigated in terms of the effect of the PS sphere size, morphological effect of the microstructured substrate, key factors influencing liquid film-rupture self-assembly, and optical transmittance of the fabricated samples. A maximum rupture rate of 95.4% was achieved with an optimized geometric and dimensional design. Compared with other nanoparticle-based self-assembly methods used to form patterned arrays, the proposed approach reduces the waste of nanoparticles substantially because all nanoparticles self-assemble around the prepatterned microstructures. More nanoparticles assemble to form prepatterned arrays, which could strengthen the nanoparticle array network without affecting the initial features of prepatterned microstructures.

Deep learning-based diagnosis of osteoblastic bone metastases and bone islands in computed tomograph images: a multicenter diagnostic study.

OBJECTIVE: To develop and validate a deep learning (DL) model based on CT for differentiating bone islands and osteoblastic bone metastases. MATERIALS AND METHODS: The patients with sclerosing bone lesions (SBLs) were retrospectively included in three hospitals. The images from site 1 were randomly assigned to the training (70%) and intrinsic verification (10%) datasets for developing the two-dimensional (2D) DL model (single-slice input) and "2.5-dimensional" (2.5D) DL model (three-slice input) and to the internal validation dataset (20%) for evaluating the performance of both models. The diagnostic performance was evaluated using the internal validation set from site 1 and additional external validation datasets from site 2 and site 3. And statistically analyze the performance of 2D and 2.5D DL models. RESULTS: In total, 1918 SBLs in 728 patients in site 1, 122 SBLs in 71 patients in site 2, and 71 SBLs in 47 patients in site 3 were used to develop and test the 2D and 2.5D DL models. The best performance was obtained using the 2.5D DL model, which achieved an AUC of 0.996 (95% confidence interval [CI], 0.995-0.996), 0.958 (95% CI, 0.958-0.960), and 0.952 (95% CI, 0.951-0.953) and accuracies of 0.950, 0.902, and 0.863 for the internal validation set, the external validation set from site 2 and site 3, respectively. CONCLUSION: A DL model based on a three-slice CT image input (2.5D DL model) can improve the prediction of osteoblastic bone metastases, which can facilitate clinical decision-making. KEY POINTS: • This study investigated the value of deep learning models in identifying bone islands and osteoblastic bone metastases. • Three-slice CT image input (2.5D DL model) outweighed the 2D model in the classification of sclerosing bone lesions. • The 2.5D deep learning model showed excellent performance using the internal (AUC, 0.996) and two external (AUC, 0.958; AUC, 0.952) validation sets.

Does kidney biopsy in pediatric lupus patients "complement" the management and outcomes of silent lupus nephritis? Lessons learned from a pediatric cohort.

BACKGROUND: Silent lupus nephritis (SLN) is systemic lupus erythematosus (SLE) without clinical and laboratory features of kidney involvement but with biopsy-proven nephritis. This study aims to describe and compare the baseline characteristics and outcomes of pediatric SLN with overt LN (OLN) and to identify associated risk factors and biochemical markers. METHODS: In this retrospective, observational study, multivariate logistic regression and receiver operating characteristic (ROC) analyses studied age, sex, race, serum complements, anti-double-stranded-DNA antibody, anti-Smith antibody, eGFR, and proliferative nephritis. RESULTS: In our cohort of 69 patients, 47 were OLN, and 22 were SLN. OLN (OR = 4.9, p = 0.03) and non-African Americans (AA) (OR = 13.0, p < 0.01) had higher odds, and increasing C3 and C4 were associated with lower odds of proliferative nephritis (OR 0.95 and 0.65 per one unit increase in C3 and C4, respectively, p < 0.01). They demonstrated a good discriminative ability to detect proliferative nephritis as assessed by the area under the ROC curve (C3 = 0.78, C4 = 0.78). C3 and C4 in proliferative SLN and OLN were comparable and significantly lower than their non-proliferative counterparts. No association was observed between age, sex, anti-double-stranded-DNA antibody, anti-Smith antibody, eGFR, and proliferative nephritis. Proliferative SLN and OLN patients received similar treatments. Adverse events were identified in the proliferative OLN only. CONCLUSIONS: Lower complement levels are associated with proliferative lesions in pediatric LN-both SLN and OLN. The non-AA population had higher odds of having proliferative nephritis than the AA. Prospective, randomized, long-term follow-up of proliferative SLN patients is needed to ascertain the beneficial effect of early diagnosis and treatment. A higher resolution version of the Graphical abstract is available as Supplementary information.

Effect of magnesium sulfate perioperative infusion on postoperative catheter-related bladder discomfort in male patients undergoing laparoscopic radical resection of gastrointestinal cancer: a prospective, randomized and controlled study.

BACKGROUND: Laparoscopic radical resection of gastrointestinal cancer is associated with a high incidence of postoperative catheter-related bladder discomfort (CRBD). Studies on the benefits of magnesium sulfate intravenous infusion during the perioperative period post-laparoscopic surgery are yet lacking. METHODS: A total of 88 gastrointestinal cancer male patients scheduled for laparoscopic radical resection were randomly divided into two groups: normal saline (control) and magnesium. In the magnesium group, a 40 mg/kg loading dose of intravenous magnesium sulfate was administered for 10 min just after the induction of anesthesia, followed by continuous intravenous infusion of 15 mg/kg/h magnesium sulfate until the end of the surgery; the control group was administered the same dose of normal saline. Subsequently, 2 µg/kg sufentanil was continuously infused intravenously by a postoperative patient-controlled intravenous analgesia (PCIA) device. The primary outcome was the incidence of CRBD at 0 h after the surgery. The secondary outcomes included incidence of CRBD at 1, 2, and 6 h postsurgery, the severity of CRBD at 0, 1, 2, and 6 h postsurgery. Remifentanil requirement during surgery, sufentanil requirement within 24 h postsurgery, the postoperative numerical rating scale (NRS) score at 48 h after the surgery, magnesium-related side effects and rescue medication (morphine) requirement were also assessed. RESULTS: The incidence of CRBD at 0, 1, 2, and 6 h postoperatively was lower in the magnesium group than the control group (0 h: P = 0.01; 1 h: P = 0.003; 2 h: P = 0.001; 6 h: P = 0.006). The incidence of moderate to severe CRBD was higher in the control group at postoperative 0 and 1 h (0 h: P = 0.002; 1 h: P = 0.028), remifentanil requirement during surgery were significantly lower in the magnesium group than the control group. Sufentanil requirements during the 24 h postoperative period were significantly lower in the magnesium group than the control group. The NRS score was reduced in the magnesium group compared to the control group in the early postoperative period. Magnesium-related side effects and rescue medication (morphine) did not differ significantly between the two groups. CONCLUSIONS: Intravenous magnesium sulfate administration reduces the incidence and severity of CRBD and remifentanil requirement in male patients undergoing radical resection of gastrointestinal cancer. Also, no significant side effects were observed. TRIAL REGISTRATION: Chictr.org.cn ChiCTR2100053073. The study was registered on 10/11/2021.

New Type of Dynamically "Solid-Liquid" Interconvertible Electrolyte for High-Rate Zn Metal Battery.

The practical application of aqueous high-rate Zn metal battery (ZMB) is limited due to accelerated dendrite formation at high current densities. It is urgent to find an electrolyte, which could not only be mechanically stiff to clamp down dendrites but also not sacrifice ionic conductivity and interfacial compatibility. Herein, a new type of dynamically "solid-liquid" interconvertible electrolyte based on non-Newtonian fluid (NNFE) is proposed. Liquidity characteristic of NNFE is favorable for electrochemical kinetics and interfacial compatibility. Furthermore, in an area with high current rate NNFE would respond and mechanically stiffen to dissuade localized increase in Zn dendrite growth. Even at a current density of 50 mA cm-2, NNFE enables reversible and stable operation of a Zn symmetrical cell over 20 000 cycles. For Zn//Na5V12O32 (NVO) full cell, the NNFE also realizes lengthy cycling for 5000 periods at 5 A g-1. This research opens up new inspirations to high-rate Zn metal even other metal batteries.

[Effects of mycorrhizal planting on small molecular chemical components of Dendrobium officinale].

This study aimed to provide a scientific basis for the application of the mycorrhizal planting technology of Dendrobium officinale by investigating the effects of mycorrhizal planting on the fingerprints of D. officinale and the content of six chemical components. Seventeen samples of D. officinale under mycorrhizal and conventional planting were collected from four regions, such as Jinhua of Zhejiang. The HPLC fingerprints were established to evaluate the similarity of the samples. The content of six chemical components of the samples was determined by HPLC. There were 15 common peaks in the fingerprints, and five of them were identified by marker compounds, which were naringenin, 4,4'-dihydroxy-3,5-dimethoxybibenzyl, 3,4'-dihydroxy-5-methoxybibenzyl, 3',4-dihydroxy-3,5'-dimethoxybibenzyl(gigantol), and 3,4-dihydroxy-4',5-dimethoxybibenzyl(DDB-2). The similarities of the fingerprints of mycorrhizal and conventional planting samples and the control fingerprint were in the ranges of 0.733-0.936 and 0.834-0.942, respectively. The influences of mycorrhizal planting on fingerprints were related to planting regions, the germplasm of D. officianle, and the amount of fungal agent. The content of six chemical components in the samples varied greatly, and the content of DDB-2 was the highest, ranging from 69.83 to 488.47 µg·g~(-1). The mycorrhizal planting samples from Chongming of Shanghai and Taizhou of Jiangsu showed an increase in the content of 5-6 components, while samples from Zhangzhou of Fujian and Jinhua of Zhejiang showed an increase in the content of 1-2 components. The results showed that mycorrhizal planting technology did not change the chemical profile of small molecular chemical components of D. officinale, but affected the content of chemical components such as bibenzyls, which has a good application prospect.

Second-Order Real Nodal-Line Semimetal in Three-Dimensional Graphdiyne.

Real topological phases featuring real Chern numbers and second-order boundary modes have been a focus of current research, but finding their material realization remains a challenge. Here, based on first-principles calculations and theoretical analysis, we reveal the already experimentally synthesized three-dimensional (3D) graphdiyne as the first realistic example of the recently proposed second-order real nodal-line semimetal. We show that the material hosts a pair of real nodal rings, each protected by two topological charges: a real Chern number and a 1D winding number. The two charges generate distinct topological boundary modes at distinct boundaries. The real Chern number leads to a pair of hinge Fermi arcs, whereas the winding number protects a double drumhead surface bands. We develop a low-energy model for 3D graphdiyne which captures the essential topological physics. Experimental aspects and possible topological transition to a 3D real Chern insulator phase are discussed.

Recent Trends in Synthesis and Applications of Porous MXene Assemblies: A Topical Review.

MXene possesses high conductivity, excellent hydrophilicity, rich surface chemistry, hence holds great potential in various applications. However, MXene materials have low surface area utilization due to the agglomeration of ultrathin nanosheets. Assembling 2D MXene nanosheets into 3D multi-level architectures is an effective way to circumvent this issue. Incorporation of MXene with other nanomaterials during the assembly process could rationally tune and tailor the specific surface area, porosity and surface chemistry of the MXene assemblies. The complementary and synergistic effect between MXene and nanomaterials could expand their advantages and make up for their disadvantages, thus boost the performance of 3D porous MXene composites. Herein, we summarize the recent progress in fabrication of porous MXene architectures from 2D to 3D, and also discuss the potential applications of MXene nanostructures in energy harvesting systems, sensing, electromagnetic interference shielding, water purification and photocatalysis.

Association of dietary inflammatory potential with risk of overall and cause-specific mortality.

Inflammation is a central mechanism in metabolic disorders associated with morbidity and mortality and dietary factors can modulate inflammation. We aimed to prospectively investigate the association between an empirically developed, food-based dietary inflammatory pattern (EDIP) score and the risk of overall and cause-specific mortality, using data from the US National Health and Nutrition Examination Survey from 1999 to 2014. EDIP score was derived by entering thirty-nine predefined commonly consumed food groups into the reduced rank regression models followed by stepwise linear regression, which was most predictive of two plasma inflammation biomarkers including C-reactive protein and leucocyte count among 25 500 US adults. This score was further validated in a testing set of 9466 adults. Deaths from baseline until 31 December 2015 were identified through record linkage to the National Death Index. During a median follow-up of 7·8 years among 40 074 participants, we documented 4904 deaths. Compared with participants in the lowest quintile of EDIP score, those in the highest quintile had a higher risk of overall death (hazard ratio (HR) = 1·19, 95 % CI 1·08, 1·32, Ptrend = 0·002), and deaths from cancer (HR = 1·41, 95 % CI 1·14, 1·74, Ptrend = 0·017) and CVD (HR = 1·22, 95 % CI 0·98, 1·53, Ptrend = 0·211). When stratified by age, the association of EDIP with overall mortality was stronger among individuals under 65 years of age (Pinteraction = 0·001). Diets with a higher inflammatory potential were associated with increased risk of overall and cancer-specific mortality. Interventions to reduce the adverse effect of pro-inflammatory diets may potentially promote health and longevity.

Discovery and preclinical profile of LX-039, a novel indole-based oral selective estrogen receptor degrader (SERD).

We previously described the discovery of a novel indole series compounds as oral SERD for ER positive breast cancer treatment. Further SAR exploration focusing on substitutions on indole moiety of compound 12 led to the discovery of a clinical candidate LX-039. We report herein its profound anti-tumor activity, desirable ER antagonistic characteristics combined with favorable pharmacokinetic and preliminary safety properties. LX-039 is currently in clinical trial (NCT04097756).

New Insight into CO2 Reduction to Formate by In Situ Hydrogen Produced from Hydrothermal Reactions with Iron.

To reveal the nature of CO2 reduction to formate with high efficiency by in situ hydrogen produced from hydrothermal reactions with iron, DFT calculations were used. A reaction pathway was proposed in which the formate was produced through the key intermediate species, namely iron hydride, produced in situ in the process of hydrogen gas production. In the in situ hydrogenation of CO2, the charge of H in the iron hydride was -0.135, and the Fe-H bond distance was approximately 1.537 Å. A C-H bond was formed as a transition state during the attack of Hδ- on Cδ+. Finally, a HCOO species was formed. The distance of the C-H bond was 1.107 Å. The calculated free energy barrier was 16.43 kcal/mol. This study may provide new insight into CO2 reduction to formate in hydrothermal reactions with metal.

[Bladder wall neourethra technique improves early urinary continence after laparoscopic radical prostatectomy].

OBJECTIVE: To study the effect of the bladder wall neourethra (BWN) technique on early urinary continence after laparoscopic radical prostatectomy (LRP). METHODS: We prospectively selected 40 cases of LRP performed in our hospital from August 2020 to August 2021 and randomly divided them into a BWN group (n = 20) and a control group (n = 20). We recorded the urinary continence rate of the two groups of patients at 7, 30, 90 and 180 days, and measured the maximum urethral pressure (MUP), functional urethral length (FUL) and functional urethral area (UFA) and observed the shape of the neourethra closure by MRI at 1 month after catheter removal. RESULTS: The urinary continence rates were significantly higher in the BWN than in the control group at 7 days (90.0% vs 25.0%, P < 0.001), 30 days (95.0% vs 35.0%, P < 0.001), 90 days (100% vs 60.0%, P < 0.05) and 180 days (100% vs 90.0%, P > 0.05) after catheter removal. No statistically significant difference was observed in MUP between the two groups (P > 0.05). FUL and FUA were remarkably higher in the BWN than in the control group (P < 0.01). MRI showed tight closure of the neourethra in the BWN group in the urine storage period. CONCLUSION: The BWN technique can significantly prolong FUL and improve early urinary continence after LRP.

The Ca2+ channel CatSper is not activated by cAMP/PKA signaling but directly affected by chemicals used to probe the action of cAMP and PKA.

The sperm-specific Ca2+ channel CatSper (cation channel of sperm) controls the influx of Ca2+ into the flagellum and, thereby, the swimming behavior of sperm. A hallmark of human CatSper is its polymodal activation by membrane voltage, intracellular pH, and oviductal hormones. Whether CatSper is also activated by signaling pathways involving an increase of cAMP and ensuing activation of PKA is, however, a matter of controversy. To shed light on this question, we used kinetic ion-sensitive fluorometry, patch-clamp recordings, and optochemistry to study transmembrane Ca2+ flux and membrane currents in human sperm from healthy donors and from patients that lack functional CatSper channels. We found that human CatSper is neither activated by intracellular cAMP directly nor indirectly by the cAMP/PKA-signaling pathway. Instead, we show that nonphysiological concentrations of cAMP and membrane-permeable cAMP analogs used to mimic the action of intracellular cAMP activate human CatSper from the outside via a hitherto-unknown extracellular binding site. Finally, we demonstrate that the effects of common PKA inhibitors on human CatSper rest predominantly, if not exclusively, on off-target drug actions on CatSper itself rather than on inhibition of PKA. We conclude that the concept of an intracellular cAMP/PKA-activation of CatSper is primarily based on unspecific effects of chemical probes used to interfere with cAMP signaling. Altogether, our findings solve several controversial issues and reveal a novel ligand-binding site controlling the activity of CatSper, which has important bearings on future studies of cAMP and Ca2+ signaling in sperm.

Lopinavir-ritonavir alone or combined with arbidol in the treatment of 73 hospitalized patients with COVID-19: A pilot retrospective study.

OBJECTIVES: This study aimed to evaluate the antiviral efficacy of lopinavir-ritonavir alone or combined with arbidol in the treatment of hospitalized patients with common coronavirus disease-19 (COVID-19). MATERIALS AND METHODS: In this retrospective observational study, hospitalized COVID-19 patients were identified and divided into two groups based on the antiviral agents during their hospitalization. Patients in group LR were treated with lopinavir-ritonavir 400 mg/100 mg, twice a day, while patients in group LR+Ar were treated with lopinavir-ritonavir 400 mg/100 mg twice a day and arbidol 200 mg three times a day for at least 3 days. Data from these patients were collected from electronic medical record management system. RESULTS: 73 patients were divided into two groups: group LR (34 cases) and group LR+Ar (39 cases), according to the antiviral agents. The overall cure rate of COVID-19 in group LR+Ar and group LR were 92.3% and 97.1%, respectively, with no significant difference (p = 0.62). In a modified intention-to-treat analysis, lopinavir-ritonavir combined with arbidol led to a median time of hospital stay that was shorter by 1.5 days than in group LR (12.5 days vs. 14 days). The percentages of -COVID-19 RNA clearance was 92.3 in group LR and 97.1 in group LR+Ar which was similar to the cure rate. The median time to nucleic acid turning negative = (date of first negative PCR test) - (date of last positive PCR test) was 8.0 days in both groups with no significant difference (p = 0.59). Treatment of lopinavir-ritonavir combined with arbidol did not significantly accelerate main symptom improvement and promote the image absorption of pulmonary inflammation. CONCLUSION: No benefit was observed in the antiviral effect of lopinavir-ritonavir combined with arbidol compared with lopinavir-ritonavir alone in the hospitalized patients with COVID-19. More clinical observations in COVID-19 patients may help to confirm or exclude the effect of antiviral agents.