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Recent groundbreaking advances in the structural biology of the glucose transporter 9 (GLUT9) and urate transporter 1 (URAT1) have provided critical insights into the molecular mechanisms underlying urate recognition and transport. Using cryo-electron microscopy (cryo-EM), researchers have elucidated the structures of these transporters at high resolution, thus revealing their substrate preferences and interactions with inhibitors. Several studies have highlighted the potential of specific inhibitors, such as apigenin for GLUT9, and have demonstrated the role of chloride-mediated inhibition in URAT1 function. These findings provide an excellent starting point for developing targeted therapies for hyperuricemia and gout, to enable the design of more effective and selective drugs in the future.

HIV-1 reverse transcriptase (RT) has received great attention as an attractive therapeutic target for acquired immune deficiency syndrome (AIDS), but the inevitable drug resistance and side effects have always been major challenges faced by non-nucleoside reverse transcriptase inhibitors (NNRTIs). This work aimed to identify novel chemotypes of anti-HIV-1 agents with improved drug-resistance profiles, reduced toxicity, and excellent druggability. A series of diarylpyrimidine (DAPY) derivatives were prepared via structural modifications of the leads K-5a2 and 25a. Among them, 15a with dimethylphosphine oxide moiety showed the most prominent antiviral potency against all of the tested viral panel, being 1.6-fold (WT, EC50 = 1.75 nmol/L), 3.0-fold (L100I, EC50 = 2.84 nmol/L), 2.4-fold (K103N, EC50 = 1.27 nmol/L), 3.3-fold (Y181C, EC50 = 5.38 nmol/L), 2.9-fold (Y188L, EC50 = 7.96 nmol/L), 2.5-fold (E138K, EC50 = 4.28 nmol/L), 4.8-fold (F227L/V106A, EC50 = 3.76 nmol/L) and 5.3-fold (RES056, EC50 = 15.8 nmol/L) more effective than that of the marketed drug ETR. Molecular docking results illustrated the detailed interactions formed by compound 15a and WT, F227L/V106A, and RES056 RT. Moreover, 15a·HCl carried outstanding pharmacokinetic (t1/2 = 1.32 h, F = 40.8%) and safety profiles (LD50 > 2000 mg/kg), which demonstrated that 15a HCl is a potential anti-HIV-1 drug candidate.

The N-methyl-d-aspartate (NMDA) receptors, which belong to the ionotropic Glutamate receptors, constitute a family of ligand-gated ion channels. Within the various subtypes of NMDA receptors, the GluN1/2A subtype plays a significant role in central nervous system (CNS) disorders. The present article aims to provide a comprehensive review of ligands targeting GluN2A-containing NMDA receptors, encompassing negative allosteric modulators (NAMs), positive allosteric modulators (PAMs) and competitive antagonists. Moreover, the ligands’ structure–activity relationships (SARs) and the binding models of representative ligands are also discussed, providing valuable insights for the clinical rational design of effective drugs targeting CNS diseases.

In this study, a nonionic surfactant (JFC-M) was used as an additive for hydrothermal pretreatment of crushed poplar wood. The pseudo-lignin extracted from holocellulose after hydrothermal pretreatment was characterized, and the composition of liquid and solid fractions obtained after pretreatment at different experimental conditions was analyzed. The results showed that the addition of JFC-M surfactant accelerated the dissolution of biomass cellulose and effectively inhibited the production of pseudo-lignin in hydrothermal processes, under the same hydrothermal pretreatment conditions. The pseudo-lignin yield for the control group was 14.2% (no JFC surfactant added), whereas when the JFC-M concentration was 2%, the pseudo-lignin yield was 9.8%.

With our continuous endeavors in seeking potent anti-HIV-1 agents, we reported here the discovery, biological characterization, and druggability evaluation of a class of nonnucleoside reverse transcriptase inhibitors. To fully explore the chemical space of the NNRTI-binding pocket, novel series of dihydrothiopyrano [3,2-d]pyrimidines were developed by employing the structure-based design strategy. Most of the derivatives were endowed with prominent antiviral activities against HIV-1 wild-type and resistant strains at nanomolar levels. Among them, compound 23h featuring the aminopiperidine moiety was identified as the most potent inhibitor, with EC50 values ranging from 3.43 to 21.4 nmol/L. Especially, for the challenging double-mutants F227L + V106A and K103N + Y181C, 23h exhibited 2.3- to 14.5-fold more potent activity than the first-line drugs efavirenz and etravirine. Besides, the resistance profiles of 23h achieved remarkable improvement compared to efavirenz and etravirine. The binding target of 23h was further confirmed to be HIV-1 reverse transcriptase. Molecular modeling studies were also performed to elucidate the biological evaluation results and give guidance for the optimization campaign. Furthermore, no apparent inhibition of the major CYP450 enzymes and hERG channel was observed for 23h. Most importantly, 23h was characterized by good pharmacokinetic properties and excellent safety in vivo. Collectively, 23h holds great promise as a potential candidate for its effective antiviral efficacy and favorable drug-like profiles.

While it is assumed that trade unions may influence the gender wage gap, evidence is scarce on this issue. This study investigates the issue in China using national longitudinal survey data from 2010 to 2020. The results reveal that the union wage premium is greater for women than for men. Furthermore, the union wage premium is more beneficial for women in the public sector compared to the private sector. The gender disparity in endowment return effect among non-union members is the primary factor contributing to the formation of the gender wage gap in both public and private sectors, with the effect being more pronounced in the public sector. Additionally, the gender disparity in unionism reduces the gender wage gap in the public sector while widening the wage gap in the private sector.

Abstract The Vietnam upwelling is a crucial circulation feature in the South China Sea. Although previous studies have shown that various coastal upwellings around the world may intensify under global warming, future changes in the Vietnam upwelling remain unclear. To address this knowledge gap, we analyzed the long‐term trend in the Vietnam upwelling under a high‐emission scenario for the period 2006–2100, using simulation results from a global eddy‐resolving climate model. In this model, the summertime Vietnam upwelling is projected to intensify in the 21st century and is statistically significant between 12°N and 14°N. A volume flux budget analysis indicates that wind stress curl is the most important contributor to the intensification. The geostrophic flow, to some extent, may suppress the upwelling intensification. The projected increase in upwelling is shown to significantly reduce local ocean warming and freshening and thus may have vital impacts on the local climate and circulation.

The main protease (Mpro) of SARS-CoV-2 is an attractive target in anti-COVID-19 therapy for its high conservation and major role in the virus life cycle. The covalent Mpro inhibitor nirmatrelvir (in combination with ritonavir, a pharmacokinetic enhancer) and the non-covalent inhibitor ensitrelvir have shown efficacy in clinical trials and have been approved for therapeutic use. Effective antiviral drugs are needed to fight the pandemic, while non-covalent Mpro inhibitors could be promising alternatives due to their high selectivity and favorable druggability. Numerous non-covalent Mpro inhibitors with desirable properties have been developed based on available crystal structures of Mpro. In this article, we describe medicinal chemistry strategies applied for the discovery and optimization of non-covalent Mpro inhibitors, followed by a general overview and critical analysis of the available information. Prospective viewpoints and insights into current strategies for the development of non-covalent Mpro inhibitors are also discussed.

Abstract Background Declined skeletal muscle mass and function are inevitable consequences of long‐term diabetes and bring about many adverse events. Muscle fibre atrophy and interstitial fibrosis are major pathological manifestations of diabetic sarcopenia. Stimulator of interferon genes (STING) participates in various metabolic diseases. We aimed to explore whether and how STING regulates the above pathological manifestations of diabetic sarcopenia. Methods Wild‐type and STINGgt/gt C57BL/6J mice and C2C12 myotubes were used to study the role of STING in the regulation of diabetic sarcopenia and the underlying mechanisms. Results STING was abnormally activated in diabetic muscles and in PA‐treated myotubes (P

Influenza is an acute respiratory infection caused by influenza viruses (IFV), According to the World Health Organization (WHO), seasonal IFV epidemics result in approximately 3–5 million cases of severe illness, leading to about half a million deaths worldwide, along with severe economic losses and social burdens. Unfortunately, frequent mutations in IFV lead to a certain lag in vaccine development as well as resistance to existing antiviral drugs. Therefore, it is of great importance to develop anti-IFV drugs with high efficiency against wild-type and resistant strains, needed in the fight against current and future outbreaks caused by different IFV strains. In this review, we summarize general strategies used for the discovery and development of antiviral agents targeting multiple IFV strains (including those resistant to available drugs). Structure-based drug design, mechanism-based drug design, multivalent interaction-based drug design and drug repurposing are amongst the most relevant strategies that provide a framework for the development of antiviral drugs targeting IFV.

Abstract The 2D semiconductors are an ideal platform for exploration of bosonic fluids composed of coupled photons and collective excitations of atoms or excitons, primarily due to large excitonic binding energies and strong light‐matter interaction. Based on first‐principles calculations, it is demonstrated that the phonon polaritons formed by two infrared‐active phonon modes in monolayer MoSi2N4 and WSi2N4 possess ultra‐high confinement factors of around ≈105 and 103, surpassing those of conventional polaritonic thin‐film materials by two orders of magnitude. It is observed that the first bright exciton possesses a substantial binding energies of 750 and 740 meV in these two monolayers, with the radiative recombination lifetimes as long as 25 and 188 ns, and the Rabi splitting of the formed cavity‐exciton polaritons reaching 373 and 321 meV, respectively. The effective masses of the cavity exciton polaritons are approximately 10−5me, providing the potential for high‐temperature quantum condensation. The ultra‐confined and ultra‐low‐loss phonon polaritons, as well as strongly‐coupled cavity exciton polaritons with ultra‐small polaritonic effective masses in these two monolayers, offering the flexible control of light at the nanoscale, probably leading to practical applications in nanophotonics, meta‐optics, and quantum materials.

The seasonal and spatial evolution of the mixed layer (ML) in the Red Sea (RS) and the influence of atmospheric buoyancy and momentum forcing are analyzed for the 2001–2015 period using a high-resolution (1/100°, 50 vertical layers) ocean circulation model. The simulation reveals a strong spatiotemporal variability reflecting the complex patterns associated with the air–sea buoyancy flux and wind forcing, as well as the significant impact of the basin’s general and mesoscale circulation. During the spring and summer months, buoyancy forcing intensifies stratification, resulting in a generally shallow ML throughout the basin. Nevertheless, the results reveal local maxima associated with the influence of mesoscale circulation and regular wind induced mixing. Under the influence of surface buoyancy loss, the process of deepening of the ML commences in early September, reaching its maximum depth in January and February. The northern Gulf of Aqaba and the western parts of the northern RS, exhibit the deepest ML, with a gradual shoaling toward the south, primarily due to the surface advection of relatively fresh water that enters the basin from the Gulf of Aden. The mixed layer depth (MLD) variability is primarily driven by atmospheric buoyancy forcing, especially its heat flux component. Although evaporative fluxes dominate the annually averaged surface buoyancy forcing, they exhibit weak seasonal and spatial variability. Wind induced mixing exerts a significant impact on the MLD only locally, especially during summer. Of particular importance are strong winds channeled by topography, such as those in the vicinity of the Strait of Bab-Al-Mandeb and the straits connecting the two gulfs in the north, as well as lateral jets venting through mountain gaps, such as the Tokar Jet in the central RS. The analysis highlights the complex patterns of air-sea interactions, thermohaline circulation, and mesoscale activity, all of them strongly imprinted on the MLD distribution.

Abstract In the quest to connect bulk topological quantum numbers to measurable parameters in real materials, current established approaches often necessitate specific conditions, limiting their applicability. Here we propose and demonstrate an approach to link the non-trivial hierarchical bulk topology to the multidimensional partition of local density of states (LDOS), denoted as the bulk-LDOS correspondence. In finite-size topologically nontrivial photonic crystals, we observe the LDOS partitioned into three distinct regions: a two-dimensional interior bulk area, a one-dimensional edge region, and zero-dimensional corner sites. Contrarily, topologically trivial cases exhibit uniform LDOS distribution across the entire two-dimensional bulk area. Our findings provide a general framework for distinguishing topological insulators and uncovering novel aspects of topological directional band-gap materials, even in the absence of in-gap states.

Inspired by our previous work on the modification of diarylpyrimidine-typed non-nucleoside reverse transcriptase inhibitors (NNRTIs) and the reported crystallographic studies, a series of novel amino acids (analogues)-substituted thiophene[3,2-d]pyrimidine derivatives were designed and synthesized by targeting the solvent-exposed region of the NNRTI-binding pocket. The biological evaluation results showed that compound 5k was the most active inhibitor, exhibiting moderate-to-excellent potency against HIV-1 wild-type (WT) and a panel of NNRTI-resistant strains, with EC50 values ranging from 0.042 μM to 7.530 μM. Of special note, 5k exhibited the most potent activity against single-mutant strains (K103N and E138K), with EC50 values of 0.031 μM and 0.094 μM, being about 4.3-fold superior to EFV (EC50 = 0.132 μM) and 1.9-fold superior to NVP (EC50 = 0.181 μM), respectively. In addition, 5k demonstrated lower cytotoxicity (CC50 = 27.9 μM) and higher selectivity index values. The HIV-1 reverse transcriptase (RT) inhibition assay was further performed to confirm their binding target. Moreover, preliminary structure–activity relationships (SARs) and molecular docking studies were also discussed in order to provide valuable insights for further structural optimizations. In summary, 5k turned out to be a promising NNRTI lead compound for further investigations of treatments for HIV-1 infections.

Viral infections represent a major threat to human health and the global economy; however, most of the currently available antiviral drugs are not fully effective in restricting viral replication and selecting for drug-resistant variants. Targeted protein degradation technologies are promising strategies to avoid or delay the emergence of drug resistance. Among the protein degradation-based multi-specific approaches, proteolysis targeting chimera (PROTAC) is the main strategy applied in the antiviral field. In this review we will introduce the elements and mechanisms of action used by PROTAC technology, as well as the advantages of PROTACs over available antiviral drugs. We also summarize the latest progress in the application of PROTACs in antiviral research, discuss existing challenges and look into future opportunities for antiviral drug discovery.

Indolylarylsulfones (IASs) are classical HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) with a unique scaffold and possess potent antiviral activity. To address the high cytotoxicity and improve safety profiles of IASs, we introduced various sulfonamide groups linked by alkyl diamine chain to explore the entrance channel of non-nucleoside inhibitors binding pocket. 48 compounds were designed and synthesized to evaluate their anti-HIV-1 activities and reverse transcriptase inhibition activities. Especially, compound R10L4 was endowed with significant inhibitory activity towards wild-type HIV-1 (EC50(WT) = 0.007 μmol/L, SI = 30,930) as well as a panel of single-mutant strains exemplified by L100I (EC50 = 0.017 μmol/L, SI = 13,055), E138K (EC50 = 0.017 μmol/L, SI = 13,123) and Y181C (EC50 = 0.045 μmol/L, SI = 4753) which were superior to Nevirapine and Etravirine. Notably, R10L4 was characterized with significantly reduced cytotoxicity (CC50 = 216.51 μmol/L) and showed no remarkable in vivo toxic effects (acute and subacute toxicity). Moreover, the computer-based docking study was also employed to characterize the binding mode between R10L4 and HIV-1 RT. Additionally, R10L4 presented an acceptable pharmacokinetic profile. Collectively, these results deliver precious insights for next optimization and indicate that the sulfonamide IAS derivatives are promising NNRTIs for further development.

The average life expectancy (ALE) of persons with disabilities (PWDs) is much shorter than that of the total population in many countries. However, there have been relatively few empirical studies on the ALE of PWDs in China. This study estimates the ALE and compiles the life tables of PWDs in China using data on 1,359,812 PWDs registered in the Special Surveys of Basic Services and Needs of the Disabled (SSBSND) in K Province in China from 2015 to 2017. The ALE of PWDs at age 20 is 45.2 years (95% CI: 44.7–45.8) for men and 48.1 years (95% CI: 47.6–48.6) for women, which is 15.0 years (men) and 16.5 years (women) lower than that of the entire population. The ALE of those with the most severe disability is only 33.7 years (95% CI: 32.2–45.1) for men and 37.1 years (95% CI: 35.3–38.8) for women. The ALE is relatively short for persons with intellectual and physical disabilities; moderate for those with hearing, speech, and mental disabilities; and relatively long for those with visual and multiple disabilities. Of the PWDs participating in basic old-age insurance (BOI), more than 30% do not live long enough to receive their pensions. As such, because a large proportion of PWDs die before 60 years old, social policies for PWDs should be specially designed.

Our previous studies have shown that the introduction of structurally diverse benzyl side chains at the C5-NH2 position of oseltamivir to occupy 150-cavity contributes to the binding affinity with neuraminidase and anti-influenza activity. To obtain broad-spectrum neuraminidase inhibitors, we designed and synthesised a series of novel oseltamivir derivatives bearing different N-heterocycles substituents that have been proved to induce opening of the 150-loop of group-2 neuraminidases. Among them, compound 6k bearing 4-((r)-2-methylpyrrolidin-1-yl) benzyl group exhibited antiviral activities similar to or weaker than those of oseltamivir carboxylate against H1N1, H3N2, H5N1, H5N6 and H5N1-H274Y mutant neuraminidases. More encouragingly, 6k displayed nearly 3-fold activity enhancement against H3N2 virus over oseltamivir carboxylate and 2-fold activity enhancement over zanamivir. Molecular docking studies provided insights into the explanation of its broad-spectrum potency against wild-type neuraminidases. Overall, as a promising lead compound, 6k deserves further optimisation by fully considering the ligand induced flexibility of the 150-loop.

Abstract HIV-1 reverse transcriptase is one of the most attractive targets for the treatment of AIDS. However, the rapid emergence of drug-resistant strains and unsatisfactory drug-like properties seriously limit the clinical application of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Here we show that a series of piperazine sulfonyl-bearing diarylpyrimidine-based NNRTIs were designed to improve the potency against wild-type and NNRTI-resistant strains by enhancing backbone-binding interactions. Among them, compound 18b1 demonstrates single-digit nanomolar potency against the wild-type and five mutant HIV-1 strains, which is significantly better than the approved drug etravirine. The co-crystal structure analysis and molecular dynamics simulation studies were conducted to explain the broad-spectrum inhibitory activity of 18b1 against reverse transcriptase variants. Besides, compound 18b1 demonstrates improved water solubility, cytochrome P450 liability, and other pharmacokinetic properties compared to the currently approved diarylpyrimidine (DAPY) NNRTIs. Therefore, we consider compound 18b1 a potential lead compound worthy of further study.

The combination of higher-order topological insulators and valley photonic crystals has recently aroused extensive attentions due to the great potential in flexible and efficient optical field manipulations. Here, we computationally propose a photonic device for the 1550 nm communication band, in which the topologically protected electromagnetic modes with high quality can be selectively triggered and modulated on demand. Through introducing two valley photonic crystal units without any structural alteration, we successfully achieve multi-dimensional coupled topological states thanks to the diverse electromagnetic characteristics of two valley edge states. According to the simulations, the constructed topological photonic devices can realize Fano lines on the spectrum and show high-quality localized modes by tuning the coupling strength between the zero-dimensional valley corner states and the one-dimensional valley edge states. Furthermore, we extend the valley-locked properties of edge states to higher-order valley topological insulators, where the selected corner states can be directionally excited by chiral source. More interestingly, we find that the modulation of multi-dimensional coupled photonic topological states with pseudospin dependence become more efficient compared with those uncoupled modes. This work presents a valuable approach for multi-dimensional optical field manipulation, which may support potential applications in on-chip integrated nanophotonic devices.

A 3D high-resolution general ocean circulation model was implemented and validated to study the characteristics and seasonal variability of the internal tides in the Arabian Sea (AS). Three major source locations of internal tides were identified: Socotra Island, the northeastern shelf area of AS, and the Maldives. Around Socotra Island, internal tides propagate both southward and northward, before quickly dissipating. The internal tides generated in the northeastern AS split into two branches: Branch-I propagates perpendicular to the shelf, whereas Branch-II propagates more southernly. The internal tides originated in the Maldives propagate almost latitudinally both eastwards and westwards. Generally, the internal tides in the AS are more pronounced in January as shown by the forcing function, energy flux, and conversion rate. The hourly average conversion rate for the entire domain, including the AS, the Red Sea, and the Arabian Gulf – was 34.28 GW in January and 20.51 GW in July, suggesting a slightly larger barotropic-to-baroclinic conversion rate in January, probably due to the strong stratification around 100 meters in winter.

Background: Acquired immunodeficiency syndrome (AIDS) has seriously endangered human life and health, the main pathogenic agent is human immunodeficiency virus type 1 (HIV-1). The combination antiretroviral therapy (cART) has shown serious drug resistance and side effects, and the discovery of HIV-1 capsid inhibitors is an effective way to solve the problem. Recent studies have shown significant progress in the research of HIV-1 capsid inhibitors. However, there is still a lack of comprehensive overview of bibliometric analysis in this field. This study aimed to provide the research trends and hotspots of HIV-1 capsid inhibitors.Method: Publications related to HIV-1 capsid inhibitors from 2000 to 2022 were searched on the Web of Science Core Collection (WoSCC) database and screened according to inclusion criteria. VOSviewer was conducted to evaluate the results.Results: 96 publications from 25 countries were finally included, and the number of annual publications related to HIV-1 capsid inhibitors showed an increasing trend. The United States was the most productive country with the most publication number, H-index, and total citation number, as well as the widest international cooperation. The most popular journal in this field was Journal of Virology. Drexel University was the most productive institution, and Simon Cocklin participated in the most publications. Keywords co-occurrence analysis exhibited that studying the molecular mechanism of capsid protein, discovering drug candidates, and improving antiretroviral therapy are the main and hot topics in this field.Conclusion: This is the first bibliometric study in the field of HIV-1 capsid inhibitors, which comprehensively analyzed the research trends and hotspots in this direction. This work is expected to provide the scientific community with new insights to promote the research of HIV-1 capsid inhibitors.

Photocatalyst-enzyme coupling process for visible light driven biotransformation holds promise in producing solar chemicals. In this work, aiming to produce furfuryl alcohol, the important bulk chemical that is typically derived from renewable lignocellulose, a highly selective furfural hydrogenation process is proposed by coordinating the alcohol dehydrogenase with the ZnIn2S4 assistant reduced form of nicotinamide adenine dinucleotid (NADH) regeneration. Results indicated that under visible light irradiation, the hierarchical ZnIn2S4 microspheres exhibited excellent holes and electrons separating efficiency, affording to high NADH regeneration (yield of 90.2±3.28%). When adopting the photo-biocoupled reduction process in furfural transformation, a furfuryl alcohol yield of 79.4±1.95% was achieved under the optimized conditions. The photocatalyst-enzyme coupling process also showed good stability, exceeding 70% of catalytic activity was reserved after reusing the catalysts for 10 cycles. The novel photo-biocoupled system showed promising in extending to the highly selective hydrogenation of other biochemicals from lignocelluloses.

Abstract Background The prognosis of hepatocellular carcinoma (HCC) varies considerably among patients with the same disease stage and characteristics, and only about two thirds show high levels of α-fetoprotein (AFP), a common prognostic indicator for HCC. Here, we assessed whether the combination of presurgical serum levels of AFP and carbohydrate antigen 19-9 (CA19-9) can predict the prognosis of HCC patients after hepatectomy. Methods The clinicopathological characteristics and post-hepatectomy outcomes of 711 HCC patients were retrospectively reviewed. The patients were classified into three groups based on whether their preoperative serum levels of both AFP and CA19-9 were higher than the respective cut-offs of 400 ng/ml and 37 U/ml [double positive (DP)], the level of only one marker was higher than the cut-off [single positive (SP)], or neither level was higher than the cut-off [negative (N)]. The overall survival (OS) and recurrence-free survival (RFS) rates were estimated using Kaplan–Meier curves. Univariate and multivariate survival analyses were performed to identify the clinicopathological factors significantly associated with HCC prognosis. Results The 1-year, 3-year, and 5-year RFS and OS rates in the N group were significantly higher than those in the SP group, while the DP group showed the lowest rates. Multivariate Cox regression analysis showed that large tumor size (> 5 cm), multiple tumors (≥ 2), incomplete tumor capsule, positive microvascular invasion, Barcelona Clinic Liver Cancer C stage, and CA19-9 level > 37 U/mL were independent risk factors for RFS and OS in HCC patients. Moreover, aspartate aminotransferase levels > 40 U/L proved to be an independent prognostic factor for OS. Conclusion The combination of serum AFP and CA19-9 levels may be a useful prognostic marker for HCC patients after hepatectomy.

Abstract Coastal lagoons are biodiversity hotspots that support neighboring ecosystems and various services. They can exhibit distinct biophysical characteristics compared to the adjacent open sea and act paradoxically as autonomous ecosystems. Using remotely sensed observations and state‐of‐the‐art numerical simulations, the role of water column hydrodynamics in shaping the seasonal succession of phytoplankton biomass was investigated for a non‐estuarine coastal lagoon situated in the northeastern Red Sea. Observations reveal that seasonal phytoplankton blooms inside the lagoon occur during a distinctively different period compared to the adjacent open sea. We provide evidence that this striking difference is due to the contrasting hydrodynamic conditions between inside and outside the lagoon, through their effects on stratification that regulate nutrient availability and hence favorable conditions to sustain rapid phytoplankton growth. The proposed mechanism may offer new insights into understanding the biophysical dynamics of non‐estuarine coastal lagoons in other tropical regions of the global oceans.

Influenza is an acute respiratory infectious disease caused by the influenza virus, affecting people globally and causing significant social and economic losses. Due to the inevitable limitations of vaccines and approved drugs, there is an urgent need to discover new anti-influenza drugs with different mechanisms. The viral ribonucleoprotein complex (vRNP) plays an essential role in the life cycle of influenza viruses, representing an attractive target for drug design. In recent years, the functional area of constituent proteins in vRNP are widely used as targets for drug discovery, especially the PA endonuclease active site, the RNA-binding site of PB1, the cap-binding site of PB2 and the nuclear export signal of NP protein. Encouragingly, the PA inhibitor baloxavir has been marketed in Japan and the United States, and several drug candidates have also entered clinical trials, such as favipiravir. This article reviews the compositions and functions of the influenza virus vRNP and the research progress on vRNP inhibitors, and discusses the representative drug discovery and optimization strategies pursued.

Novel therapies are urgently needed to improve global treatment of SARS-CoV-2 infection. Herein, we briefly provide a concise report on the medicinal chemistry strategies towards the development of effective SARS-CoV-2 inhibitors with representative examples in different strategies from the medicinal chemistry perspective.

Abstract As a highly pathogenic human coronavirus, SARS-CoV-2 has to counteract an intricate network of antiviral host responses to establish infection and spread. The nucleic acid-induced stress response is an essential component of antiviral defense and is closely related to antiviral innate immunity. However, whether SARS-CoV-2 regulates the stress response pathway to achieve immune evasion remains elusive. In this study, SARS-CoV-2 NSP5 and N protein were found to attenuate antiviral stress granule (avSG) formation. Moreover, NSP5 and N suppressed IFN expression induced by infection of Sendai virus or transfection of a synthetic mimic of dsRNA, poly (I:C), inhibiting TBK1 and IRF3 phosphorylation, and restraining the nuclear translocalization of IRF3. Furthermore, HEK293T cells with ectopic expression of NSP5 or N protein were less resistant to vesicular stomatitis virus infection. Mechanistically, NSP5 suppressed avSG formation and disrupted RIG-I–MAVS complex to attenuate the RIG-I–mediated antiviral immunity. In contrast to the multiple targets of NSP5, the N protein specifically targeted cofactors upstream of RIG-I. The N protein interacted with G3BP1 to prevent avSG formation and to keep the cofactors G3BP1 and PACT from activating RIG-I. Additionally, the N protein also affected the recognition of dsRNA by RIG-I. This study revealed the intimate correlation between SARS-CoV-2, the stress response, and innate antiviral immunity, shedding light on the pathogenic mechanism of COVID-19.

Summary: Background: Universal health coverage (UHC) is a core element of Sustainable Development Goals and has become a global healthcare priority. China has been committing to provide all citizens with affordable and equitable basic healthcare over past decades. However, progress towards UHC in China has not been comprehensively assessed. This study aims to comprehensively evaluate the progress towards UHC in China by examining trends in service coverage and financial protection from 1993 to 2018, and estimating the probability of achieving UHC targets by 2030. Methods: Following the framework proposed by World Health Organization and World Bank, we selected 12 prevention service indicators, 12 treatment service indicators, and two financial protection indicators to evaluate China's progress towards UHC. We used data from four nationally representative household surveys to assess the trends in service coverage and financial protection between 1993 and 2018, as well as their inequalities across subgroups. Meta-analysis was used to construct the composite prevention and treatment indices. The regression-based relative index of inequality was used to measure the income-related inequality of UHC indicators. Bayesian linear regression was conducted to predict progress towards UHC by 2030, and the probability of achieving UHC targets. Findings: Of the 24 service coverage indicators used in this study, most of them experienced improvements between 1993 and 2018. The composite prevention index increased from 65.6% (95% CI: 52.1%–77.9%) to 87.7% (95% CI: 81.8%–92.6%) and the composite treatment index increased from 57.1% (95% CI: 43.5%–70.1%) to 75.5% (95% CI: 66.6%–83.5%). The inequalities of service coverage experienced significant declines during this period. Based on our projections, most indicators except ones in the area of non-communicable diseases (NCD) will achieve the 80% coverage target by 2030, and the prevention and treatment indices will increase to 92.7% (95% CrI: 90.3%–94.7%) and 83.2% (95% CrI: 75.1%–88.8%) by then. However, we observed limited reductions in the incidences of catastrophic health expenditure and medical impoverishment. Inequalities in financial protection remained large in 2018. Interpretation: China had made significant progress in improving healthcare service coverage and reducing inequalities between 1993 and 2018. However, China faces great challenges in improving financial protection and controlling NCD on its path towards UHC. Establishment of a primary-healthcare-based integrated delivery system and provision of better financial protection for vulnerable population should be prioritized. Funding: None.

ObjectiveThis study was performed to compare the clinical effect of arthroscopic debridement vs. arthroscopic microfracture in the treatment of osteochondral lesions of the talus.MethodsWe retrospectively reviewed patients with osteochondral lesion of talus who were admitted to our hospital from April 2020 to April 2021. The patients were divided into Group A (arthroscopic debridement group, n = 39) and Group B (arthroscopic microfracture group, n = 42), and the intraoperative details in the two groups were analyzed. The American Orthopaedic Foot and Ankle Society (AOFAS) score and visual analogue scale (VAS) score were compared between the two groups before surgery and at the last follow-up.ResultsThe postoperative AOFAS score (Group A, 40.9–82.26; Group B, 38.12–87.38), VAS score (Group A, 6.44–3.92; Group B, 6.38–2.05) significantly improved in both groups, but the improvement was significantly greater in Group B than in Group A (P

Various boron-containing drugs have been approved for clinical use over the past two decades, and more are currently in clinical trials. The increasing interest in boron-containing compounds is due to their unique binding properties to biological targets; for example, boron substitution can be used to modulate biological activity, pharmacokinetic properties, and drug resistance. In this perspective, we aim to comprehensively review the current status of boron compounds in drug discovery, focusing especially on progress from 2015 to December 2020. We classify these compounds into groups showing anticancer, antibacterial, antiviral, antiparasitic and other activities, and discuss the biological targets associated with each activity, as well as potential future developments.

BackgroundChina's uneven development under the urban-rural dichotomy has led to the discouraging development of children in rural areas. China is a large agricultural country and agricultural disasters are relatively common. Rural children aged 10–15 whose families depend on the agricultural economy may experience far-reaching negative effects from these disasters.ObjectiveThis study explored the effects of agricultural disasters on rural children's development, including cognitive and noncognitive skills, and academic pressure.MethodsSurvey data from the China Family Panel Survey and the National Meteorological Administration for 2010–2018 and a fixed-effect panel model with difference-in-differences regressions were used in the study.ResultsThe fixed effects model results showed evidence that agricultural disasters have a negative impact on rural children's cognitive and noncognitive skills and a positive impact on academic pressure. The statistically significant coefficients are −0.092, −0.938, and 0.223, respectively. School and family environments also explain children's development. Robustness tests confirmed these results.ConclusionsEvidence shows that agricultural disasters have a significant negative impact on rural child development. It may be inferred that these will increase the difficulty of narrowing the urban-rural development gap. China is committed to promoting prosperity for all its people. Special attention should be paid to the consequences of disasters at the child level and appropriate measures should be taken to mitigate possible negative impacts.

Connectivity, the exchange of individuals and genes among geographically separated marine populations, plays a key role in coral reef biodiversity and resilience. The Red Sea is a semi-enclosed basin with dynamic circulation and abundant coral reefs, making it a natural laboratory for coral reef connectivity research. Previous studies broadly investigated Red Sea connectivity, but were spatially restricted to regional or sparsely-distributed reef sites. Here, using hydrodynamic and particle tracking models, a high-resolution circulation-driven physical connectivity atlas covering every Red Sea coral reef, including seasonality, was simulated and further validated against available in-situ genetic datasets. The simulation was conducted without incorporating larval traits to isolate and quantify the connectivity contributed by circulation. Our validation experiment suggests the importance of circulation in shaping the genetic structure of Red Sea reef species, supporting the Isolation By Circulation (IBC) theory in the Red Sea seascape genetics. The simulated atlas reveals that reefs in the northern Red Sea are better sources and destinations than those in the southern basin, regardless of season. The east-west connections between the southern reefs are identified to be weak. Complex circulation dynamics drive a regional-specific seasonality, e.g., the Farasan Islands reefs are better sources during summer while the nearby Bab-Al-Mandeb strait reefs are better sources during winter. The west-coast reefs are generally winter-intensified sources whereas the east-coast reefs are generally summer-intensified sources. The revealed seasonality of physical connectivity is important for larval dispersal processes as reef species may spawn in different seasons. This physical connectivity atlas provides a reference for designing marine conservation strategies from a circulation perspective and easy-to-access physical connectivity datasets for the future Red Sea seascape genetic studies.

In the face of the current energy and environmental problems, the full use of biomass resources instead of fossil energy to produce a series of high-value chemicals has great application prospects. 5-hydroxymethylfurfural (HMF), which can be synthesized from lignocellulose as a raw material, is an important biological platform molecule. Its preparation and the catalytic oxidation of subsequent products have important research significance and practical value. In the actual production process, porous organic polymer (POP) catalysts are highly suitable for biomass catalytic conversion due to their high efficiency, low cost, good designability, and environmentally friendly features. Here, we briefly describe the application of various types of POPs (including COFs, PAFs, HCPs, and CMPs) in the preparation and catalytic conversion of HMF from lignocellulosic biomass and analyze the influence of the structural properties of catalysts on the catalytic performance. Finally, we summarize some challenges that POPs catalysts face in biomass catalytic conversion and prospect the important research directions in the future. This review provides valuable references for the efficient conversion of biomass resources into high-value chemicals in practical applications.

Abstract This study investigates the risk from oil spills along the main shipping lane in the Red Sea based upon oil spill model trajectories forced by the outputs of validated high resolution regional met-ocean data. Following the intra-annual variations in the met-ocean conditions, the results are presented by classifying the basin into three regions: northern, central and southern Red Sea. The maximum distance traveled by the slick is presented for 1, 2, 5, 10, 14 and 20 days after the commencement of a spill. Different measures of hazard assessment in terms of the concentration of beached oil alongside the corresponding probability maps are also analyzed. The volume fractions of beached, dispersed and evaporated oil, 20 days after the commencement of a spill are quantified. The Red Sea general circulation is characterized by rich mesoscale eddies, which appear to be the most prevailing dynamics in oil transport in the basin. Two case events are analyzed to closely examine the effects of the mesoscale circulations on the fate of spilled oil. The results of this study provide a comprehensive assessment of oil spill hazards in the Red Sea, stemming its main shipping lane and identifies the areas at high risk that require timely mitigation strategies.

As a semienclosed marginal sea, the Red Sea connects with the open ocean through a narrow strait at its southern end, known as the Bab-al-Mandeb (BAM) strait. The water exchange between the Red Sea and the Gulf of Aden at the BAM strait is crucial for the water mass transformations and thermohaline circulation in the Red Sea as well as for nutrient supply to the open ocean. In this study, a three-dimensional high-resolution nonhydrostatic MIT general circulation model (MITgcm) was used to investigate the tidal influence on the water exchange in the BAM strait through simulations with and without tidal forcing. We found that the tidal effects on the water exchange in winter were insignificant; however, the summer intrusion of the Gulf of Aden Intermediate Water (GAIW) was strongly affected. When the simulation includes tidal forcing, the along-axis northern extension of the GAIW intrusion is reduced by u to 100 km and the monthly mean volume transport is decreased by 20% on average. Two actors that possibly contribute to the hindrance effects of tides in summer are (i) the tidal residual currents that propagate in a direction opposite to the pathway of the GAIW intrusion currents nd (ii) the enhanced vertical mixing at the pycnocline and near the benthic topography of the BAM strait, which triggers more instabilities along the pathway of the intrusion.

Abstract Background Rilpivirine (RPV) was approved by the U.S. FDA (Food and Drug Administration) in 2011 to treat individuals infected with human immunodeficiency virus 1 (HIV-1). Significantly, rilpivirine is three fold more potent than etravirine. Once-daily, it is used with a low oral dose (25 mg/tablet), decreasing the drug administration and bringing a better choice to the patients. However, there are many shortcomings in the existing synthesis route of RPV, such as the high cost, prolonged reaction time and low yield (18.5%). Results This article describes our efforts to develop an efficient and practical microwave-promoted method to synthesize rilpivirine using less toxic organic reagents and low boiling solvents. The last step's reaction time decreased from 69 h to 90 min through this optimized synthetic procedure, and the overall yield improved from 18.5 to 21%. In addition, the yield of intermediate 3 increased from 52 to 62% compared to the original patent. Conclusion Overall, through a series of process optimization, we have developed a practical synthesis method of rilpivirine, which is easy to scale with higher yield and shorter reaction time.

Detecting mesoscale ocean eddies provides a better understanding of the oceanic processes that govern the transport of salt, heat, and carbon. Established eddy detection techniques rely on physical or geometric criteria, and they notoriously fail to predict eddies that are neither circular nor elliptical in shape. Recently, deep learning techniques have been applied for semantic segmentation of mesoscale eddies, relying on the outputs of traditional eddy detection algorithms to supervise the training of the neural network. However, this approach limits the network’s predictions because the available annotations are either circular or elliptical. Moreover, current approaches depend on the sea-surface height, temperature, or currents as inputs to the network, and these data may not provide all the information necessary to accurately segment eddies. In the present work, we have trained a neural network for the semantic segmentation of eddies using human-based—and expert-validated—annotations of eddies in the Arabian Sea. Training with human-annotated datasets enables the network predictions to include more complex geometries, which occur commonly in the real ocean. We then examine the impact of different combinations of input surface variables on the segmentation performance of the network. The results indicate that providing additional surface variables as inputs to the network improves the accuracy of the predictions by approximately 5%. We have further fine-tuned another pre-trained neural network to segment eddies and achieved a reduced overall training time and higher accuracy compared to the results from a network trained from scratch.

Abstract Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has quickly spread worldwide and has affected more than 10 million individuals. A typical feature of COVID-19 is the suppression of type I and III interferon (IFN)-mediated antiviral immunity. However, the molecular mechanism by which SARS-CoV-2 evades antiviral immunity remains elusive. Here, we reported that the SARS-CoV-2 membrane (M) protein inhibits the production of type I and III IFNs induced by the cytosolic dsRNA-sensing pathway mediated by RIG-I/MDA-5–MAVS signaling. In addition, the SARS-CoV-2 M protein suppresses type I and III IFN induction stimulated by SeV infection or poly (I:C) transfection. Mechanistically, the SARS-CoV-2 M protein interacts with RIG-I, MAVS, and TBK1, thus preventing the formation of the multiprotein complex containing RIG-I, MAVS, TRAF3, and TBK1 and subsequently impeding the phosphorylation, nuclear translocation, and activation of IRF3. Consequently, ectopic expression of the SARS-CoV-2 M protein facilitates the replication of vesicular stomatitis virus. Taken together, these results indicate that the SARS-CoV-2 M protein antagonizes type I and III IFN production by targeting RIG-I/MDA-5 signaling, which subsequently attenuates antiviral immunity and enhances viral replication. This study provides insight into the interpretation of SARS-CoV-2-induced antiviral immune suppression and illuminates the pathogenic mechanism of COVID-19.

The quantum spin Hall effect is limited to one-dimensional lower boundary states which limits the possibilities for its exploitation in photonic devices. Here, the authors demonstrate a higher-order quantum spin Hall effect in a photonic crystal and observe opposite pseudospin corner states.

In this report, a series of novel piperidine-substituted thiophene[3,2-d]pyrimidine derivatives were designed to explore the hydrophobic channel of the non-nucleoside reverse transcriptase inhibitors binding pocket (NNIBP) by incorporating an aromatic moiety to the left wing of the lead K-5a2. The newly synthesized compounds were evaluated for anti-HIV potency in MT-4 cells and inhibitory activity to HIV-1 reverse transcriptase (RT). Most of the synthesized compounds exhibited broad-spectrum activity toward wild-type and a wide range of HIV-1 strains carrying single non-nucleoside reverse transcriptase inhibitors (NNRTI)-resistant mutations. Especially, compound 26 exhibited the most potent activity against wild-type and a panel of single mutations (L100I, K103N, Y181C, Y188L and E138K) with an EC50 ranging from 6.02 to 23.9 nmol/L, which were comparable to those of etravirine (ETR). Moreover, the RT inhibition activity, preliminary structure–activity relationship and molecular docking were also investigated. Furthermore, 26 exhibited favorable pharmacokinetics (PK) profiles and with a bioavailability of 33.8%. Taken together, the results could provide valuable insights for further optimization and compound 26 holds great promise as a potential drug candidate for the treatment of HIV-1 infection.

The catalytic reduction of renewable furfural into furfuryl alcohol for various applications is in the ascendant. Nonetheless, the conventional chemo-catalysis hydrogenation of furfural always suffers from poor selectivity, harsh conditions, and expensive catalysts. Herein, to overcome the serious technical barriers of conventional furfuryl alcohol production, an alternative bio-electrocatalytic hydrogenation system was established under mild and neutral conditions, where the dissolved cofactor (NADH) and the alcohol dehydrogenase (ADH) participated in a tandem reaction driven by the electron from a novel Rh (III) complex fixed cathode. Under the optimized conditions, 81.5% of furfural alcohol selectivity can be realized at −0.43 V vs. RHE. This contribution presents a ‘green’ and promising route for the valorization of furfural and other biomass compounds.

This study presents proof of concept for designing a novel HIV-1 covalent inhibitor targeting the highly conserved Tyr318 in the HIV-1 non-nucleoside reverse transcriptase inhibitors binding pocket to improve the drug resistance profiles. The target inhibitor ZA-2 with a fluorosulfate warhead in the structure was found to be a potent inhibitor (EC50 = 11–246 nM) against HIV-1 IIIB and a panel of NNRTIs-resistant strains, being far superior to those of NVP and EFV. Moreover, ZA-2 was demonstrated with lower cytotoxicity (CC50 = 125 µM). In the reverse transcriptase inhibitory assay, ZA-2 exhibited an IC50 value of 0.057 µM with the ELISA method, and the MALDI-TOF MS data demonstrated the covalent binding mode of ZA-2 with the enzyme. Additionally, the molecular simulations have also demonstrated that compounds can form covalent binding to the Tyr318.

The Coronavirus Disease 2019 (COVID-19) and dengue fever (DF) pandemics both remain to be significant public health concerns in the foreseeable future. Anti-SARS-CoV-2 drugs and vaccines are both indispensable to eliminate the epidemic situation. Here, two piperazine-based polyphenol derivatives DF-47 and DF-51 were identified as potential inhibitors directly blocking the active site of SARS-CoV-2 and DENV RdRp. Data through RdRp inhibition screening of an in-house library and in vitro antiviral study selected DF-47 and DF-51 as effective inhibitors of SARS-CoV-2/DENV polymerase. Moreover, in silico simulation revealed stable binding modes between the DF-47/DF-51 and SARS-CoV-2/DENV RdRp, respectively, including chelating with Mg2+ near polymerase active site. This work discovered the inhibitory effect of two polyphenols on distinct viral RdRp, which are expected to be developed into broad-spectrum, non-nucleoside RdRp inhibitors with new scaffold.

HIV-1 capsid (CA) performs multiple roles in the viral life cycle and is a promising target for antiviral development. In this work, we describe the design, synthesis, assessment of antiviral activity, and mechanistic investigation of 20 piperazinone phenylalanine derivatives with a terminal indole or benzene ring. Among them, F2-7f exhibited moderate anti-HIV-1 activity with an EC50 value of 5.89 μM, which was slightly weaker than the lead compound PF74 (EC50 = 0.75 μM). Interestingly, several compounds showed a preference for HIV-2 inhibitory activity, represented by 7f with an HIV-2 EC50 value of 4.52 μM and nearly 5-fold increased potency over anti-HIV-1 (EC50 = 21.81 μM), equivalent to PF74 (EC50 = 4.16 μM). Furthermore, F2-7f preferred to bind to the CA hexamer rather than to the monomer, similar to PF74, according to surface plasmon resonance results. Molecular dynamics simulation indicated that F2-7f and PF74 bound at the same site. Additionally, we computationally analyzed the ADMET properties for 7f and F2-7f. Based on this analysis, 7f and F2-7f were predicted to have improved drug-like properties and metabolic stability over PF74, and no toxicities were predicted based on the chemotype of 7f and F2-7f. Finally, the experimental metabolic stability results of F2-7f in human liver microsomes and human plasma moderately correlated with our computational prediction. Our findings show that F2-7f is a promising small molecule targeting the HIV-1 CA protein with considerable development potential.