Inhibition of M. tuberculosis and human ATP synthase by BDQ and TBAJ-587.

Bedaquiline (BDQ), a first-in-class diarylquinoline anti-tuberculosis drug, and its analogue, TBAJ-587, prevent the growth and proliferation of Mycobacterium tuberculosis by inhibiting ATP synthase1,2. However, BDQ also inhibits human ATP synthase3. At present, how these compounds interact with either M. tuberculosis ATP synthase or human ATP synthase is unclear. Here we present cryogenic electron microscopy structures of M. tuberculosis ATP synthase with and without BDQ and TBAJ-587 bound, and human ATP synthase bound to BDQ. The two inhibitors interact with subunit a and the c-ring at the leading site, c-only sites and lagging site in M. tuberculosis ATP synthase, showing that BDQ and TBAJ-587 have similar modes of action. The quinolinyl and dimethylamino units of the compounds make extensive contacts with the protein. The structure of human ATP synthase in complex with BDQ reveals that the BDQ-binding site is similar to that observed for the leading site in M. tuberculosis ATP synthase, and that the quinolinyl unit also interacts extensively with the human enzyme. This study will improve researchers' understanding of the similarities and differences between human ATP synthase and M. tuberculosis ATP synthase in terms of the mode of BDQ binding, and will allow the rational design of novel diarylquinolines as anti-tuberculosis drugs.

Microplastics release from face masks: Characteristics, influential factors, and potential risks.

Since the COVID-19 pandemic, face masks have been used popularly and disposed of improperly, leading to the generation of a large amount of microplastics. The objective of this review is to provide a comprehensive insight into the characteristics of mask-derived microplastics, the influential factors of microplastics release, and the potential risks of these microplastics to the environment and organisms. Mask-derived microplastics were predominantly transparent fibers, with a length of <1 mm. The release of microplastics from masks is mainly influenced by mask types, use habits, and weathering conditions. Under the same conditions, surgical masks release more microplastics than other types of masks. Long-term wearing of masks and the disinfection for reuse can promote the release of microplastics. Environmental media, UV irradiation, temperature, pH value, and mechanical shear can also influence the microplastics release. The risks of mask-derived microplastics to human health via inhalation cannot be neglected. Future studies should pay more attention to the release of microplastics from the masks with alternative materials and under more weathering conditions.

Solid pseudopapillary neoplasm: Report of a case of primary ovarian origin and review of the literature.

Background: Solid pseudopapillary neoplasms (SPNs) are uncommon tumors of low malignancy with a generally favorable prognosis, mostly originating from the pancreas. To date, 12 cases of SPNs with a primary ovarian origin (SPN-Os) have been reported globally, and their detailed characteristics have not been fully elucidated. Case description: We reported the 13th SPN-O case, which occurred in a 52-year-old woman with an 18.5 cm left ovarian mass. Four imaging methods, including ultrasound, computed tomography, magnetic resonance imaging and positron emission tomography, were utilized before surgery. An elevated level of serum cancer antigen 125 was detected and a total hysterectomy plus bilateral salpingo-oophorectomy was performed. Microscopic examination revealed a typical solid pseudopapillary structure. The tumor cells were stained focally for pan-cytokeratin, synaptophysin, CD99 and CD10, while ß-catenin, vimentin and CD56 were diffusely expressed. The Ki-67 proliferation index was 3%, and immunohistochemical (IHC) staining for chromogranin-A, inhibin-a, and E-cadherin was negative. No evidence of recurrence or metastasis was observed by clinical and imaging data during a 5-month postoperative follow-up. Conclusion: This is a report of an unusual case of a primary ovarian SPN with an up-to-date review of SPN-Os. A minimum combination of imaging methods and IHC stains was proposed for SPN-Os, which may prove beneficial in clinical practice.

Structure of the human ATP synthase.

Biological energy currency ATP is produced by F1Fo-ATP synthase. However, the molecular mechanism for human ATP synthase action remains unknown. Here, we present snapshot images for three main rotational states and one substate of human ATP synthase using cryoelectron microscopy. These structures reveal that the release of ADP occurs when the ß subunit of F1Fo-ATP synthase is in the open conformation, showing how ADP binding is coordinated during synthesis. The accommodation of the symmetry mismatch between F1 and Fo motors is resolved by the torsional flexing of the entire complex, especially the γ subunit, and the rotational substep of the c subunit. Water molecules are identified in the inlet and outlet half-channels, suggesting that the proton transfer in these two half-channels proceed via a Grotthus mechanism. Clinically relevant mutations are mapped to the structure, showing that they are mainly located at the subunit-subunit interfaces, thus causing instability of the complex.

Social support and posttraumatic growth: A meta-analysis.

BACKGROUND: The beneficial role of social support on posttraumatic growth (PTG) has been assumed by theoretical models and established in some studies. However, there are inconsistent findings and little knowledge on moderators. The present study aims to investigate the overall effect size of the relationship and identify factors affecting the association. METHODS: Six electronic databases were searched. Newcastle-Ottawa Quality Assessment Scale (NOS) were used to evaluate the quality of studies. Study quality, study design, trauma type, PTG measure, social support measure, continent, publishing language, sample size, gender, religion, and age were analyzed as moderators. Meta-regression was conducted with the significant differential predictors in moderator analysis. RESULTS: The meta-analysis included 217 samples and a total of 47,940 participants from both longitudinal and cross-sectional studies. There was a medium positive effect size between social support and PTG in random effect model, r = 0.418, p < .001. The meta-regression analysis indicated that the association between social support and PTG was stronger among caregivers (vs. other traumatized samples), Chinese, older individuals and studies with smaller sample size. LIMITATIONS: Only survey results were included in the analysis. The retrospective self-report may limit a more objective assessment of the relations. In addition, 87 % of the studies were cross-sectional, which may influence the estimation of a valid effect size. CONCLUSIONS: Regarding the medium positive association between social support and PTG, it is important to enhance social support for trauma survivors. It will be especially effective for caregivers, Chinese, and older people.

Super-resolution microscopy enabled by high-efficiency surface-migration emission depletion.

Nonlinear depletion of fluorescence states by stimulated emission constitutes the basis of stimulated emission depletion (STED) microscopy. Despite significant efforts over the past decade, achieving super-resolution at low saturation intensities by STED remains a major technical challenge. By harnessing the surface quenching effect in NaGdF4:Yb/Tm nanocrystals, we report here high-efficiency emission depletion through surface migration. Using a dual-beam, continuous-wave laser manipulation scheme (975-nm excitation and 730-nm de-excitation), we achieved an emission depletion efficiency of over 95% and a low saturation intensity of 18.3 kW cm-2. Emission depletion by surface migration through gadolinium sublattices enables super-resolution imaging with sub-20 nm lateral resolution. Our approach circumvents the fundamental limitation of high-intensity STED microscopy, providing autofluorescence-free, re-excitation-background-free imaging with a saturation intensity over three orders of magnitude lower than conventional fluorophores. We also demonstrated super-resolution imaging of actin filaments in Hela cells labeled with 8-nm nanoparticles. Combined with the highly photostable lanthanide luminescence, surface-migration emission depletion (SMED) could provide a powerful mechanism for low-power, super-resolution imaging or biological tracking as well as super-resolved optical sensing/writing and lithography.

Phase Separation-Mediated Chromatin Organization and Dynamics: From Imaging-Based Quantitative Characterizations to Functional Implications.

As an effective and versatile strategy to compartmentalize cellular components without the need for lipid membranes, phase separation has been found to underpin a wide range of intranuclear processes, particularly those involving chromatin. Many of the unique physico-chemical properties of chromatin-based phase condensates are harnessed by the cell to accomplish complex regulatory functions in a spatially and temporally controlled manner. Here, we survey key recent findings on the mechanistic roles of phase separation in regulating the organization and dynamics of chromatin-based molecular processes across length scales, packing states and intranuclear functions, with a particular emphasis on quantitative characterizations of these condensates enabled by advanced imaging-based approaches. By illuminating the complex interplay between chromatin and various chromatin-interacting molecular species mediated by phase separation, this review sheds light on an emerging multi-scale, multi-modal and multi-faceted landscape that hierarchically regulates the genome within the highly crowded and dynamic nuclear space. Moreover, deficiencies in existing studies also highlight the need for mechanism-specific criteria and multi-parametric approaches for the characterization of chromatin-based phase separation using complementary techniques and call for greater efforts to correlate the quantitative features of these condensates with their functional consequences in close-to-native cellular contexts.

In situ preparation of BiOCl0.75I0.25/g-C3N4-Cl in reduced graphene hydrogel photoanode for simultaneous removal of tetracycline hydrochloride and hexavalent chromium with efficient electricity generation.

A novel three-dimensional porous photoanode of BiOCl0.75I0.25/g-C3N4-Cl/reduced graphene hydrogel (BOCI/CNCl/rGH) was successfully fabricated by a combined in-situ growth and re-dispersion strategy. It was verified that BOCI/CNCl composite exhibited photocatalytic efficiency, and the introduced rGH not only provided superior conductivity which was favorable for charge transfer, but also increased the specific surface area and reactive sites than the fluorine-doped tin oxide (FTO) coated glass. On the basis of these advantages, the short-circuit current and maximum power density were increased by 5.1 and 1.2 times, and the respective removal efficiency of tetracycline hydrochloride (TCH) and hexavalent chromium (Cr(VI)) was increased by 29% and 32% in BOCI/CNCl/rGH, comparing with BOCI/CNCl/FTO. Notably, the removal efficiencies could reach 87% and 85% in TCH and Cr(VI) coexistence system, which were higher than those in TCH or Cr(VI) alone system. This study provides a novel strategy for designing highly efficient photoanode for multiple pollutants removal and electricity generation.

Nitrogen Vacancy-Modulated Peroxymonosulfate Nonradical Activation for Organic Contaminant Removal via High-Valent Cobalt-Oxo Species.

Rapid generation of high-valent cobalt-oxo species (Co(IV)═O) for the removal of organic contaminants has been challenging because of the low conversion efficiency of Co(III)/Co(II) and the high activation energy barrier of the Co(II)-oxidant complex. Herein, we introduced nitrogen (N) vacancies into graphite carbon nitride imbedded with cobalt carbonate (CCH/CN-Vn) in a peroxymonosulfate (PMS)/visible light system to break the limitations of a conventional two-electron transfer path. These N vacancies enhanced the electron distribution of the Co 3d orbital and lowered the energy barrier to cleave the O-O bond of PMS in the Co(II)-PMS complex, achieving the modulation of major active species from 1O2 to Co(IV)═O. The developed synergistic system that exhibited adsorption and oxidation showed remarkable selectivity and contaminant removal performance in inorganic (Cl-, NO3-, HCO3-, and HPO4-) organic (HA) and even practical aqueous matrices (tap water and secondary effluent). This study provides a novel mechanistic perspective to modulate the nonradical path for refractory contaminant treatment via defect engineering.

Identification of putative binding interface of PI(3,5)P2 lipid on rice black-streaked dwarf virus (RBSDV) P10 protein.

Rice black-streaked dwarf virus (RBSDV) is an important reovirus that infects both plants and its transmission vector small brown planthopper, causing severe crop loss. High affinity binding between RBSDV P10 and PI(3,5)P2 lipid layer was measured using biolayer interferometry (BLI). Subcellular co-localization of PI(3,5)P2 and RBSDV P10 was observed on membranous structures in insect cells with stochastic optical reconstruction microscopy (STORM) imaging. Putative interacting sites of PI(3,5)P2 lipid on a computational predicted RBSDV P10 structure were mapped to its "C-domain" (250-470 aa), using HDXMS data. The BLI and STORM results showed binding and co-localization of RBSDV P10, and PI(3,5)P2 on vesicle-like membranous structures were corroborated with the prediction of the binding interface. Understanding the lipid binding sites on viral proteins will lead to developing strategies to block viral-lipid interaction and disrupt viral pathogenesis in insect vectors and to block virus transmission and achieve disease control of crops in the field.

One-step surface modification strategy with composition-tunable microgels: From bactericidal surface to cell-friendly surface.

As modifiers for biomaterial surfaces, soft colloidal particles not only have good film-forming properties, but can also contribute to the function of the biomaterial via their chemical and biological properties. This general approach has proven effective for surface modification, but little is known about methods to control the properties of the colloidal particles to regulate film formation and biological function. In this work, we prepared poly (N-isopropylacrylamide) microgels (ZQP) containing both a zwitterionic component (Z) to provide anti-fouling functionality, and a quaternary ammonium salt (Q) to give bactericidal functionality. Fine-tuning of the Z and Q contents allowed the preparation of microgels over a range of particle size, size distribution, charge, and film-forming capability. The films showed anti-adhesion and contact-killing properties versus Escherichia coli (E. Coli), depending on the chemical composition. They also showed excellent cytocompatibility relative to L929 cells. A variety of microgel-coated substrates (silicon wafer, PDMS, PU, PVC) showed long-term anti-bacterial activity and resistance to chemical and mechanical treatments. It is concluded that this approach allows the preparation of effective bactericidal, cytocompatible surfaces. The properties can be fine-tuned by regulation of the microgel composition, and the method is applicable universally, i.e., independent of substrate.

Technology challenges among deaf and hard of hearing elders in China during COVID-19 pandemic emergency isolation: A qualitative study.

Digital technology can be an effective tool to facilitate emergency assistance in a pandemic, but many deaf and hard-of-hearing elders may experience challenges in using and adopting these technologies. In the context of the second wave of the COVID-19 outbreak, this study employs a qualitative research method based on in-depth interviews to explore technology challenges among deaf and hard-of-hearing elders in China. The results showed that this group's technology challenges arose mainly from barriers to the mastery of digital technology tools, among which barriers to the use of smartphones, to the accessibility of online medical consultations, and to the presentation of health codes, were most noteworthy. For the informants, these barriers led to social isolation and technology avoidance. What's more, the expectation of individuals to adopt certain types of digital intelligence technologies can inadvertently create inequities for disadvantaged groups and exacerbate the "digital divide." This study highlights the need for emergency management systems to be inclusive of elders with hearing loss in times of public health crises, by providing effective technology support and training to facilitate individuals' access to services and to safeguard their health, interests, and livelihood.

External Communication Barriers among Elderly Deaf and Hard of Hearing People in China during the COVID-19 Pandemic Emergency Isolation: A Qualitative Study.

The COVID-19 pandemic poses a great risk to older people with hearing impairment, who face a higher threshold of external communication after the implementation of the emergency isolation policy. As part of a study on the optimization of external communication among the deaf and hard of hearing (DHH) population in central China, this study employed a qualitative research method based on in-depth interviews to explore the needs and difficulties faced by the older DHH group in external communication during public health emergencies in Wuhan, China, in the context of the COVID-19 pandemic. The results showed that older DHH people had weak reception of critical information about the epidemic, and had suboptimal access to medical care during emergency quarantine, which increased interpersonal communication barriers to this group. The current findings highlight the urgent need for targeted strengthening of the original emergency communication and coordination mechanisms in public health emergencies, and for improving policy inclusiveness for older DHH individuals during the COVID-19 pandemic and emergencies alike.

Exogenous hydrogen sulfide inhibits neutrophils extracellular traps formation via the HMGB1/TLR4/p-38 MAPK/ROS axis in hyperhomocysteinemia rats.

Hydrogen sulfide (H2S) prevents platelet activation and neutrophils extracellular traps (NETs) formation. However, the mechanism of sodium hydrosulfide (NaHS, a donor that produces H2S) inhibits the formation of NETs in hyperhomocysteinemia (HHcy) rats has not been previously investigated. In the experiment, the expressions of HMGB1 of platelets, the expressions of TLR4, PAD4 and the phosphor-p38 of neutrophils were measured. The NETs formations, the concentration of DNA in the serum and the culture solution of cultured neutrophils which was stimulated by platelet-rich plasma (PRP) were tested. Additionally, the cellular ROS level and SOD activity were detected. The platelets were activated and the expression of HMGB1 of platelets and NETs formation, the concentration of DNA, and the expressions of TLR4, phosphor-p38 and PAD4, the ROS level were all increased while the activity of SOD decreased in the HHcy group compared to the control group. NaHS significantly inhibited the activation of platelets, the production of ROS and the formation of NETs in neutrophils, reversed the expressions of HMGB1, TLR4, phosphor-p38, PAD4 and decreased concentration of DNA which was caused by high homocysteine. Our results demonstrate that the donor of H2S inhibits NETs formation of neutrophils via the HMGB1/TLR4/p38 MAPK/ROS pathway in hyperhomocysteinemia.

Author Correction: Highly specific multiplexed RNA imaging in tissues with split-FISH.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Highly specific multiplexed RNA imaging in tissues with split-FISH.

We present split-FISH, a multiplexed fluorescence in situ hybridization method that leverages a split-probe design to achieve enhanced specificity. Split-FISH reduces off-target background fluorescence, decreases false positives and enables accurate RNA profiling in uncleared tissues. We demonstrate the efficacy of split-FISH on various mouse tissues by quantifying the distribution and abundance of 317 genes in single cells and reveal diverse localization patterns for spatial regulation of the transcriptome in complex tissues.

Superresolution imaging reveals spatiotemporal propagation of human replication foci mediated by CTCF-organized chromatin structures.

Mammalian DNA replication is initiated at numerous replication origins, which are clustered into thousands of replication domains (RDs) across the genome. However, it remains unclear whether the replication origins within each RD are activated stochastically or preferentially near certain chromatin features. To understand how DNA replication in single human cells is regulated at the sub-RD level, we directly visualized and quantitatively characterized the spatiotemporal organization, morphology, and in situ epigenetic signatures of individual replication foci (RFi) across S-phase at superresolution using stochastic optical reconstruction microscopy. Importantly, we revealed a hierarchical radial pattern of RFi propagation dynamics that reverses directionality from early to late S-phase and is diminished upon caffeine treatment or CTCF knockdown. Together with simulation and bioinformatic analyses, our findings point to a "CTCF-organized REplication Propagation" (CoREP) model, which suggests a nonrandom selection mechanism for replication activation at the sub-RD level during early S-phase, mediated by CTCF-organized chromatin structures. Collectively, these findings offer critical insights into the key involvement of local epigenetic environment in coordinating DNA replication across the genome and have broad implications for our conceptualization of the role of multiscale chromatin architecture in regulating diverse cell nuclear dynamics in space and time.

Universal Antibacterial Surfaces Fabricated from Quaternary Ammonium Salt-Based PNIPAM Microgels.

Because of the excellent film-forming ability of poly(N-isopropylacrylamide) (PNIPAM) microgel and high-efficient bactericidal property of quaternary ammonium salt (QAS), QAS-based PNIPAM (QAS-PNIPAM) microgels are synthesized and employed to modify the surface of a range of commonly used materials including metal, plastic, and elastomer. Bacterial culture is carried out on such QAS-PNIPAM microgel-modified surfaces to examine the viability of the attached bacteria. It is found that the bactericidal efficiency is nearly 100% on the modified surfaces of all the studied materials. We attribute the high-efficient bactericidal performance of QAS-PNIPAM microgel film to the QAS component rather than the topography of the microgel film itself. In addition, the microgel film is robust and shows great integrity even after culture of the bacteria and repeated rinses, and the cell experiment demonstrates that this microgel film is cyto-compatible. Therefore, such a simple, versatile method of preparing antibacterial films paves the way for future bactericidal applications.