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Compared with the traditional mobile robots, the new concept mobile robots have greater deformation capability and richer mobile gait; similarly, they have a better capability to adapt to the environment. This paper presents a ring four-array rolling mechanism that consists of four anti-parallelogram mechanisms with revolute joints. The mechanism is connected by four anti-parallelograms in a looped configuration and has a not-totally-closed ring shape, whose external contour is similar to that of a quadrangular prism. The mechanism has planar and spherical patterns of locomotion, in which the planar pattern of locomotion includes the parallelogram rolling gait and the anti-parallelogram tumbling gait, and the spherical pattern of locomotion includes the spherical rolling gait. On this basis, the kinematic analysis of the two patterns of locomotion is carried out to obtain the positions of each point and the center of mass (CM) of the mechanism. The feasibility of the rolling locomotion of the mechanism is verified by the moving trajectory of the CM. According to analyzing the feasibility of the mechanism's obstacle-crossing and moving strategy, the mechanism is made to complete the switch between different motion modes. Through the establishment of a dynamic model and simulation, the analysis of the rolling gait of the mechanism is completed, and a prototype is made for experimental research. The results show that the anti-parallelogram ring four-array rolling mechanism has the basic rolling capability of linear movement and steering. Furthermore, in the initial state of the mechanism, the mechanism enables flexible switching between multiple rolling gaits.

This study investigates the influence of varying rolling reduction on the evolution of microstructure and mechanical properties of Mg10Gd (in wt%) alloys by caliber rolling (CR). By increasing the rolling reduction from 45 % to 65 %, a uniform bimodal structure is obtained in which coarse grains (CGs) larger than 10 µm are surrounded by fine grains (FGs). The MgGd alloy subjected to 65 % reduction exhibits superior mechanical properties, i.e. yield strength (YS) of ∼424 MPa, ultimate tensile strength (UTS) of ∼500 MPa and elongation (El.) of ∼3.3 %. The synergistic improvement in strength and ductility is primarily attributed to the combined effects of low-angle grain boundary (LAGB) strengthening, precipitation strengthening, and the coordinated deformation exhibited by the bimodal structure. In addition, caliber rolling also provides a novel approach for the design of Mg alloys with uniform bimodal structures that exhibit both high strength and ductility.

Abstract Glioblastoma (GBM) is the most aggressive primary brain tumor in adults, with a universally lethal prognosis despite maximal standard therapies. Here, we present a consensus treatment protocol based on the metabolic requirements of GBM cells for the two major fermentable fuels: glucose and glutamine. Glucose is a source of carbon and ATP synthesis for tumor growth through glycolysis, while glutamine provides nitrogen, carbon, and ATP synthesis through glutaminolysis. As no tumor can grow without anabolic substrates or energy, the simultaneous targeting of glycolysis and glutaminolysis is expected to reduce the proliferation of most if not all GBM cells. Ketogenic metabolic therapy (KMT) leverages diet-drug combinations that inhibit glycolysis, glutaminolysis, and growth signaling while shifting energy metabolism to therapeutic ketosis. The glucose-ketone index (GKI) is a standardized biomarker for assessing biological compliance, ideally via real-time monitoring. KMT aims to increase substrate competition and normalize the tumor microenvironment through GKI-adjusted ketogenic diets, calorie restriction, and fasting, while also targeting glycolytic and glutaminolytic flux using specific metabolic inhibitors. Non-fermentable fuels, such as ketone bodies, fatty acids, or lactate, are comparatively less efficient in supporting the long-term bioenergetic and biosynthetic demands of cancer cell proliferation. The proposed strategy may be implemented as a synergistic metabolic priming baseline in GBM as well as other tumors driven by glycolysis and glutaminolysis, regardless of their residual mitochondrial function. Suggested best practices are provided to guide future KMT research in metabolic oncology, offering a shared, evidence-driven framework for observational and interventional studies.

Abstract A significant challenge in measurements of neutrino oscillations is reconstructing the incoming neutrino energies. While modern fully-active tracking calorimeters such as liquid argon time projection chambers in principle allow the measurement of all final state particles above some detection threshold, undetected neutrons remain a considerable source of missing energy with little to no data constraining their production rates and kinematics. We present the first demonstration of tagging neutrino-induced neutrons in liquid argon time projection chambers using secondary protons emitted from neutron-argon interactions in the MicroBooNE detector. We describe the method developed to identify neutrino-induced neutrons and demonstrate its performance using neutrons produced in muon-neutrino charged current interactions. The method is validated using a small subset of MicroBooNE’s total dataset. The selection yields a sample with $$60\%$$ 60 % of selected tracks corresponding to neutron-induced secondary protons. At this purity, the integrated efficiency is 8.4% for neutrons that produce a detectable proton.

In groundwater pumping optimization (GPO), offline-trained data-driven surrogates can be used to replace numerical-intensive simulators in order to save computing time. The traditional offline training approach involves building surrogates prior to optimization, fitting training datasets that cover the input space uniformly or randomly, which can prove inefficient due to the potential oversampling of low-gradient areas and under-sampling of high-gradient areas. This study proposes an offline machine-learning (ML) algorithm that ranks candidate training points by scoring them based on their distance to the closest training point and on the local gradient of the surrogate estimate and then choosing the highest-rank point. This method is applied to develop surrogates for solving a two-objective GPO problem formulated on a three-dimensional (3D) island aquifer, using hydrogeological conditions representative of San Salvador Island, Bahamas. The objectives are to minimise the supply cost (fOC) resulting from groundwater pumping and desalination and maximise fresh groundwater supply (Qp), subject to constraints on seawater intrusion (SWI) control expressed in terms of aquifer drawdown Δs at pumping locations and aquifer salt mass increase ΔSM. Gaussian Process (GP) is the technique applied to construct surrogates of objectives and constraints, alongside the estimation of uncertainties. Using GP models, it is possible to estimate the probability of “Pareto optimality” for each pumping scheme by Monte Carlo simulation. Pareto optimal pumping schemes (POPS) are then characterized by a probability of occurrence, which can be verified by numerical simulation. The GP training strategy's effectiveness in generating POPS is compared to traditional training approaches, showing that such a strategy can efficiently identify reliable POPS.

ABSTRACT Mycobacterium tuberculosis, the causative agent of the airborne infection tuberculosis (TB), contains 13 mycobacterial membrane protein large (MmpL) transporters that can be divided into two distinct subclasses. These MmpL proteins play important functional roles within the mycobacterium and subsequently are considered attractive drug targets to combat TB infection. Previously, we reported both X-ray and cryo-electron microscopy (cryo-EM) structures of the MmpL3 transporter, providing high-resolution structural information for this subclass of the MmpL proteins. Thus far, there is no structural information available for the other subclass, which includes MmpL5, an inner membrane transporter that plays a critical role in iron hemostasis. Here, we report the first cryo-EM structure of the Mycobacterium smegmatis MmpL5 transporter bound with the meromycolate extension acyl carrier protein M (AcpM) to a resolution of 2.81 Å. Our structural data reveals that MmpL5 and AcpM interact in the cytoplasm to form a complex, and this allows us to propose that MmpL5 may also associate with the mycobactin L (MbtL) protein in a similar fashion to form a heterocomplex important for iron acquisition, which enables the survival and replication of the mycobacterium.IMPORTANCEThe emergence and spread of multidrug-resistant tuberculosis (TB) present enormous challenges to the global public health. The causative agent, Mycobacterium tuberculosis, has now infected more than one-third of the world's population. Here, we report the first structure of the mycobacterial membrane protein large 5 (MmpL5), an essential transporter for iron acquisition, bound with the meromycolate extension acyl carrier protein M (AcpM), indicating a plausible pathway for mycobactin translocation. Our studies will ultimately inform an era in structure-guided drug design to combat TB infection.

IntroductionAs research advances in vascularized composite allotransplantation (VCA), large animal models are essential for translational studies related to immune rejection and graft survival. However, procurement of large flaps can cause significant defects, complicating wound closure and increasing postoperative risks. This study details the surgical techniques and outcomes of autologous vertical rectus abdominis myocutaneous (VRAM) flap transplantation and neck flap isolation with induced ischemia in a swine model. The purpose of this study was to identify the most effective control procedure for use in future VRAM flap allotransplantation research.MethodsWe performed two left heterotopic autologous VRAM flap transplants and two right anterolateral neck flap isolations using female Yucatan pigs. Postoperatively, animals were monitored for complications and flap healing, with punch biopsies taken on POD1, 5, and at the end of the study for histological analysis. Transcutaneous oxygen and temperature were also recorded.ResultsBoth autologous flaps survived after vessel anastomosis, with effective closure of abdominal defects using suturable mesh, and no postoperative complications were observed. Histology revealed mild dermal edema and perivascular inflammation on POD5. In the neck flap group, both flaps survived temporary ischemia, however, postoperative complications included dorsal flap necrosis and wound dehiscence, requiring reoperation. No gross inflammation or edema was observed following surgery and histologically there was only mild dermal edema on POD5.DiscussionWe have developed a low-risk, technically feasible porcine autologous VRAM flap transplantation model and our findings support its use in future VCA studies.

Abstract Gastrointestinal (GI) disruptions and inflammatory bowel disease (IBD) are commonly associated with Parkinson’s disease (PD), but how they may impact risk for PD remains poorly understood. Herein, we provide evidence that prodromal intestinal inflammation expedites and exacerbates PD endophenotypes in rodent carriers of the human PD risk allele LRRK2 G2019S in a sex-dependent manner. Chronic intestinal damage in genetically predisposed male mice promotes α-synuclein aggregation in the substantia nigra, loss of dopaminergic neurons and motor impairment. This male bias is preserved in gonadectomized males, and similarly conferred by sex chromosomal complement in gonadal females expressing human LRRK2 G2019S. The early onset and heightened severity of neuropathological and behavioral outcomes in male LRRK2 G2019S mice is preceded by increases in α-synuclein in the colon, α-synuclein-positive macrophages in the colonic lamina propria, and loads of phosphorylated α-synuclein within microglia in the substantia nigra. Taken together, these data reveal that prodromal intestinal inflammation promotes the pathogenesis of PD endophenotypes in male carriers of LRRK2 G2019S, through mechanisms that depend on genotypic sex and involve early accumulation of α-synuclein in myeloid cells within the gut.

Abstract Novel methods for sampling and characterizing biodiversity hold great promise for re-evaluating patterns of life across the planet. The sampling of airborne spores with a cyclone sampler, and the sequencing of their DNA, have been suggested as an efficient and well-calibrated tool for surveying fungal diversity across various environments. Here we present data originating from the Global Spore Sampling Project, comprising 2,768 samples collected during two years at 47 outdoor locations across the world. Each sample represents fungal DNA extracted from 24 m3 of air. We applied a conservative bioinformatics pipeline that filtered out sequences that did not show strong evidence of representing a fungal species. The pipeline yielded 27,954 species-level operational taxonomic units (OTUs). Each OTU is accompanied by a probabilistic taxonomic classification, validated through comparison with expert evaluations. To examine the potential of the data for ecological analyses, we partitioned the variation in species distributions into spatial and seasonal components, showing a strong effect of the annual mean temperature on community composition.

This study investigates the microstructural evolution and mechanical properties of pure zinc (Zn) during extrusion and multi-pass caliber rolling (CR). Electron backscatter diffraction (EBSD) and transmission electron microscopy (TEM) analyses indicate that plastic deformation induces dynamic recrystallization (DRX), resulting in the formation of numerous low angle grain boundaries (LAGBs) and substructures. In particular, significant grain refinement (∼1.6 μm) is achieved with the texture deviating 30 ± 5° from the direction. The as-extruded pure Zn exhibits a yield strength (YS) of 130 MPa, an ultimate tensile strength (UTS) of 151 MPa, and an elongation (EL.) of 8.8 %, respectively. Subsequent caliber rolling significantly improved these mechanical properties (i.e., YS: 225 MPa; UTS: 301 MPa; EL.: 31%) due to the combined effect of grain refinement, dislocations and texture strengthening. In addition, the deformation mechanism shifts from an initial influence of both dislocations and twins to a predominance of dislocations alone.

The Mycobacterium tuberculosis (Mtb) pathogen, the causative agent of the airborne infection tuberculosis (TB), harbors a number of mycobacterial membrane protein large (MmpL) transporters. These membrane proteins can be separated into 2 distinct subclasses, where they perform important functional roles, and thus, are considered potential drug targets to combat TB. Previously, we reported both X-ray and cryo-EM structures of the MmpL3 transporter, providing high-resolution structural information for this subclass of the MmpL proteins. Currently, there is no structural information available for the subclass associated with MmpL4 and MmpL5, transporters that play a critical role in iron homeostasis of the bacterium. Here, we report cryo-EM structures of the M. smegmatis MmpL4 and MmpL5 transporters to resolutions of 2.95 Å and 3.00 Å, respectively. These structures allow us to propose a plausible pathway for siderophore translocation via these 2 transporters, an essential step for iron acquisition that enables the survival and replication of the mycobacterium.

The technical progress in the development and industrialization of floating offshore wind turbines (FOWTs) over the past decade has been significant. Yet, the higher levelized cost of energy (LCOE) of FOWTs compared to onshore wind turbines is still limiting the market share. One of the reasons for this is the larger motions and loads caused by the rough environmental excitations. Many prototype projects tend to employ more conservative substructure designs to meet the requirements for motion dynamics and structural safety. Another challenge lies in the multidisciplinary nature of a FOWT system, which consists of several strongly coupled subsystems. If these subsystems cannot work in synergy, the overall system performance may not be optimized. Previous research has shown that a well-designed blade pitch controller is able to reduce the motions and structural loads of FOWTs. Nevertheless, due to the negative aerodynamic damping effect, improvement in the performance by tuning the controller is limited. One of the solutions is adding tuned liquid multi-column dampers (TLMCDs), meaning that there is a structural solution to mitigate this limiting factor for the controller performance. It has been found that the additional damping, provided by TLMCDs, is able to improve the platform pitch stability, which allows a larger blade pitch controller bandwidth and thus a better dynamic response. However, if a TLMCD is not designed with the whole FOWT system dynamics taken into account, it may even deteriorate the overall performance. Essentially, an integrated optimization of these subsystems is needed. For this paper, we develop a control co-design optimization framework for FOWTs installed with TLMCDs. Using the multi-objective optimizer non-dominated sorting genetic algorithm II (NSGA-II), the objective is to optimize the platform, the blade pitch controller, and the TLMCD simultaneously. Five free variables characterizing these subsystems are selected, and the objective function includes the FOWT's volume of displaced water (displacement) and several motion and load indicators. Instead of searching for a unique optimal design, an optimal Pareto surface of the defined objectives is determined. It has been found that the optimization is able to improve the dynamic performance of the FOWT, which is quantified by motions and loads, when the displacement remains similar. On the other hand, if motions and loads are constant, the displacement of the FOWT can be reduced, which is an important indication of lower manufacturing, transportation, and installation costs. In conclusion, this work demonstrates the potential of advanced technologies such as TLMCDs to advance FOWTs for commercial competitiveness.

With the development of motor technology, sensorless control attracts more and more attention. In this paper, an improved flux linkage observer is proposed to overcome issues including inaccurate initial positions and sampling noise. The voltage and current models are combined, and a sliding-mode observer is designed based on the hybrid model to obtain the compensation voltage. Therefore, the estimated flux linkage after compensation can greatly resist the influence caused by inaccurate initial positions or sampling noise. Phase-locked loop technology is used to process the estimated flux linkage to get the stable estimated speed and position. The proposed scheme has a simple structure and only one parameter. It is easy to use and adjust in practice. The simulation and experimental results verify that the proposed algorithm is effective, and the estimated flux linkage and position is accurate with an inaccurate initial position.

Abstract Developing heterogeneous photocatalysts for the applications in harsh conditions is of high importance but challenging. Herein, by converting the imine linkages into quinoline groups of triphenylamine incorporated covalent organic frameworks (COFs), two photosensitive COFs, namely TFPA-TAPT-COF-Q and TFPA-TPB-COF-Q, are successfully constructed. The obtained quinoline-linked COFs display improved stability and photocatalytic activity, making them suitable photocatalysts for photocatalytic reactions under harsh conditions, as verified by the recyclable photocatalytic reactions of organic acid involving oxidative decarboxylation and organic base involving benzylamine coupling. Under strong oxidative condition, the quinoline-linked COFs show a high efficiency up to 11831.6 μmol·g−1·h−1 and a long-term recyclable usability for photocatalytic production of H2O2, while the pristine imine-linked COFs are less catalytically active and easily decomposed in these harsh conditions. The results demonstrate that enhancing the linkage robustness of photoactive COFs is a promising strategy to construct heterogeneous catalysts for photocatalytic reactions under harsh conditions.

Abstract Mitochondrial fission is a critical cellular event to maintain organelle function. This multistep process is initiated by the enhanced recruitment and oligomerization of dynamin-related protein 1 (Drp1) at the surface of mitochondria. As such, Drp1 is essential for inducing mitochondrial division in mammalian cells, and homologous proteins are found in all eukaryotes. As a member of the dynamin superfamily of proteins (DSPs), controlled Drp1 self-assembly into large helical polymers stimulates its GTPase activity to promote membrane constriction. Still, little is known about the mechanisms that regulate correct spatial and temporal assembly of the fission machinery. Here we present a cryo-EM structure of a full-length Drp1 dimer in an auto-inhibited state. This dimer reveals two key conformational rearrangements that must be unlocked through intramolecular rearrangements to achieve the assembly-competent state observed in previous structures. This structural insight provides understanding into the mechanism for regulated self-assembly of the mitochondrial fission machinery.

The rich and unique energy level structure arising from 4fn inner shell configuration of trivalent lanthanide ions (Ln3+) renders them highly attractive for light‐emitting applications. Currently, research primarily focuses on Ln3+ doping in either traditional garnets or the recently developed perovskite phosphors. However, there have been few reports on stable phosphors crystallized with pure lanthanide elements. Herein, a universal solution‐based route to eight Ln3+‐based metal halides from the organic‐inorganic A4LnX7 family is described, where A+ = 4,4‐difluoropiperidinium (DFPD+), Ln3+ = Nd3+, Eu3+, Ho3+, Sm3+, Tm3+, Tb3+, Yb3+, Er3+, and X− = Cl−, Br−. Visible photoluminescence (PL) is observed from Tb3+‐, Eu3+‐, Ho3+‐, and Sm3+‐based compounds with Tb and Eu compositions exhibiting high PL quantum yields of 90–100%; Nd3+‐, Tm3+‐, Yb3+‐, and Er3+‐based crystals show fascinating near‐infrared emission. Light‐emitting diodes (LEDs) fabricated with (DFPD)4TbCl7 yield characteristic emission of Tb3+, representing the first demonstration of electroluminescence from these organic‐inorganic Ln3+‐based metal halides. Moreover, these materials exhibit distinct excitation wavelength‐dependent emission after alloying with different Ln3+ ions, making them interesting for multicolor display and multilevel information encryption applications. It is foreseen that this study will open up the way to a possible design of robust optoelectronic devices based on lanthanide metal halides.

Abstract The high‐cost and limited availability of raw materials for lithium‐ion batteries hinder their future development and urge researchers to explore alternative battery systems. Among them, batteries utilizing the electrochemical redox reaction of metals such as Cu, Fe, Sn, etc. as the cathode to reversibly store and release energy are attractive because their raw materials are common and abundant. This review examines this type of novel battery system, introduces its basic mechanism and problems, analyses the strategies that are used to improve its reversibility and cycling stability and also proposes some possible future directions of investigations.

The Global Navigation Satellite System (GNSS) is well recognized as a valuable tool for studying ionospheric variation, providing a means to measure variations in the Total Electron Content (TEC) of the ionosphere. In this manuscript, we focus specifically on the use of GNSS networks to study ionospheric diurnal variation over China, highlighting some of the key findings and challenges in this area. We begin by describing the basic principles of GNSS-based TEC measurements. We then analyze ionospheric diurnal variation using about 320 GNSS stations in China, including the Southern, Middle, and Northern areas. We also discuss some of the challenges associated with GNSS-based TEC measurement and analysis, such as the effects of receiver and satellite biases and understanding of spatial–temporal TEC variation. Finally, we highlight the sunset enhancement and scintillation of GNSS-based ionospheric diurnal variation research. Overall, this abstract provides a valuable overview of the use of GNSS networks for studying ionospheric diurnal variation and its potential applications for improving space weather forecasting and mitigating the effects of ionospheric disturbances on GNSS-based navigation systems.

Electrochromic materials are capable of reversibly switching their colors or optical properties through redox reactions under applied voltages, which have shown great potential applications including smart windows, non-emissive displays, optical filters, among others. Although the current rigid electrochromic devices have shown emerging interest and developed rapidly, many applications (e.g., wearable/deformable optoelectronics) are blocked due to their inflexible features. Herein, the adaption of rigid electrochromic devices to flexible ones is of particular interest for the new era of smart optoelectronics. In this review, the current state-of-the-art achievements of flexible electrochromic devices (FECDs) are highlighted, along with their design strategies and the choice of electrochromic materials. The recent research progress of FECDs is reviewed in detail, and the challenges and corresponding solutions for real-world applications of FECDs are discussed. Furthermore, we summarize the basic fabrication strategies of FECDs and their potential applications. In addition, the development trend, the perspectives, and the outlook of FECDs are discussed at the end of this Review, which may provide recommendations and potential directions to advance the practical applications of FECDs.

Highlights La3+/Na+ bimetallically doped vanadate, designed for the first time, is promising in many electrochemical applications (e.g., batteries, electrochromics). This is the first report of electrochromic displays employing bimetallically doped vanadate. It is demonstrated for the first time that zinc dendrites and vanadate dissolution are significantly inhibited by employing an aqueous hybrid Zn2+/Na+ electrolyte.

ABSTRACT Campylobacter jejuni is a foodborne pathogen commonly found in the intestinal tracts of animals. This pathogen is a leading cause of gastroenteritis in humans. Besides its highly infectious nature, C. jejuni is increasingly resistant to a number of clinically administrated antibiotics. As a consequence, the Centers for Disease Control and Prevention has designated antibiotic-resistant Campylobacter as a serious antibiotic resistance threat in the United States. The C. jejuni CosR regulator is essential to the viability of this bacterium and is responsible for regulating the expression of a number of oxidative stress defense enzymes. Importantly, it also modulates the expression of the CmeABC multidrug efflux system, the most predominant and clinically important system in C. jejuni that mediates resistance to multiple antimicrobials. Here, we report structures of apo-CosR and CosR bound with a 21 bp DNA sequence located at the cmeABC promotor region using both single-particle cryo-electron microscopy and X-ray crystallography. These structures allow us to propose a novel mechanism for CosR regulation that involves a long-distance conformational coupling and rearrangement of the secondary structural elements of the regulator to bind target DNA.IMPORTANCECampylobacter jejuni has emerged as an antibiotic-resistant threat worldwide. CosR is an essential regulator for this bacterium and is important for Campylobacter adaptation to various stresses. Here, we describe the structural basis of CosR binding to target DNA as determined by cryo-electron microscopy and X-ray crystallography. Since CosR is a potential target for intervention, our studies may facilitate the development of novel therapeutics to combat C. jejuni infection.

Introduction Rapid genomic sequencing (rGS) in critically ill infants with suspected genetic disorders has high diagnostic and clinical utility. However, rGS has primarily been available at large referral centres with the resources and expertise to offer state-of-the-art genomic care. Critically ill infants from racial and ethnic minority and/or low-income populations disproportionately receive care in safety-net and/or community settings lacking access to state-of-the-art genomic care, contributing to unacceptable health equity gaps. VIrtual GenOme CenteR is a ‘proof-of-concept’ implementation science study of an innovative delivery model for genomic care in safety-net neonatal intensive care units (NICUs).Methods and analysis We developed a virtual genome centre at a referral centre to remotely support safety-net NICU sites predominantly serving racial and ethnic minority and/or low-income populations and have limited to no access to rGS. Neonatal providers at each site receive basic education about genomic medicine from the study team and identify eligible infants. The study team enrols eligible infants (goal n of 250) and their parents and follows families for 12 months. Enrolled infants receive rGS, the study team creates clinical interpretive reports to guide neonatal providers on interpreting results, and neonatal providers return results to families. Data is collected via (1) medical record abstraction, (2) surveys, interviews and focus groups with neonatal providers and (3) surveys and interviews with families. We aim to examine comprehensive implementation outcomes based on the Proctor Implementation Framework using a mixed methods approach.Ethics and dissemination This study is approved by the institutional review board of Boston Children’s Hospital (IRB-P00040496) and participating sites. Participating families are required to provide electronic written informed consent and neonatal provider consent is implied through the completion of surveys. The results will be disseminated via peer-reviewed publications and data will be made accessible per National Institutes of Health (NIH) policies.Trial registration number NCT05205356/clinicaltrials.gov.

Autism spectrum disorder (ASD) significantly affects social and motor skills development in early, middle or even late childhood. To promote social and motor skills development among autistic children, an intervention consisting of Taekwondo and elements of music therapy was designed and implemented in Hong Kong. The objective of the current study is to investigate the effectiveness of this training, based on parents’ observations of their children who had completed the key stage of the training. Thirteen parents or caregivers (n = 13) whose children with autism participated in our Taekwondo training for two months were interviewed. Three major themes were identified by thematic analysis: (A) social skills-related change after the intervention, (B) motor skills-related change after the intervention, (C) characteristics of the intervention (i.e., session arrangement, tutor/coach attitude). Our findings show that our training was perceived by parents to have a significant impact on the promotion of physical ability and social communication in autistic children.

Summary: While ATM loss of function has long been identified as the genetic cause of ataxia-telangiectasia (A-T), how it leads to selective and progressive degeneration of cerebellar Purkinje and granule neurons remains unclear. ATM expression is enriched in microglia throughout cerebellar development and adulthood. Here, we find evidence of microglial inflammation in the cerebellum of patients with A-T using single-nucleus RNA sequencing. Pseudotime analysis revealed that activation of A-T microglia preceded upregulation of apoptosis-related genes in granule and Purkinje neurons and that microglia exhibited increased neurotoxic cytokine signaling to granule and Purkinje neurons in A-T. To confirm these findings experimentally, we performed transcriptomic profiling of A-T induced pluripotent stem cell (iPSC)-derived microglia, which revealed cell-intrinsic microglial activation of cytokine production and innate immune response pathways compared to controls. Furthermore, A-T microglia co-culture with either control or A-T iPSC-derived neurons was sufficient to induce cytotoxicity. Taken together, these studies reveal that cell-intrinsic microglial activation may promote neurodegeneration in A-T.

We propose a method based on the Hilbert–Huang transform (HHT) to recover the high-energy waveform of low-frequency quasiperiodic oscillations (QPOs). Based on the method, we successfully obtain the modulation of the phase-folded light curve above 170 keV using the QPO phase reconstructed at lower energies in MAXI J1535–571 with Insight-HXMT observations. A comprehensive simulation study is conducted to demonstrate that such modulation indeed originates from the QPO. Thus, the highest energies turn out to significantly exceed the upper limit of ∼100 keV for QPOs reported previously using the Fourier method, marking the first opportunity to study QPO properties above 100 keV in this source. Detailed analyses of these high-energy QPO profiles reveal different QPO properties between the 30–100 and 100–200 keV energy ranges: the phase lag remains relatively stable, and the amplitude slightly increases below ∼100 keV, whereas above this threshold, soft phase lags and a decrease in amplitude are observed. Given the reports of a hard-tail detection in broad spectroscopy, we propose that the newly discovered QPO properties above 100 keV are dominated by the hard-tail component, possibly stemming from a relativistic jet. Our findings also indicate a strong correlation between the QPOs originating from the jet and corona, supporting the scenario of jet–corona coupling precession. We emphasize that our proposed HHT-based method can serve as an efficient manner in expanding the high-energy band for studying QPOs, thereby enhancing our understanding of their origin.

In situ measurements of coronal mass ejections (CMEs) when they pass over an interplanetary probe are one of the main ways we directly measure their properties. However, such in situ profiles are subject to several observational constraints that are still poorly understood. This work aims at quantifying one of them, namely, the aging effect, using a CME simulated with a three-dimensional magnetohydrodynamical code. The synthetic in situ profile and the instantaneous profile of the magnetic field strength differ more from each other when taken close to the Sun than far from it. Moreover, out of three properties we compute in this study (i.e., size, distortion parameter, and expansion speed), only the expansion speed shows a dependence of the aging as a function of distance. It is also the property that is the most impacted by the aging effect as it can amount to more than 100 km s ^−1 for CMEs observed closer than 0.15 au. This work calls for caution when deducing the expansion speed from CME profiles when they still are that close to the Sun since the aging effect can significantly impact the derived properties.

ABSTRACTNew approaches for combating microbial infections are needed. One strategy for disrupting pathogenesis involves developing compounds that interfere with bacterial virulence. A critical molecular determinant of virulence for Gram-negative bacteria are efflux pumps of the resistance-nodulation-division family, which includes AcrAB-TolC. We previously identified small molecules that bind AcrB, inhibit AcrAB-TolC, and do not appear to damage membranes. These efflux pump modulators (EPMs) were discovered in an in-cell screening platform called SAFIRE (Screen for Anti-infectives using Fluorescence microscopy of IntracellulaR Enterobacteriaceae). SAFIRE identifies compounds that disrupt the growth of a Gram-negative human pathogen, Salmonella enterica serotype Typhimurium (S. Typhimurium), in macrophages. We used medicinal chemistry to iteratively design ~200 EPM35 analogs and test them for activity in SAFIRE, generating compounds with nanomolar potency. Analogs were demonstrated to bind AcrB in a substrate binding pocket by cryo-electron microscopy. Despite having amphipathic structures, the EPM analogs do not disrupt membrane voltage, as monitored by FtsZ localization to the cell septum. The EPM analogs had little effect on bacterial growth in standard Mueller Hinton Broth. However, under broth conditions that mimic the micro-environment of the macrophage phagosome, acrAB is required for growth, the EPM analogs are bacteriostatic, and the EPM analogs increase the potency of antibiotics. These data suggest that under macrophage-like conditions, the EPM analogs prevent the export of a toxic bacterial metabolite(s) through AcrAB-TolC. Thus, compounds that bind AcrB could disrupt infection by specifically interfering with the export of bacterial toxic metabolites, host defense factors, and/or antibiotics.IMPORTANCEBacterial efflux pumps are critical for resistance to antibiotics and for virulence. We previously identified small molecules that inhibit efflux pumps (efflux pump modulators, EPMs) and prevent pathogen replication in host cells. Here, we used medicinal chemistry to increase the activity of the EPMs against pathogens in cells into the nanomolar range. We show by cryo-electron microscopy that these EPMs bind an efflux pump subunit. In broth culture, the EPMs increase the potency (activity), but not the efficacy (maximum effect), of antibiotics. We also found that bacterial exposure to the EPMs appear to enable the accumulation of a toxic metabolite that would otherwise be exported by efflux pumps. Thus, inhibitors of bacterial efflux pumps could interfere with infection not only by potentiating antibiotics, but also by allowing toxic waste products to accumulate within bacteria, providing an explanation for why efflux pumps are needed for virulence in the absence of antibiotics.

The time-hopping (TH) pulsed pseudolite (PL) can be used to enhance the performance of global navigation satellite systems (GNSS), and the slot index table (SIT) is an important part to form this PL signal. In this paper, a new method to generate SITs for multiple PLs is proposed. The general process of the proposed method is that first different time-hopping slot index (THSI) base matrices are generated based on the constructed congruence codes, and then by combining several different THSI base matrices to constitute a new matrix, the SIT for a PL is formed. Further by changing the combined matrices, different SITs for different PLs can be generated. During this process, two critical factors that affect the performance of the given method, i.e., the collision or hit property of the generated THSI base matrix and the correlation property of the formed SIT, are analyzed in detail. The simulations given at the end of this paper show that compared with many other similar schemes, the SITs given by the proposed method can obtain better correlation performance and detection performance in the receiver, and these results also imply that the proposed method offers a more effective way to design this kind of PL signal.

Shape memory alloy (SMA) is a kind of active deformation material with a self-sensing and driving ability. It is very similar to the performance of human muscles, and through temperature changes to produce phase changes to output force and displacement, it has the ability to restore the initial shape and size. The combination of SMA and wearable robotic technology has the advantages of being light weight, energy-saving, and having great human–exoskeleton interaction. However, the existing flexible exoskeletons driven by SMA are only designed with bionic primary muscles, ignoring the role of antagonistic muscles. This study presents a novel soft bionic elbow exoskeleton based on SMA spring actuators (Sobee-SMA). The exoskeleton adopts a bionic design, combining active deformation material SMA and a high-elastic-material rubber band to simulate the contraction and relaxation of elbow skeletal muscles. Through a pulse width modulation (PWM) experiment, the driving voltage is selected as 12 V, the PWM duty cycle is 90 % during heating, and the PWM duty cycle is 18 % during heat preservation. In a relaxed state of healthy subjects, the range of motion of the elbow is about 0–80∘, and the maximum temperature is about 60–70 ∘C. During the circular movement of the elbow, the maximum temperature can be maintained within the SMA operating temperature without a high temperature. In conclusion, the exoskeleton provides elbow-assisted motion and ensures the safety of the heating process.

Case-based reasoning (CBR) simplifies knowledge acquisition and is suitable for researching complex geographical problems. However, CBR analyses of land-use changes are difficult to apply in the study of urban growth due to shortcomings in the case structure and model algorithms. In response, this study proposes a three-step urban-growth simulation model based on CBR (UGSCBR). First, to adapt the CBR to an urban-growth simulation process, the characteristics of regional differentiation in geographical spaces are determined. Second, a comprehensive retrieval method is developed that improves upon traditional case-retrieval methods by giving full play to the comprehensive function of each component of the case. Third, a quantity demand constraint indirectly adds a time factor to solve the initial blurriness of the traditional CBR-inference cycle. Taking Jixi city as the research area, we test the accuracy of the proposed model. The total accuracy of simulation results is 95.4%, and the Kappa is 87.4%. The figure of merit and Mathews correlation coefficient are 0.151 and 0.23, respectively, indicating that the model can meet the application requirements. The results show that the UGSCBR model has strong flexibility and simplicity, and it provides an effective prediction method for urban growth.

Permafrost has been warming and thawing globally, with subsequent effects on the climate, hydrology, and the ecosystem. However, the permafrost thermal state variation in the northern lower limit of the permafrost zone (Xidatan) on the Qinghai–Tibet Plateau (QTP) is unclear. This study attempts to explore the changes and variability in this permafrost using historical (1970–2019) and future projection datasets from remote-sensing-based land surface temperature product (LST) and climate projections from Earth system model (ESM) outputs of the Coupled Model Intercomparison Project Phase 5 and 6 (CMIP5, CMIP6). Our model considers phase-change processes of soil pore water, thermal-property differences between frozen and unfrozen soil, geothermal flux flow, and the ground ice effect. Our model can consistently reproduce the vertical ground temperature profiles and active layer thickness (ALT), recognizing permafrost boundaries, and capture the evolution of the permafrost thermal regime. The spatial distribution of permafrost and its thermal conditions over the study area were controlled by elevation with a strong influence of slope orientation. From 1970 to 2019, the mean annual ground temperature (MAGT) in the region warmed by 0.49 ∘C in the continuous permafrost zone and 0.40 ∘C in the discontinuous permafrost zone. The lowest elevation of the permafrost boundary (on the north-facing slopes) rose approximately 47 m, and the northern boundary of discontinuous permafrost retreated southwards by approximately 1–2 km, while the lowest elevation of the permafrost boundary remained unchanged for the continuous permafrost zone. The warming rate in MAGT is projected to be more pronounced under shared socioeconomic pathways (SSPs) than under representative concentration pathways (RCPs), but there are no distinct discrepancies in the areal extent of the continuous and discontinuous permafrost and seasonally frozen ground among SSP and RCP scenarios. This study highlights the slow delaying process of the response of permafrost in the QTP to a warming climate, especially in terms of the areal extent of permafrost distribution.

Summary: MCL-1 is a high-priority target due to its dominant role in the pathogenesis and chemoresistance of cancer, yet clinical trials of MCL-1 inhibitors are revealing toxic side effects. MCL-1 biology is complex, extending beyond apoptotic regulation and confounded by its multiple isoforms, its domains of unresolved structure and function, and challenges in distinguishing noncanonical activities from the apoptotic response. We find that, in the presence or absence of an intact mitochondrial apoptotic pathway, genetic deletion or pharmacologic targeting of MCL-1 induces DNA damage and retards cell proliferation. Indeed, the cancer cell susceptibility profile of MCL-1 inhibitors better matches that of anti-proliferative than pro-apoptotic drugs, expanding their potential therapeutic applications, including synergistic combinations, but heightening therapeutic window concerns. Proteomic profiling provides a resource for mechanistic dissection and reveals the minichromosome maintenance DNA helicase as an interacting nuclear protein complex that links MCL-1 to the regulation of DNA integrity and cell-cycle progression.

Over 1 million Americans are currently living with T1D and improvements in diabetes management have increased the number of adults with T1D living into later decades of life. This growing population of older adults with diabetes is more susceptible to aging comorbidities, including both vascular disease and osteoporosis. Indeed, adults with T1D have a 2- to 3- fold higher risk of any fracture and up to 7-fold higher risk of hip fracture compared to those without diabetes. Recently, diabetes-related vascular deficits have emerged as potential risks factors for impaired bone blood flow and poor bone health and it has been hypothesized that there is a direct pathophysiologic link between vascular disease and skeletal outcomes in T1D. Indeed, microvascular disease (MVD), one of the most serious consequences of diabetes, has been linked to worse bone microarchitecture in older adults with T1D compared to their counterparts without MVD. The association between the presence of microvascular complications and compromised bone microarchitecture indicates the potential direct deleterious effect of vascular compromise, leading to abnormal skeletal blood flow, altered bone remodeling, and deficits in bone structure. In addition, vascular diabetic complications are characterized by increased vascular calcification, decreased arterial distensibility, and vascular remodeling with increased arterial stiffness and thickness of the vessel walls. These extensive alterations in vascular structure lead to impaired myogenic control and reduced nitric-oxide mediated vasodilation, compromising regulation of blood flow across almost all vascular beds and significantly restricting skeletal muscle blood flow seen in those with T1D. Vascular deficits in T1D may very well extend to bone, compromising skeletal blood flow control, and resulting in reduced blood flow to bone, thus negatively impacting bone health. Indeed, several animal and ex vivo human studies report that diabetes induces microvascular damage within bone are strongly correlated with diabetes disease severity and duration. In this review article, we will discuss the contribution of diabetes-induced vascular deficits to bone density, bone microarchitecture, and bone blood flow regulation, and review the potential contribution of vascular disease to skeletal fragility in T1D.

MicroRNA (miRNA) profiles vary with the nutritional and pathological conditions of cattle. In this study, we aimed to investigate the effects of inulin supplement on miRNA profiles derived from serum extracellular vesicles (EVs). Our goal was to determine the differences in miRNA expressions and analyse the pathways in which they are involved. Based on the results of California mastitis test and milk somatic cell counts, ten lactating cows with subclinical mastitis were randomly divided into two groups: an inulin group and a control group (n = 5 in each group). The inulin group received a daily supplement of 300 g of inulin while the control group did not receive any supplementation. After a 5-week treatment period, serum-derived EV-miRNAs from each cow were isolated. High-throughput sequencing was conducted to identify differentially expressed miRNAs. GO and KEGG bioinformatics analysis was performed to examine the target genes of these differentially expressed miRNAs. The EV-RNA concentration and small RNA content were not affected by the inulin treatment. A total of 162 known miRNAs and 180 novel miRNAs were identified from 10 samples in the two groups. Among the known miRNAs, 23 miRNAs were found to be differentially expressed between the two groups, with 18 upregulated and five downregulated in the inulin group compared to the control group. Pathway analysis revealed the involvement of these differentially expressed miRNAs in the regulation of cell structure and function, lipid oxidation and metabolism, immunity and inflammation, as well as digestion and absorption of nutrients. Overall, our study provides a molecular-level explanation for the reported beneficial health effects of inulin supplementation in cows with subclinical mastitis.

Vanadium oxides are highly valued as electrochromic materials because of their multicolor capabilities. However, their practical applications have been limited due to challenges such as the dissolution of vanadate into aqueous electrolytes, leading to poor long‐term stability. Herein, a solution is proposed to the vanadate dissolution issue by utilizing a hybrid electrolyte consisting of tetraethylene glycol dimethyl ether (TEGDME) and water. This electrolyte has the unique ability to form a robust cathode electrolyte interface layer on vanadium oxide electrodes. As a proof of concept, zinc‐anode‐based multicolor transparent electrochromic displays are prepared using layered potassium vanadate (K2V6O16·1.5H2O, KVO) with a TEGDME–water hybrid electrolyte. By soaking the KVO electrode in the hybrid electrolyte, it is demonstrated that KVO has remarkable stability against dissolution. Furthermore, it is shown that KVO has superior electrochromic performance compared to sodium vanadate (NaV3O8·1.5H2O, SVO), due to the wide KVO interlayer spacing. Given the enhanced performance of this hybrid electrolyte and KVO cathode material, a zinc‐anode‐based electrochromic display prototype is shown to exhibit compelling performance. As such, this work is expected to be a significant catalyst for accelerating the development of vanadate‐based electrochromic displays.

Abstract On 15 January 2022, the Hunga Tonga‐Hunga Ha'apai (HT) eruption injected SO2 and water into the middle stratosphere. The SO2 is rapidly converted to sulfate aerosols. The aerosol and water vapor anomalies have persisted in the Southern Hemisphere throughout 2022. The water vapor anomaly increases the net downward IR radiative flux whereas the aerosol layer reduces the direct solar forcing. The direct solar flux reduction is larger than the increased IR flux. Thus, the net tropospheric forcing will be negative. The changes in radiative forcing peak in July and August and diminish thereafter. Scaling to the observed cooling after the 1991 Pinatubo eruption, HT would cool the 2022 Southern Hemisphere's average surface temperatures by less than 0.037°C.

ABSTRACT Campylobacter jejuni is a bacterium that is commonly present in the intestinal tracts of animals. It is also a major foodborne pathogen that causes gastroenteritis in humans. The most predominant and clinically important multidrug efflux system in C. jejuni is the CmeABC (Campylobacter multidrug efflux) pump, a tripartite system that includes an inner membrane transporter (CmeB), a periplasmic fusion protein (CmeA), and an outer membrane channel protein (CmeC). This efflux protein machinery mediates resistance to a number of structurally diverse antimicrobial agents. A recently identified CmeB variant, termed resistance enhancing CmeB (RE-CmeB), can increase its multidrug efflux pump activity, likely by influencing antimicrobial recognition and extrusion. Here, we report structures of RE-CmeB in its apo form as well as in the presence of four different drugs by using single-particle cryo-electron microscopy (cryo-EM). Coupled with mutagenesis and functional studies, this structural information allows us to identify critical amino acids that are important for drug resistance. We also report that RE-CmeB utilizes a somewhat unique subset of residues to bind different drugs, thereby optimizing its ability to accommodate different compounds with distinct scaffolds. These findings provide insights into the structure-function relationship of this newly emerged antibiotic efflux transporter variant in Campylobacter. IMPORTANCE Campylobacter jejuni has emerged as one of the most problematic and highly antibiotic-resistant pathogens, worldwide. The Centers for Disease Control and Prevention have designated antibiotic-resistant C. jejuni as a serious antibiotic resistance threat in the United States. We recently identified a C. jejuni resistance enhancing CmeB (RE-CmeB) variant that can increase its multidrug efflux pump activity and confers an exceedingly high-level of resistance to fluoroquinolones. Here, we report the cryo-EM structures of this prevalent and clinically important C. jejuni RE-CmeB multidrug efflux pump in both the absence and presence of four antibiotics. These structures allow us to understand the action mechanism for multidrug recognition in this pump. Our studies will ultimately inform an era in structure-guided drug design to combat multidrug resistance in these Gram-negative pathogens.

The starting rotation of a porous sphere induced by the sudden application of a continuous torque about its diameter at the center of a spherical cavity filled with an incompressible Newtonian fluid at low Reynolds numbers is analyzed. The unsteady Stokes and Brinkman equations governing the fluid velocities outside and inside the porous particle, respectively, are solved via the Laplace transform, and an explicit formula of its dynamic angular velocity as a function of the pertinent parameters is obtained. The behavior of the start-up rotation of an isolated porous particle and the cavity wall effect on the particle rotation are interesting. The angular velocity of the particle grows incessantly over time from an initial zero to its final value, while the angular acceleration declines with time continuously. In general, the transient angular velocity is an increasing function of the porosity of the particle. A porous sphere with higher fluid permeability rotates at higher angular velocity and acceleration relative to the reference particle at any elapsed time but lags behind the reference particle in the percentage growth of angular velocity towards the respective terminal values. The transient angular velocity decreases with increasing particle-to-cavity radius ratio, but it is not a sensitive function of the radius ratio when the resistance to fluid flow inside the porous particle or the radius ratio itself is small.

Mutations in the TECPR2 gene are the cause of an ultra-rare neurological disorder characterized by intellectual disability, impaired speech, motor delay, and hypotonia evolving to spasticity, central sleep apnea, and premature death (SPG49 or HSAN9; OMIM: 615031). Little is known about the biological function of TECPR2, and there are currently no available disease-modifying therapies for this disease. Here we describe implementation of an antisense oligonucleotide (ASO) exon-skipping strategy targeting TECPR2 c.1319delT (p.Leu440Argfs∗19), a pathogenic variant that results in a premature stop codon within TECPR2 exon 8. We used patient-derived fibroblasts and induced pluripotent stem cell (iPSC)-derived neurons homozygous for the p.Leu440Argfs∗19 mutation to model the disease in vitro. Both patient-derived fibroblasts and neurons showed lack of TECPR2 protein expression. We designed and screened ASOs targeting sequences across the TECPR2 exon 8 region to identify molecules that induce exon 8 skipping and thereby remove the premature stop signal. TECPR2 exon 8 skipping restored in-frame expression of a TECPR2 protein variant (TECPR2ΔEx8) containing 1,300 of 1,411 amino acids. Optimization of ASO sequences generated a lead candidate (ASO-005-02) with ∼27 nM potency in patient-derived fibroblasts. To examine potential functional rescue induced by ASO-005-02, we used iPSC-derived neurons to analyze the neuronal localization of TECPR2ΔEx8 and showed that this form of TECPR2 retains the distinct, punctate neuronal expression pattern of full-length TECPR2. Finally, ASO-005-02 had an acceptable tolerability profile in vivo following a single 20-mg intrathecal dose in cynomolgus monkeys, showing some transient non-adverse behavioral effects with no correlating histopathology. Broad distribution of ASO-005-02 and induction of TECPR2 exon 8 skipping was detected in multiple central nervous system (CNS) tissues, supporting the potential utility of this therapeutic strategy for a subset of patients suffering from this rare disease.

Abstract Genomic sequencing is a powerful diagnostic tool in critically ill infants, but performing exome or genome sequencing (ES/GS) in the context of a research study is different from implementing these tests clinically. We investigated the integration of rapid ES into routine clinical care after a pilot research study in a Level IV Neonatal Intensive Care Unit (NICU). We performed a retrospective cohort analysis of infants admitted with suspected genetic disorders to the NICU from December 1, 2018 to March 31, 2021 and compared results to those obtained from a previous research study cohort (March 1, 2017 to November 30, 2018). Clinical rapid ES was performed in 80/230 infants (35%) with a suspected genetic disorder and identified a genetic diagnosis in 22/80 infants (28%). The majority of diagnoses acutely impacted clinical management (14/22 (64%)). Compared to the previous research study, clinically integrated rapid ES had a significantly lower diagnostic yield and increased time from NICU admission and genetics consult to ES report, but identified four genetic diagnoses that may have been missed by the research study selection criteria. Compared to other genetic tests, rapid ES had similar or higher diagnostic yield and similar or decreased time to result. Overall, rapid ES was utilized in the NICU after the pilot research study, often as the first-tier sequencing test, and could identify the majority of disease-causing variants, shorten the diagnostic odyssey, and impact clinical care. Based on our experience, we have identified strategies to optimize the clinical implementation of rapid ES in the NICU.

Summary: We applied raw human liver microsome lysate to a holey carbon grid and used cryo-electron microscopy (cryo-EM) to define its composition. From this sample we identified and simultaneously determined high-resolution structural information for ten unique human liver enzymes involved in diverse cellular processes. Notably, we determined the structure of the endoplasmic bifunctional protein H6PD, where the N- and C-terminal domains independently possess glucose-6-phosphate dehydrogenase and 6-phosphogluconolactonase enzymatic activity, respectively. We also obtained the structure of heterodimeric human GANAB, an ER glycoprotein quality-control machinery that contains a catalytic α subunit and a noncatalytic β subunit. In addition, we observed a decameric peroxidase, PRDX4, which directly contacts a disulfide isomerase-related protein, ERp46. Structural data suggest that several glycosylations, bound endogenous compounds, and ions associate with these human liver enzymes. These results highlight the importance of cryo-EM in facilitating the elucidation of human organ proteomics at the atomic level.

ABSTRACT The continued challenges of the COVID-19 pandemic combined with the growing problem of antimicrobial-resistant bacterial infections has severely impacted global health. Specifically, the Gram-negative pathogen Klebsiella pneumoniae is one of the most prevalent causes of secondary bacterial infection in COVID-19 patients, with approximately an 83% mortality rate observed among COVID-19 patients with these bacterial coinfections. K. pneumoniae belongs to the ESKAPE group of pathogens, a group that commonly gives rise to severe infections that are often life-threatening. Recently, K. pneumoniae carbapenemase (KPC)-producing K. pneumoniae has drawn wide public attention, as the mortality rate for this infection can be as high as 71%. The most predominant and clinically important multidrug efflux system in K. pneumoniae is the acriflavine resistance B (AcrB) multidrug efflux pump. This pump mediates resistance to different classes of structurally diverse antimicrobial agents, including quinolones, β-lactams, tetracyclines, macrolides, aminoglycosides, and chloramphenicol. We here report single-particle cryo-electron microscopy (cryo-EM) structures of K. pneumoniae AcrB, in both the absence and the presence of the antibiotic erythromycin. These structures allow us to elucidate specific pump-drug interactions and pinpoint exactly how this pump recognizes antibiotics. IMPORTANCE Klebsiella pneumoniae has emerged as one of the most problematic and highly antibiotic-resistant pathogens worldwide. It is the second most common causative agent involved in secondary bacterial infection in COVID-19 patients. K. pneumoniae carbapenemase (KPC)-producing K. pneumoniae is a major concern in global public health because of the high mortality rate of this infection. Its drug resistance is due, in a significant part, to active efflux of these bactericides, a major mechanism that K. pneumoniae uses to resist to the action of multiple classes of antibiotics. Here, we report cryo-electron microscopy (cryo-EM) structures of the prevalent and clinically important K. pneumoniae AcrB multidrug efflux pump, in both the absence and the presence of the erythromycin antibiotic. These structures allow us to understand the action mechanism for drug recognition in this pump. Our studies will ultimately inform an era in structure-guided drug design to combat multidrug resistance in these Gram-negative pathogens.

The streptothricin natural product mixture (also known as nourseothricin) was discovered in the early 1940s, generating intense initial interest because of excellent gram-negative activity. Here, we establish the activity spectrum of nourseothricin and its main components, streptothricin F (S-F, 1 lysine) and streptothricin D (S-D, 3 lysines), purified to homogeneity, against highly drug-resistant, carbapenem-resistant Enterobacterales (CRE) and Acinetobacter baumannii. For CRE, the MIC50 and MIC90 for S-F and S-D were 2 and 4 μM, and 0.25 and 0.5 μM, respectively. S-F and nourseothricin showed rapid, bactericidal activity. S-F and S-D both showed approximately 40-fold greater selectivity for prokaryotic than eukaryotic ribosomes in in vitro translation assays. In vivo, delayed renal toxicity occurred at >10-fold higher doses of S-F compared with S-D. Substantial treatment effect of S-F in the murine thigh model was observed against the otherwise pandrug-resistant, NDM-1-expressing Klebsiella pneumoniae Nevada strain with minimal or no toxicity. Cryo-EM characterization of S-F bound to the A. baumannii 70S ribosome defines extensive hydrogen bonding of the S-F steptolidine moiety, as a guanine mimetic, to the 16S rRNA C1054 nucleobase (Escherichia coli numbering) in helix 34, and the carbamoylated gulosamine moiety of S-F with A1196, explaining the high-level resistance conferred by corresponding mutations at the residues identified in single rrn operon E. coli. Structural analysis suggests that S-F probes the A-decoding site, which potentially may account for its miscoding activity. Based on unique and promising activity, we suggest that the streptothricin scaffold deserves further preclinical exploration as a potential therapeutic for drug-resistant, gram-negative pathogens.

In steep wildfire-burned terrains, intense rainfall can produce large runoff that can trigger highly destructive debris flows. However, the ability to accurately characterize and forecast debris flow susceptibility in burned terrains using physics-based tools remains limited. Here, we augment the Weather Research and Forecasting Hydrological modeling system (WRF-Hydro) to simulate both overland and channelized flows and assess postfire debris flow susceptibility over a regional domain. We perform hindcast simulations using high-resolution weather-radar-derived precipitation and reanalysis data to drive non-burned baseline and burn scar sensitivity experiments. Our simulations focus on January 2021 when an atmospheric river triggered numerous debris flows within a wildfire burn scar in Big Sur – one of which destroyed California's famous Highway 1. Compared to the baseline, our burn scar simulation yields dramatic increases in total and peak discharge and shorter lags between rainfall onset and peak discharge, consistent with streamflow observations at nearby US Geological Survey (USGS) streamflow gage sites. For the 404 catchments located in the simulated burn scar area, median catchment-area-normalized peak discharge increases by ∼ 450 % compared to the baseline. Catchments with anomalously high catchment-area-normalized peak discharge correspond well with post-event field-based and remotely sensed debris flow observations. We suggest that our regional postfire debris flow susceptibility analysis demonstrates WRF-Hydro as a compelling new physics-based tool whose utility could be further extended via coupling to sediment erosion and transport models and/or ensemble-based operational weather forecasts. Given the high-fidelity performance of our augmented version of WRF-Hydro, as well as its potential usage in probabilistic hazard forecasts, we argue for its continued development and application in postfire hydrologic and natural hazard assessments.

Abstract Developing stable perovskite nanocrystals (NCs) with enhancing luminescent properties holds great importance for future potential applications in optoelectronics. Here, we engaged perovskite NCs in Cu2+ ion-based metal–organic framework (MOF) Cu-BTC (BTC = 1,3,5-benzene tricarboxylate) by physical mixing of MOF with CsPbBr3 NCs in toluene solution. MOF-protected perovskite NCs achieved high photoluminescence quantum yield 96.51% than pristine state CsPbBr3 NCs (51.66%). Along with the improvement in optical properties, the long-term stability of CsPbBr3 NCs in the solution phase also increases considerably upon loading in Cu-BTC MOF. Moreover, the changes in the luminescent intensity of the samples have been observed for 3 months in the solution. After 1 month, pristine CsPbBr3 NCs lose their emission intensity 68% from the initial, while the MOF-protected CsPbBr3 NCs show only a 10% reduction from the initial. These results indicate that the effective passivation of Cu-BTC MOF inhibits the aggregation of NCs, protecting them from the defective atmosphere. The excellent photoluminescence findings provide a new pathway for future optoelectronic applications.