bluuebunny/crossref_metadata_2025 huggingface dataset:
Insights into the anatectic origin of granites parental to tungsten mineralization: A case study from the trans‐Aravalli terrane, NW India
Authors: Roy Jitendra Kumar , Naik Aditya , Bhattacharya Sourabh
Published: February 2024

Potential progenitors for W (±Sn) deposits include peraluminous granites of S‐type affinity. The anatectic origin of such granites parental to W mineralization has received little attention. This study focuses on Balda Granite (BG), a peraluminous intrusion parental to W‐rich ore bodies in the Sirohi region (NW India). We reflect upon the potential source for BG and investigate its anatectic origin through open‐system phase equilibria modeling. On the prograde path, muscovite‐ and biotite‐dehydration reactions at 675–745°C and 755–870°C yield ~10 and 13 wt.% melt, respectively. Si, K, Al, and Fe contents of the cumulative melt increased with progressive anatexis. Modeling results suggest high‐T (>800°C) stability of the peritectic garnet, which is abundantly observed in the leucosome‐dominated migmatitic patches. Cumulative melt extracted till 868°C was chosen to model the crystal fractionation along three polybaric gradients of 30, 45, and 60°C/kbar. As the modeled anatectic melt cooled, its peraluminosity and maficity decreased progressively. With the intermediate cooling gradient of 45°C/kbar, the melt achieved complete crystallization at ~7 km, the depth at which the BG had been emplaced and evolved into a W‐rich residual (fractionated) model melt. In terms of peraluminosity, and major and trace element (Lu, Sc, Dy, Y, Yb) chemistry, the fractionated (residual) model melt compares well with BG. This study also models the W concentration in the anatectic melt during its generation and fractional crystallization. We argue for the origin of BG through high‐T anatexis of Sirohi Group metapelites and cooling (and fractional crystallization) of the parent anatectic melt at the maximum gradient of 45°C/kbar. Thus, a high‐T anatectic origin of granites parental to W deposits may be more prevalent than so far inferred.
Trade in services related to intangibles and the profit shifting hypothesis
Authors: Accoto Nadia , Federico Stefano , Oddo Giacomo
Published: February 2024

This paper focuses on the international trade in services related to intangible assets and intellectual property products (IPP), and it explores to what extent they might be used as a channel to shift the profits of multinational firms to tax havens. Using survey data on Italian firms, we first provide a geographical and sectoral analysis of Italy's trade in IPP services. We then estimate the amount of profit shifted abroad by foreign‐owned firms in our sample, applying at various levels of aggregation a methodology recently put forward in the literature. Finally, we look for a correlation at the firm level between estimated shifted profits and imports of IPP services. We find that while the overall correlation is very low, there is a small cluster of firms displaying a positive correlation between these two variables.
Ulectomy in a patient with nephrotic syndrome under investigation for Galloway‐Mowat syndrome: a case report
Authors: Alves Gabriela Reis , Javaroni Julia Biliato , Moura Ana Paula Gomes e , Consolaro Alberto , Segato Raquel Assed Bezerra
Published: February 2024

The aim of this study is to report a case in which a patient with nephrotic syndrome underwent surgery to remove fibrous gum tissue (ulectomy). An 8‐year‐old patient, diagnosed with early onset nephrotic syndrome due to a mutation in the NUP107 gene, had received a kidney transplant and was therefore taking various medications, including immunosuppressants. On oral examination, the patient was found to have a fibrous gingiva that was preventing the eruption of the upper permanent central incisors. A ulectomy was performed and the gingival tissue was sent for histopathological analysis, which showed normal aspects. The upper right central incisor was seen in the oral cavity 15 days after surgery. A second procedure was carried out to facilitate the eruption of the upper left incisor, which was visualized in the oral cavity 30 days later. In addition, oral manifestations such as maxillary atresia, ogival palate and mouth breathing were observed. Therefore, the role of the dental surgeon in the lives of transplanted children is considered important, as they often take various medications that can affect their oral health. Thus, early diagnosis and effective treatment will be essential to prevent future malocclusions and thus improve the quality of life of these patients.
Mucocutaneous histoplasmosis as the first manifestation of AIDS
Authors: Medina Janaina B. , Monguilhott‐Falbo Francèle , Teixeira‐Leite Cristiane , Trierveiler Marilia , Braz‐Silva Paulo Henrique , Ortega Karem L.
Published: February 2024

Immunosuppressed patients can present with opportunistic infections resulting from an intrinsic systemic disease, which easily evolves into more aggressive and less common conditions. This work reports a clinical case of a female patient with histoplasmosis lesions in the nasal and oral mucosa, including pulmonary, hematological, and hepatic impairment, which led to the diagnosis of HIV seropositivity. In the presence of severe immunosuppression, morbidity is increased due to deep fungal infections and their unusual clinical characteristics can make diagnosis difficult. Therefore, it can be very helpful to recognize these clinical characteristics in order to determine early diagnostic interventions. It is important to recognize mucocutaneous manifestations of histoplasmosis because the biopsy of these lesions, and subsequent histopathological analysis, is one of the quickest, safest, and cheapest methods of diagnosis.
Unidirectional and combined transitional flow bedforms: Controls on process and distribution in submarine slope settings
Authors: Taylor William J. , Hodgson David M. , Peakall Jeff , Kane Ian A. , Morris Emma A. , Flint Stephen S.
Published: February 2024

Mixed grain‐size bedforms comprise alternating sand‐rich and poorly sorted mud‐rich laminae and bands. These bedforms have been identified in distal submarine settings formed underneath unidirectional flows. This study documents mixed grain‐size bedforms in a proximal submarine slope setting formed beneath both unidirectional and combined flows. Core and outcrop data with well‐constrained palaeogeographical context are used to describe two types of mixed grain‐size bedform. Type A bedforms comprise mud‐rich current ripples and low‐amplitude bed‐waves with alternating concave and planar sandstone–mudstone foresets that pass into mud‐rich troughs, and aggradational sinusoidal laminasets. Type B bedforms consist of sandstone–mudstone laminasets that comprise rounded, biconvex ripples with sigmoidal‐shaped foresets and swale and hummock‐like laminasets and banded sets. These bedforms occur in channel‐margin, internal‐levée and external‐levée, intraslope and disconnected lobe environments, and represent 27 to 63% by stratigraphic thickness of the studied successions. They are interpreted as deposits of clay‐rich transitional flows, whose depositional style is governed by the balance of cohesive and turbulent forces, and the rate of flow deceleration. Type B bedforms are further interpreted as combined transitional flow deposits, resulting from flow deflection and ponding processes by seabed topography. Upward and lateral transitions between different bedforms create distinct bedform sequences, demonstrating progressive spatio‐temporal transformations in flow properties and their topographic interactions. By using a well‐constrained palaeogeographical setting, mixed grain‐size bedforms are shown to be situated close to sites of erosion into muddy substrates, abrupt losses in confinement, and/or changes in slope gradient. These bedforms demonstrate that flow transformation and transitional flow behaviour are not restricted to distal submarine settings. Furthermore, mixed grain‐size bedforms are not a diagnostic criterion for bottom currents, because such flows cannot account for the high mud content in laminasets, or the interlamination of sand and mud.
Effects of organisational factors and employee characteristics on employers' reporting of client violence in non‐institutional social services in Sweden
Authors: Brodin Helene , Shanks Emelie
Published: February 2024

Social services in the welfare sector consist of women‐dominated jobs generally characterised by arduous working conditions, including exposure to client violence. Although there is a rather extensive research base on client violence in institutional social services, less is known about how client violence is handled in noninstitutional social services. Using longitudinal data obtained from the Swedish Work Environment Agency's register on work injuries caused by workplace violence, we examined the effects of organisational factors and employee characteristics on the reporting of client violence in noninstitutional social services. We found that most of the reports about work injuries caused by client violence are filed by public employers and that most reports concern occupational groups performing direct care services in clients' homes. Moreover, although most reports include female employees and incidents of physical violence, reports concerning male employees are comparatively more likely to include physical violence, and reports concerning female employees are comparatively more likely to include threats. Taken together, our findings point to a much‐needed improvement of health and safety measures for care workers in noninstitutional social services in Sweden.
In search of a job—But which one? How unemployed people revise their occupational expectations
Authors: Demazière Didier
Published: February 2024

Conducting a job search implies the identification of a target—an intended job. However, this assumption has been little studied, and just two main conclusions have been drawn, namely: jobseekers have an incentive to adjust their targets to the jobs available, and returning to work tends to lead to occupational downgrading. This article explores how job search experiences shape and alter targets. Biographical interviews were conducted with 57 unemployed people registered with the French public employment service. Ultimately, all of them revise their occupational expectations as, faced with the uncertainties inherent to the job search and experiencing difficulties in reaching their priority targets, they try to adapt and define more realistic goals. Four contrasting processes of expectation revision are used to track these tensions between desirability and realism. In conclusion, we stress the following facts: that unemployed people are flexible and develop rationales in order to adapt to the labour market; that their experience of failure, alongside advice and beliefs arising in the course of the job search feed directly into these revisions, and that these revisions both vary in magnitude and reflect inequalities in the defining process of target jobs.
Transcriptome analysis of frontal fibrosis alopecia revealed involvement of immune cells and ferroptosis
Authors: Liu Lin , Xue Yuzhou , Wang Jingyu , Shen Chengcheng , Li Yuhao , Huang Yujing
Published: February 2024

Background

Frontal fibrosis alopecia (FFA) is a primary cicatricial alopecia and has received increasing attention in recent years. However, the pathogenesis of FFA has not been fully elucidated.

Methods and results

Herein, we collected the transcriptome data of scalp lesions of seven patients with FFA and seven healthy controls. The differential expression analysis and weighted gene co‐expression network analysis were conducted and we identified 458 differentially expressed genes (DEGs) in two key modules. Later, we performed functional enrichment analysis and functional modules identification, revealing the participation of immune response and fatty acid metabolism. Based on the results, we processed further studies. On the one hand, we analyzed the infiltrating immune cells of FFA through CIBERSORT algorithm, indicating the activation of M1 macrophage and CD8+ T cell. On the other hand, considering lipid metabolism of FFA and oxidative stress of hair follicle cells in alopecia, we explored the potential ferroptosis of FFA. By intersection of DEGs and ferroptosis‐related genes from FerrDb database, 19 genes were identified and their expression was validated in an external dataset containing 36 FFA cases and 12 controls. Then, we used LASSO algorithms to construct a four‐gene diagnostic model, which achieved an AUC of 0.924 in validation dataset. Additionally, the immune cells were found to be related to ferroptosis in FFA.

Conclusion

Taken together, this study contributed to reveal the molecular mechanisms of FFA and is expected to inspire future research on treatment.
Nudix hydrolase WvNUDX24 is involved in borneol biosynthesis in Wurfbainia villosa
Authors: Yang Peng , Chen Yuan‐Xia , Wang Tian‐Tian , Huang Xue‐Shuang , Zhan Ruo‐Ting , Yang Jin‐Fen , Ma Dong‐Ming
Published: February 2024

Borneol, camphor, and bornyl acetate are highly promising monoterpenoids widely used in medicine, flavor, food, and chemical applications. Bornyl diphosphate (BPP) serves as a common precursor for the biosynthesis of these monoterpenoids. Although bornyl diphosphate synthase (BPPS) that catalyzes the cyclization of geranyl diphosphate (GPP) to BPP has been identified in multiple plants, the enzyme responsible for the hydrolysis of BPP to produce borneol has not been reported. Here, we conducted in vitro and in vivo functional characterization to identify the Nudix hydrolase WvNUDX24 from W. villosa, which specifically catalyzes the hydrolysis of BPP to generate bornyl phosphate (BP), and then BP forms borneol under the action of phosphatase. Subcellular localization experiments indicated that the hydrolysis of BPP likely occurs in the cytoplasm. Furthermore, site‐directed mutagenesis experiments revealed that four critical residues (R84, S96, P98, and G99) for the hydrolysis activity of WvNUDX24. Additionally, the functional identification of phosphatidic acid phosphatase (PAP) demonstrated that WvPAP5 and WvPAP10 were able to hydrolyze geranylgeranyl diphosphate (GGPP) and farnesyl diphosphate (FPP) to generate geranylgeranyl phosphate (GGP) and farnesyl phosphate (FP), respectively, but could not hydrolyze BPP, GPP, and neryl diphosphate (NPP) to produce corresponding monophosphate products. These findings highlight the essential role of WvNUDX24 in the first step of BPP hydrolysis to produce borneol and provide genetic elements for the production of BPP‐related terpenoids through plant metabolic engineering and synthetic biology.
Adipocytes in synovial fluid cytology: An approach for diagnosing synovial lipomatosis
Authors: Agulla Beatriz , Vizcaíno Nùria , Velarde Roser , Estruch Josep , Domínguez Elisabet , Pastor Josep
Published: February 2024

A 2‐year‐old neutered male bullmastiff dog was presented with chronic left hind limb lameness. Physical examination revealed left stifle effusion and medial buttress without cranial tibial thrust. Radiographs showed joint effusion and new bone formation at the patella apex. Magnetic resonance imaging showed increased synovial fluid, widening of the joint space, abnormal infrapatellar fat body and thinning of the cranial cruciate ligament. Synoviocentesis and cytologic evaluation of synovial fluid revealed marked mononuclear inflammation with abundant fatty tissue, suggesting synovial lipomatosis in conjunction with the imaging findings. The disease was confirmed histologically after sampling the lesion during arthrotomy. Synovial lipomatosis, characterized by extensive synovial adipose tissue proliferation of the synovial membrane, is a rare “tumor‐like” disorder that usually affects the stifle. Although the etiology remains unclear, joint trauma, inflammation, instability, and lipid abnormalities have been proposed as causes. Inflammatory factors may promote synoviocyte and adipocyte hyperplasia that perpetuate the process. Surgical removal may be suggested to eliminate triggers and prevent future recurrences. The report provides the first cytological description of adipocytes in synovial fluid associated with the diagnosis of synovial lipomatosis in dogs. This case report underscores the potential effectiveness of cytologic analysis of synovial fluid smears, in combination with magnetic resonance imaging (MRI), for diagnosing this condition and reducing complications associated with arthrotomy for sampling purposes. Additionally, the case highlights that synovial lipomatosis should be considered as a potential differential diagnosis for synovial masses in dogs. Further cases are needed to validate these observations in veterinary medicine.
Nonautonomous double‐phase equations with strong singularity and concave perturbation
Authors: Papageorgiou Nikolaos S. , Rădulescu Vicenţiu D. , Yuan Shuai
Published: February 2024

We consider a nonlinear Dirichlet problem driven by a nonautonomous double‐phase differential operator and with a reaction consisting of a “strongly” singular term plus a concave perturbation. Using the Nehari method, we show the existence of a bounded strictly positive solution.
Notes on overdetermined singular problems
Authors: Esposito Francesco , Sciunzi Berardino , Soave Nicola
Published: February 2024

We obtain some rigidity results for overdetermined boundary value problems for singular solutions in bounded domains.
Blockage of aquaporin‐3 peroxiporin activity by organogold compounds affects melanoma cell adhesion, proliferation and migration
Authors: da Silva Inês V. , Pimpão Catarina , Paccetti‐Alves Inês , Thomas Sophie R. , Barateiro Andreia , Casini Angela , Soveral Graça
Published: February 2024

Aquaporin‐3 (AQP3) is a membrane channel with dual aquaglyceroporin/peroxiporin activity, facilitating the diffusion of water, glycerol and H2O2 across cell membranes. AQP3 shows aberrant expression in melanoma and its role in cell adhesion, migration and proliferation is well described. Gold compounds were shown to modulate AQP3 activity with reduced associated toxicity, making them promising molecules for cancer therapy. In this study, we validated the phenotype resulting from AQP3‐silencing of two melanoma cell lines, MNT‐1 and A375, which resulted in decreased H2O2 permeability. Subsequently, the AQP3 inhibitory effect of a new series of organogold compounds derived from Auphen, a potent AQP3 inhibitor, was first evaluated in red blood cells (RBCs) that highly express AQP3, and then in HEK‐293T cells with AQP3 overexpression to ascertain the compounds’ specificity. The first screening in RBCs unveiled two organogold compounds as promising blockers of AQP3 permeability. Moderate reduction of glycerol permeability but drastic inhibition of H2O2 permeability was detected for some of the gold derivatives in both AQP3‐overexpressing cells and human melanoma cell lines. Additionally, all compounds were effective in impairing cell adhesion, proliferation and migration, although in a cell type‐dependent manner. In conclusion, our data show that AQP3 peroxiporin activity is crucial for melanoma progression and highlight organogold compounds as promising AQP3 inhibitors with implications in melanoma cell adhesion, proliferation and migration, unveiling their potential as anticancer drugs against AQP3‐overexpressing tumours.

image

Key points

AQP3 affects cellular redox balance.

Gold compounds inhibit AQP3 permeability in melanoma cells.

AQP3 is involved in cell adhesion, proliferation and migration of melanoma.

Blockage of AQP3 peroxiporin activity impairs melanoma cell migration.

Gold compounds are potential anticancer drug leads for AQP3‐overexpressing cancers.
Exogenous Collagen Crosslinking is Highly Detrimental to Articular Cartilage Lubrication
Authors: Kupratis Meghan E. , Gonzalez Uriel , Rahman Atia , Burris David L. , Corbin Elise A. , Price Christopher
Published: February 2024

Healthy articular cartilage is a remarkable bearing material optimized for near-frictionless joint articulation. Because its limited self-repair capacity renders it susceptible to osteoarthritis (OA), approaches to reinforce or rebuild degenerative cartilage are of significant interest. While exogenous collagen crosslinking (CXL) treatments improve cartilage's mechanical properties and increase its resistance to enzymatic degradation, their effects on cartilage lubrication remain less clear. Here, we examined how the collagen crosslinking agents genipin (GP) and glutaraldehyde (GTA) impact cartilage lubrication using the convergent stationary contact area (cSCA) configuration. Unlike classical configurations, the cSCA sustains biofidelic kinetic friction coefficients (μk) via superposition of interstitial and hydrodynamic pressurization (i.e., tribological rehydration). As expected, glutaraldehyde- and genipin-mediated CXL increased cartilage's tensile and compressive moduli. Although net tribological rehydration was retained after CXL, GP or GTA treatment drastically elevated μk. Both healthy and “OA-like” cartilage (generated via enzymatic digestion) sustained remarkably low μk in saline- (≤0.02) and synovial fluid-lubricated contacts (≤0.006). After CXL, μk increased up to 30-fold, reaching values associated with marked chondrocyte death in vitro. These results demonstrate that mechanical properties (i.e., stiffness) are necessary, but not sufficient, metrics of cartilage function. Furthermore, the marked impairment in lubrication suggests that CXL-mediated stiffening is ill-suited to cartilage preservation or joint resurfacing.
The Post-Buckling Behavior of a Beam Constrained by Nonlinear Springy Walls
Authors: Judah Nitzan , Givli Sefi
Published: February 2024

The post-buckling behavior of a beam that is subjected to lateral constraints is of relevance to a range of medical and engineering applications, such as endoscopic examination of internal organs, the insertion of a guidewire into an artery in-stent procedures, root growth, deep-drilling, and more. In this paper, we address a disconnect between the existing literature and the reality of these systems, in which the lateral constraints are flexible and experience nonlinear deformations. As a step towards bridging this gap, we consider a beam undergoing planar deformations that is laterally constrained by a nonlinear springy wall, i.e., a wall that is laterally pushed by the beam against a nonlinear spring. Based on a simplified mathematical model, we obtain closed-form analytical solutions, which provide valuable insights and intuition. For example, we show that important features of the behavior, such as the transition from point contact to line contact and switching to the next mode, are dictated solely by a non-dimensional force, regardless of all other parameters of the system, and that the full description of the behavior is possible by means of two non-dimensional quantities that describe the relative stiffness of the nonlinear spring compared to that of the beam. The results also highlight the fundamental differences between the behavior with a stiffening spring or with a softening spring, such as the number of attainable modes and the monotonicity of the overall force–displacement relation. These results are then validated by experiments.
Optimizing Engineered Products for Their Social Impacts on Multiple Stakeholders
Authors: Stevenson Phillip D. , Mattson Christopher A. , Salmon John L. , Hatch Nile W.
Published: February 2024

Engineered products are often optimized based on engineering requirements, user requirements, cost, and performance. This strategy is well suited for most applications, but products designed specifically to improve the lives of users and communities would benefit from an approach that helps engineers optimize a product based also on its social impacts. This paper introduces several optimization problem formulations adapted from multi-stakeholder strategies in the economics and business management literature. Each optimization problem formulation optimizes a product’s social impact according to the ideology and principles inherent to the adapted multi-stakeholder strategy. A case study is presented for a cassava peeling machine that is being developed for farmers in the Brazilian Amazon. Finally, the resulting peeler design configurations and social impacts are discussed to illustrate the advantages and disadvantages of each strategy.
Multiparametric ultrasound evaluation of liver fibrosis, steatosis, and viscosity in patients with chronic liver disease
Authors: Minciuna Iulia , Taru Madalina , Fodor Andreea , Nicoara Farcau Oana , Fischer Petra , Radu Corina , Lupsor-Platon Monica , Stefanescu Horia , Procopet Bogdan
Published: February 2024

Aims: This study assessed the effectiveness of three ultrasound-based techniques (2D-SWE.PLUS, Att.PLUS, Vi.PLUS) for non-invasive evaluation of liver fibrosis, steatosis, and inflammation in chronic liver disease (CLD) patients.Materials and methods: Involving 209 consecutive compensated CLD patients, the study compared these ultrasound methods from Aixplorerwith standard Vibration-controlled Transient Elastography (VCTE) and Controlled Attenuation Parameter (CAP) from Fibroscan, alongside non-invasive serological markers.Results: High validity rates were observed in measurements: 99% for VCTE, 89% for 2D-SWE.PLUS/Vi.PLUS, and 96.6% for Att.PLUS. 2D-SWE.PLUS showed a strong correlation with VCTE (R=0.91) and excelled at a lower Stability Index (80%), with optimal cut-offs for moderate and severe fibrosis at 8 kPa and 10 kPa, respectively. 2D-SWE.PLUS was superior to Fib4, eLIFT, APRI, BARD, and NFS in detecting advanced CLD. Att.PLUS moderately correlated with CAP (R=0.47) for steatosis grades, while Viscosity was highly effective in identifying significant fibrosis (AUC=0.87) but less so for inflammation.Conclusions: 2D-SWE.PLUS demonstrated superior diagnostic precision in liver fibrosis, exceeding other non-invasive markers. Att.PLUS was relatively accurate for liver steatosis, and viscosity more effectively indicated fibrosis stages than inflammation in CLD patients.
Probing electron-hole Coulomb correlations in the exciton landscape of a twisted semiconductor heterostructure
Authors: Bange Jan Philipp , Schmitt David , Bennecke Wiebke , Meneghini Giuseppe , AlMutairi AbdulAziz , Watanabe Kenji , Taniguchi Takashi , Steil Daniel , Steil Sabine , Weitz R. Thomas , Jansen G. S. Matthijs , Hofmann Stephan , Brem Samuel , Malic Ermin , Reutzel Marcel , Mathias Stefan
Published: February 2024

In two-dimensional semiconductors, cooperative and correlated interactions determine the material’s excitonic properties and can even lead to the creation of correlated states of matter. Here, we study the fundamental two-particle correlated exciton state formed by the Coulomb interaction between single-particle holes and electrons. We find that the ultrafast transfer of an exciton’s hole across a type II band-aligned semiconductor heterostructure leads to an unexpected sub-200-femtosecond upshift of the single-particle energy of the electron being photoemitted from the two-particle exciton state. While energy relaxation usually leads to an energetic downshift of the spectroscopic signature, we show that this upshift is a clear fingerprint of the correlated interaction of the electron and hole parts of the exciton. In this way, time-resolved photoelectron spectroscopy is straightforwardly established as a powerful method to access electron-hole correlations and cooperative behavior in quantum materials. Our work highlights this capability and motivates the future study of optically inaccessible correlated excitonic and electronic states of matter.
Noncanonical interaction with microtubules via the N-terminal nonmotor domain is critical for the functions of a bidirectional kinesin
Authors: Singh Sudhir K. , Siegler Nurit , Pandey Himanshu , Yanir Neta , Popov Mary , Goldstein-Levitin Alina , Sadan Mayan , Debs Garrett , Zarivach Raz , Frank Gabriel A. , Kass Itamar , Sindelar Charles V. , Zalk Ran , Gheber Larisa
Published: February 2024

Several kinesin-5 motors (kinesin-5s) exhibit bidirectional motility. The mechanism of such motility remains unknown. Bidirectional kinesin-5s share a long N-terminal nonmotor domain (NTnmd), absent in exclusively plus-end–directed kinesins. Here, we combined in vivo, in vitro, and cryo–electron microscopy (cryo-EM) studies to examine the impact of NTnmd mutations on the motor functions of the bidirectional kinesin-5, Cin8. We found that NTnmd deletion mutants exhibited cell viability and spindle localization defects. Using cryo-EM, we examined the structure of a microtubule (MT)-bound motor domain of Cin8, containing part of its NTnmd. Modeling and molecular dynamic simulations based on the cryo-EM map suggested that the NTnmd of Cin8 interacts with the C-terminal tail of β-tubulin. In vitro experiments on subtilisin-treated MTs confirmed this notion. Last, we showed that NTnmd mutants are defective in plus-end–directed motility in single-molecule and antiparallel MT sliding assays. These findings demonstrate that the NTnmd, common to bidirectional kinesin-5s, is critical for their bidirectional motility and intracellular functions.
Rac1 promotes kidney collecting duct repair by mechanically coupling cell morphology to mitotic entry
Authors: Bock Fabian , Dong Xinyu , Li Shensen , Viquez Olga M. , Sha Eric , Tantengco Matthew , Hennen Elizabeth M. , Plosa Erin , Ramezani Alireza , Brown Kyle L. , Whang Young Mi , Terker Andrew S. , Arroyo Juan Pablo , Harrison David G. , Fogo Agnes , Brakebusch Cord H. , Pozzi Ambra , Zent Roy
Published: February 2024

Prolonged obstruction of the ureter, which leads to injury of the kidney collecting ducts, results in permanent structural damage, while early reversal allows for repair. Cell structure is defined by the actin cytoskeleton, which is dynamically organized by small Rho guanosine triphosphatases (GTPases). In this study, we identified the Rho GTPase, Rac1, as a driver of postobstructive kidney collecting duct repair. After the relief of ureteric obstruction, Rac1 promoted actin cytoskeletal reconstitution, which was required to maintain normal mitotic morphology allowing for successful cell division. Mechanistically, Rac1 restricted excessive actomyosin activity that stabilized the negative mitotic entry kinase Wee1. This mechanism ensured mechanical G
2
-M checkpoint stability and prevented premature mitotic entry. The repair defects following injury could be rescued by direct myosin inhibition. Thus, Rac1-dependent control of the actin cytoskeleton integrates with the cell cycle to mediate kidney tubular repair by preventing dysmorphic cells from entering cell division.
NU6300 covalently reacts with cysteine-191 of gasdermin D to block its cleavage and palmitoylation
Authors: Jiang Xueqin , Zhang Xinlu , Cai Xiaoying , Li Na , Zheng Hongyu , Tang Minghai , Zhu Jiangli , Su Kaiyue , Zhang Ruijia , Ye Neng , Peng Jing , Zhao Min , Wu Wenshuang , Yang Jianhong , Ye Haoyu
Published: February 2024

Gasdermin D (GSDMD) serves as a vital mediator of inflammasome-driven pyroptosis. In our study, we have identified NU6300 as a specific GSDMD inhibitor that covalently interacts with cysteine-191 of GSDMD, effectively blocking its cleavage while not affecting earlier steps such as ASC oligomerization and caspase-1 processing in AIM2- and NLRC4-mediated inflammation. On the contrary, NU6300 robustly inhibits these earlier steps in NLRP3 inflammasome, confirming a unique feedback inhibition effect in the NLRP3-GSDMD pathway upon GSDMD targeting. Our study reveals a previously undefined mechanism of GSDMD inhibitors: NU6300 impairs the palmitoylation of both full-length and N-terminal GSDMD, impeding the membrane localization and oligomerization of N-terminal GSDMD. In vivo studies further demonstrate the efficacy of NU6300 in ameliorating dextran sodium sulfate–induced colitis and improving survival in lipopolysaccharide-induced sepsis. Overall, these findings highlight the potential of NU6300 as a promising lead compound for the treatment of inflammatory diseases.
Integrating spatial and single-cell transcriptomics to characterize the molecular and cellular architecture of the ischemic mouse brain
Authors: Han Bing , Zhou Shunheng , Zhang Yuan , Chen Sina , Xi Wen , Liu Chenchen , Zhou Xu , Yuan Mengqin , Yu Xiaoyu , Li Lu , Wang Yu , Ren Hui , Xie Jian , Li Bin , Ju Minzi , Zhou You , Liu Ziqi , Xiong Zhongli , Shen Ling , Zhang Yuan , Bai Ying , Chen Jun , Jiang Wei , Yao Honghong
Published: February 2024

Neuroinflammation is acknowledged as a pivotal pathological event after cerebral ischemia. However, there is limited knowledge of the molecular and spatial characteristics of nonneuronal cells, as well as of the interactions between cell types in the ischemic brain. Here, we used spatial transcriptomics to study the ischemic hemisphere in mice after stroke and sequenced the transcriptomes of 19,777 spots, allowing us to both visualize the transcriptional landscape within the tissue and identify gene expression profiles linked to specific histologic entities. Cell types identified by single-cell RNA sequencing confirmed and enriched the spatial annotation of ischemia-associated gene expression in the peri-infarct area of the ischemic hemisphere. Analysis of ligand-receptor interactions in cell communication revealed galectin-9 to cell-surface glycoprotein CD44 (LGALS9-CD44) as a critical signaling pathway after ischemic injury and identified microglia and macrophages as the main source of galectins after stroke. Extracellular vesicle–mediated Lgals9 delivery improved the long-term functional recovery in photothrombotic stroke mice. Knockdown of
Cd44
partially reversed these therapeutic effects, inhibiting oligodendrocyte differentiation and remyelination. In summary, our study provides a detailed molecular and cellular characterization of the peri-infact area in a murine stroke model and revealed Lgals9 as potential treatment target that warrants further investigation.
Type 2–polarized memory B cells hold allergen-specific IgE memory
Authors: Koenig Joshua F. E. , Knudsen Niels Peter H. , Phelps Allyssa , Bruton Kelly , Hoof Ilka , Lund Gitte , Libera Danielle Della , Lund Anders , Christensen Lars Harder , Glass David R. , Walker Tina D. , Fang Allison , Waserman Susan , Jordana Manel , Andersen Peter S.
Published: February 2024

Allergen-specific immunoglobulin E (IgE) antibodies mediate pathology in diseases such as allergic rhinitis and food allergy. Memory B cells (MBCs) contribute to circulating IgE by regenerating IgE-producing plasma cells upon allergen encounter. Here, we report a population of type 2–polarized MBCs defined as CD23
hi
, IL-4Rα
hi
, and CD32
low
at both the transcriptional and surface protein levels. These MBC2s are enriched in IgG1- and IgG4-expressing cells while constitutively expressing germline transcripts for IgE. Allergen-specific B cells from patients with allergic rhinitis and food allergy were enriched in MBC2s. Furthermore, MBC2s generated allergen-specific IgE during sublingual immunotherapy, thereby identifying these cells as a major reservoir for IgE. The identification of MBC2s provides insights into the maintenance of IgE memory, which is detrimental in allergic diseases but could be beneficial in protection against venoms and helminths.
Biosynthesis of novel desferrioxamine derivatives requires unprecedented crosstalk between separate NRPS-independent siderophore pathways
Authors: Su Li , Souaibou Yaouba , Hôtel Laurence , Paris Cédric , Weissman Kira J. , Aigle Bertrand
Published: February 2024

Iron-chelating siderophores play important roles for their bacterial producers in the environment, but they have also found application in human medicine both in iron chelation therapy to prevent iron overload and in diagnostic imaging, as well as in biotechnology, including as agents for biocontrol of pathogens and bioremediation. In this study, we report the discovery of three novel series of related siderophores, whose biosynthesis depends on the interplay between two NRPS-independent (NIS) pathways in the producing organism
S. ambofaciens—
the first example to our knowledge of such functional cross-talk. We further reveal that two of these series correspond to acyl-desferrioxamines which incorporate four or five hydroxamate units. Although the biological importance of these novel derivatives is unknown, the increased chelating capacity of these metabolites may find utility in diagnostic imaging (for instance,
89
Zr-based immuno-PET imaging) and other applications of metal chelators.
Single-cell RNA-seq revealed heterogeneous responses and functional differentiation of hemocytes against white spot syndrome virus infection in
Litopenaeus vannamei
Authors: Cui Chuang , Tang Xiaoqian , Xing Jing , Sheng Xiuzhen , Chi Heng , Zhan Wenbin
Published: February 2024

Shrimp hemocytes are the vital immune cells participating in innate immune response to defend against viruses. However, the lack of specific molecular markers for shrimp hemocyte hindered the insightful understanding of their functional clusters and differential roles in combating microbial infections. In this study, we used single-cell RNA sequencing to map the transcriptomic landscape of hemocytes from the white spot syndrome virus (WSSV)-infected
Litopenaeus vannamei
and conjointly analyzed with our previous published single-cell RNA sequencing technology data from the healthy hemocytes. A total of 16 transcriptionally distinct cell clusters were identified, which occupied different proportions in healthy and WSSV-infected hemocytes and exerted differential roles in antiviral immune response. Following mapping of the sequencing data to the WSSV genome, we found that all types of hemocytes could be invaded by WSSV virions, especially the cluster 8, which showed the highest transcriptional levels of WSSV genes and exhibited a cell type-specific antiviral response to the viral infection. Further evaluation of the cell clusters revealed the delicate dynamic balance between hemocyte immune response and viral infestation. Unsupervised pseudo-time analysis of hemocytes showed that the hemocytes in immune-resting state could be significantly activated upon WSSV infection and then functionally differentiated to different hemocyte subsets. Collectively, our results revealed the differential responses of shrimp hemocytes and the process of immune-functional differentiation post-WSSV infection, providing essential resource for the systematic insight into the synergistic immune response mechanism against viral infection among hemocyte subtypes.

IMPORTANCE

Current knowledge of shrimp hemocyte classification mainly comes from morphology, which hinder in-depth characterization of cell lineage development, functional differentiation, and different immune response of hemocyte types during pathogenic infections. Here, single-cell RNA sequencing was used for mapping hemocytes during white spot syndrome virus (WSSV) infection in
Litopenaeus vannamei
, identifying 16 cell clusters and evaluating their potential antiviral functional characteristics. We have described the dynamic balance between viral infestation and hemocyte immunity. And the functional differentiation of hemocytes under WSSV stimulation was further characterized. Our results provided a comprehensive transcriptional landscape and revealed the heterogeneous immune response in shrimp hemocytes during WSSV infection.
An obligate microsporidian parasite modulates defense against opportunistic bacterial infection in the yellow fever mosquito
, Aedes aegypti
Authors: El-Dougdoug Noha K. , Magistrado Dom , Short Sarah M.
Published: February 2024

The ability of
Aedes aegypti
mosquitoes to transmit vertebrate pathogens depends on multiple factors, including the mosquitoes’ life history traits, immune response, and microbiota (i.e., the microbes associated with the mosquito throughout its life). The microsporidium
Edhazardia aedis
is an obligate intracellular parasite that specifically infects
Ae. aegypti
mosquitoes and severely affects mosquito survival and other life history traits critical for pathogen transmission. In this work, we investigated how
E. aedis
impacts bacterial infection with
Serratia marcescens
in
Ae. aegypti
mosquitoes. We measured development, survival, and bacterial load in both larval and adult stages of mosquitoes. In larvae,
E. aedis
exposure was either horizontal or vertical and
S. marcescens
was introduced orally. Regardless of the route of transmission,
E. aedis
exposure resulted in significantly higher
S. marcescens
loads in larvae.
E. aedis
exposure also significantly reduced larval survival but subsequent exposure to
S. marcescens
had no effect. In adult females,
E. aedis
exposure was only horizontal and
S. marcescens
was introduced orally or via intrathoracic injection. In both cases,
E. aedis
infection significantly increased
S. marcescens
bacterial loads in adult female mosquitoes. In addition, females infected with
E. aedis
and subsequently injected with
S. marcescens
suffered 100% mortality which corresponded with a rapid increase in bacterial load. These findings suggest that exposure to
E. aedis
can influence the establishment and/or replication of other microbes in the mosquito. This has implications for understanding the ecology of mosquito immune defense and potentially disease transmission by mosquito vector species.

IMPORTANCE

The microsporidium
Edhazardia aedis
is a parasite of the yellow fever mosquito,
Aedes aegypti
. This mosquito transmits multiple viruses to humans in the United States and around the world, including dengue, yellow fever, and Zika viruses. Hundreds of millions of people worldwide will become infected with one of these viruses each year.
E. aedis
infection significantly reduces the lifespan of
Ae. aegypti
and is therefore a promising novel biocontrol agent. Here, we show that when the mosquito is infected with this parasite, it is also significantly more susceptible to infection by an opportunistic bacterial pathogen,
Serratia marcescens
. This novel discovery suggests the mosquito’s ability to control infection by other microbes is impacted by the presence of the parasite.
Effects of low-frequency ultrasound combined with anti-MRSA agents on the mouse model of pulmonary infection
Authors: Yan Kaicheng , Yao Jiahui , Liu Lingling , Liang Wenxin , Cai Yun
Published: February 2024

The treatment of methicillin-resistant
Staphylococcus aureus
(MRSA)-induced pneumonia with antibiotics alone poses considerable challenges. To address these challenges, low-frequency ultrasound (LFU) emerges as a promising approach. In this study, a mouse pneumonia model was established through intratracheal injection of MRSA to investigate the therapeutic efficacy of LFU in combination with antibiotics. Minimal inhibitory concentration was assessed, and the distribution of antibiotics in the lung and plasma was determined using liquid chromatography coupled with mass spectrometry. Various parameters, including the survival rate, histopathology, lung bacterial clearance, and the expressions of cytokines and inflammation-related genes, were evaluated before and after treatment. Compared with the infection group, both the antibiotic-alone groups [vancomycin (VCM), linezolid, and contezolid (CZD)] and the groups in combination with LFU demonstrated an improvement in the survival status of mice. The average colony-forming units of lung tissue in the LFU combination groups were lower compared with the antibiotic-alone groups. While no significant changes in C-reactive protein and procalcitonin in plasma and bronchoalveolar lavage fluid were observed, histopathological results revealed reduced inflammatory damage in LFU combination groups. The secretion of interleukin-6 and tumor necrosis factor-alpha was decreased by the combination treatment, particularly in the VCM + LFU group. Furthermore, the expressions of MRSA virulence factors (
hla
and
agrA
) and inflammation-related genes (
Saa3
,
Cxcl9,
and
Orm1
) were further reduced by the combinations of LFU and antibiotics. Additionally, LFU treatment facilitated the distribution of VCM and CZD in mouse lung tissue at 30 and 45 min, respectively, after dosage.

IMPORTANCE

Treating pneumonia caused by methicillin-resistant
Staphylococcus aureus
(MRSA) with antibiotics alone poses significant challenges. In this
in vivo
study, we present compelling evidence supporting the efficacy of low-frequency ultrasound (LFU) as a promising approach to overcome these obstacles. Our findings demonstrated that LFU enhanced the effectiveness of vancomycin, linezolid, and contezolid in an MRSA pneumonia model. The combination of LFU with anti-MRSA agents markedly improved the survival rate of mice, accelerated the clearance of pulmonary bacteria, reduced inflammatory injury, inhibited the production of MRSA endotoxin, and enhanced the distribution of antibiotics in lung tissue. The application of LFU in the treatment of pulmonary infections held substantial significance. We believe that readers of your journal will find this topic of considerable interest.
Genomic characterization of
Pseudomonas syringae
pv.
syringae
from Callery pear and the efficiency of associated phages in disease protection
Authors: Holtappels D. , Abelson S. A. , Nouth S. C. , Rickus G. E. J. , Amare S. Z. , Giller J. P. , Jian D. Z. , Koskella B.
Published: February 2024

The
Pseudomonas syringae
species complex is a heterogeneous group of plant pathogenic bacteria associated with a wide distribution of plant species. Advances in genomics are revealing the complex evolutionary history of this species complex and the wide array of genetic adaptations underpinning their diverse lifestyles. Here, we genomically characterize two
P. syringae
isolates collected from diseased Callery pears (
Pyrus calleryana
) in Berkeley, California in 2019 and 2022. We also isolated a lytic bacteriophage, which we characterized and evaluated for biocontrol efficiency. Using a multilocus sequence analysis and core genome alignment, we classified the
P. syringae
isolates as members of phylogroup 2, related to other strains previously isolated from
Pyrus
and
Prunus
. An analysis of effector proteins demonstrated an evolutionary conservation of effectoromes across isolates classified in PG2 and yet uncovered unique effector profiles for each, including the two newly identified isolates. Whole-genome sequencing of the associated phage uncovered a novel phage genus related to
Pseudomonas syringae
pv.
actinidiae
phage PHB09 and the
Flaumdravirus
genus. Finally, using
in planta
infection assays, we demonstrate that the phage was equally useful in symptom mitigation of immature pear fruit regardless of the Pss strain tested. Overall, this study demonstrates the diversity of
P. syringae
and their viruses associated with ornamental pear trees, posing spill-over risks to commercial pear trees and the possibility of using phages as biocontrol agents to reduce the impact of disease.

IMPORTANCE

Global change exacerbates the spread and impact of pathogens, especially in agricultural settings. There is a clear need to better monitor the spread and diversity of plant pathogens, including in potential spillover hosts, and for the development of novel and sustainable control strategies. In this study, we characterize the first described strains of
Pseudomonas syringae
pv.
syringae
isolated from Callery pear in Berkeley, California from diseased tissues in an urban environment. We show that these strains have divergent virulence profiles from previously described strains and that they can cause disease in commercial pears. Additionally, we describe a novel bacteriophage that is associated with these strains and explore its potential to act as a biocontrol agent. Together, the data presented here demonstrate that ornamental pear trees harbor novel
P. syringae
pv.
syringae
isolates that potentially pose a risk to local fruit production, or vice versa—but also provide us with novel associated phages, effective in disease mitigation.