Browse Articles

The global burden of breast cancer among women of reproductive age: a comprehensive analysis

<i>Sinorhizobium meliloti</i> FcrX coordinates cell cycle and division during free-living growth and symbiosis by a ClpXP-dependent mechanism

Sinorhizobium meliloti is a soil bacterium that establishes a nitrogen-fixing symbiosis within root nodules of legumes. In this symbiosis, S. meliloti undergoes a drastic cellular change leading to a terminally differentiated form, called bacteroid, characterized by genome endoreduplication, increased cell size, and high membrane permeability. Bacterial cell cycle (mis)regulation is at the heart of this differentiation process. In free-living cells, the master regulator CtrA ensures the progression of cell cycle by activating cell division (controlled by FtsZ) and inhibiting DNA replication, while on the other hand the so far poorly unknown downregulation of CtrA and FtsZ is essential for bacteroid differentiation. Here, we combine cell biology, biochemistry, and bacterial genetics to understand the functions of FcrX, a factor that controls both CtrA and FtsZ in free-living growth and in symbiosis. Depletion of the essential gene fcrX led to abnormally high levels of FtsZ and CtrA and minicell formation. Using multiple complementary techniques, we showed that FcrX may interact with FtsZ and CtrA. Moreover, fcrX transcription is directly controlled by CtrA itself and the FcrX protein displays a cell cycle-dependent pattern. We showed further that FcrX also binds the degradosome complex ClpXP and its adaptors CpdR1 and RcdA, and that CtrA degradation efficiency depends on FcrX. We further showed that, despite weak homology with FliJ-like proteins, only FcrX proteins from closely related species are able to complement S. meliloti fcrX function. Finally, deregulation of FcrX showed abnormal symbiotic behaviors in plants suggesting a putative role of this factor during bacteroid differentiation.

A novel scale for anxiety-related fixation instability during laser in situ keratomileusis

Abstract This cohort study aimed to investigate the correlation between the severity of anxiety during laser in situ keratomileusis (LASIK) and fixation instability, as measured and plotted by the eye tracker during photo-ablation, and to develop a novel quantitative scale for anxiety-related fixation instability. LASIK was performed to correct myopia and hypermetropia with and without astigmatism in 2435 eyes of 2435 patients. Participants fulfilled the seven-item anxiety sub-score of the Hospital Anxiety and Depression scale questionnaire for scaling patients’ anxiety levels before LASIK into normal, borderline, and anxiety case groups. The eye-tracking pupil center position plots, patient’s heart rate, and surgeon-reported level of patient’s cooperation during the procedure were analyzed. An anxiety-related fixation instability score (FIS) was calculated, for which the best cut-off points to differentiate between normal, borderline, and anxiety case groups were defined. The FIS showed a high performance in separating participants into normal, borderline, and anxiety case groups and when used as a scale (0–90), values from 0 to 12 are considered normal, from 13 to 36 are considered borderline, and from 37 to 90 are considered anxiety cases. The FIS and scale are useful objective tools to quantify anxiety-related fixation instability during LASIK.

Characterization of diverse Cas9 orthologs for genome and epigenome editing

CRISPR-Cas9 systems have revolutionized biotechnology, creating diverse new opportunities for biomedical research and therapeutic genome and epigenome editing. Despite the abundance of bacterial CRISPR-Cas9 systems, relatively few are effective in human cells, limiting the overall potential of CRISPR technology. To expand the CRISPR-Cas toolbox, we characterized a set of type II CRISPR-Cas9 systems from select bacterial genera and species encoding diverse Cas9s. Four systems demonstrated robust and specific gene repression in human cells when used as nuclease-null dCas9s fused with a KRAB domain and were also highly active nucleases in human cells. These systems have distinct protospacer adjacent motifs (PAMs), including AT-rich motifs and sgRNA features orthogonal to the commonly used Staphylococcus aureus and Streptococcus pyogenes Cas9s. Additionally, we assessed gene activation when fused with the p300 catalytic domain. Notably, S. uberis Cas9 performed competitively against benchmarks with promising repression, activation, nuclease, and base editing activity. This study expands the CRISPR-Cas9 repertoire, enabling effective genome and epigenome editing for diverse applications.

Functionality of Toxoplasma gondii antibodies in a population of Beninese pregnant women exposed to malaria

Abstract Plasmodium falciparum and Toxoplasma gondii are two apicomplexan parasites that can lead to severe complications for the newborn when contracted during pregnancy. This study explores the cross-reactivity of antibodies specific to both pathogens in pregnant women, exposed or not to malaria. The antibody response against full-length recombinant antigens from P. falciparum ( Pf AMA1, Pfs 48/45) and T. gondii ( Tg AMA1, Tg SAG1, Tg GRA7), selected for their strong immunogenicity, was analysed on 150 plasma samples from women residing in Benin or France. The antibody functionality was assessed using P. falciparum in vitro Growth Inhibition Assay (GIA). As the main results, toxoplasmosis seropositive women with an ongoing P. falciparum infection better inhibited P. falciparum invasion compared to toxoplasmosis seronegative women (34.6% vs. 17.2%, p  ≤ 0.01). Women with positive serologies for both parasites presented a significantly higher inhibition of P. falciparum invasion compared to those only seropositive for malaria (coef = 6.27, p  = 0.076) in reference with double-negative women (coef = 11.35, p  = 0.001). These data suggest that plasma samples containing anti- T. gondii IgG may contribute reducing the development of P. falciparum parasites. This study provides insight into the immune dynamics of the co-infection by these two apicomplexans with potential implications for developing cross-protective vaccines and therapies.

A family of bacterial actin homologs forms a three-stranded tubular structure

The cytoskeleton is crucial for cell organization and movement. In Eukaryotes, it largely consists of the protein actin, that forms a double-stranded linear filamentous structure in the presence of ATP and disassemble upon ATP hydrolysis. Bacteria also possess actin homologs, that drive fundamental cellular processes, including cell division, shape maintenance, and DNA segregation. Like eukaryotic actin, bacterial actins assemble into dynamic polymers upon ATP binding, however variation in interactions between strands gives rise to striking diversity of filament architectures. Here, we report a family of bacterial actins of unknown function, conserved among the Verrucomicrobiota phylum, which assembles into a unique tubular structure in the presence of ATP. A cryo-EM structure of the filaments reveals that it consists of three strands, unlike other described bacterial actin structures. This architecture provides further insights into the organization of actin-like filaments and has implications for understanding the diversity and evolution of the bacterial cytoskeleton.

Limitations of estimating antibiotic resistance using German hospital consumption data - a comprehensive computational analysis

Abstract For almost a century, antibiotics have played an important role in the treatment of infectious diseases. However, the efficacy of these very drugs is now threatened by the development of resistances, which pose major challenges to medical professionals and decision-makers. Thereby, the consumption of antibiotics in hospitals is an important driver that can be targeted directly. To illuminate the relation between consumption and resistance depicts a very important step in this procedure. With the help of comprehensive ecological and clinical data, we applied a variety of different computational approaches ranging from classical linear regression to artificial neural networks to analyze antibiotic resistance in Germany. These mathematical and statistical models demonstrate that the amount and particularly the structure of currently available data sets lead to contradictory results and do, therefore, not allow for profound conclusions. More effort and attention on both data collection and distribution is necessary to overcome this problem. In particular, our results suggest that at least monthly or quarterly antibiotic use and resistance data at the department and ward level for each hospital (including application route and type of specimen) are needed to reliably determine the extent to which antibiotic consumption influences resistance development.

Genetic or therapeutic disruption of the Reelin/Apoer2 signaling pathway improves inflammatory arthritis outcomes

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation, pannus formation, and progressive joint destruction. The inflammatory milieu in RA drives endothelial cell activation and upregulation of adhesion molecules, thus facilitating leukocyte infiltration into the synovium. Reelin, a circulating glycoprotein previously implicated in endothelial activation and leukocyte recruitment in diseases such as atherosclerosis and multiple sclerosis, has emerged as a potential upstream regulator of these processes. However, its role in RA pathogenesis remains poorly understood. Here, we demonstrate that Reelin levels are markedly elevated in the plasma of both RA patients and mouse models of arthritis, with higher concentrations correlating with greater disease severity. Genetic deletion of the Reelin receptor Apoer2 conferred significant protection against serum transfer arthritis (STA), underscoring the relevance of this pathway in disease progression. Furthermore, therapeutic inhibition of Reelin using the CR-50 antibody yielded robust anti-inflammatory effects in multiple preclinical arthritis models, including STA, K/BxN, and collagen-induced arthritis. Notably, CR-50 treatment not only reduced leukocyte infiltration and synovial inflammation but also mitigated pannus formation. Importantly, these benefits were achieved without the gastrointestinal side effects commonly associated with nonsteroidal anti-inflammatory drugs like diclofenac. Our findings position Reelin as a proinflammatory endothelial biomarker and therapeutic target in RA. By modulating endothelial activation and leukocyte recruitment, anti-Reelin strategies offer an alternative approach to attenuate synovial inflammation and joint damage. These results provide a compelling rationale for further exploration of Reelin-targeted therapies as alternatives to conventional immunosuppressive treatments in RA and other chronic inflammatory diseases.

Construction of a machine learning-based interpretable prediction model for acute kidney injury in hospitalized patients

Machine-learning heat flux closure for multi-moment fluid modeling of nonlinear Landau damping

Nonlinear plasma physics problems are usually simulated through comprehensive modeling of phase space. The extreme computational cost of such simulations has motivated the development of multi-moment fluid models. However, a major challenge has been finding a suitable fluid closure for these fluid models. Recent developments in physics-informed machine learning have led to a renewed interest in constructing accurate fluid closure terms. In this study, we take an approach that integrates kinetic physics from the first-principles Vlasov simulations into a fluid model (through the heat flux closure term) using the Fourier neural operator—a neural network architecture. Without resolving the phase space dynamics, this new fluid model is capable of capturing the nonlinear evolution of the Landau damping process that exactly matches the Vlasov simulation results. This machine learning–assisted new approach provides a computationally affordable framework that surpasses previous fluid models in accurately modeling the kinetic evolution of complex plasma systems.

Blockchain ensuring academic integrity with a degree verification prototype

Dual-filament regulation of relaxation in mammalian fast skeletal muscle

Muscle contraction is driven by myosin motors from the thick filaments pulling on the actin-containing thin filaments of the sarcomere, and it is regulated by structural changes in both filaments. Thin filaments are activated by an increase in intracellular calcium concentration [Ca 2+ ] i and by myosin binding to actin. Thick filaments are activated by direct sensing of the filament load. However, these mechanisms cannot explain muscle relaxation when [Ca 2+ ] i decreases at high load and myosin motors are attached to actin. There is, therefore, a fundamental gap in our understanding of muscle relaxation, despite its importance for muscle function in vivo, for example, for rapid eye movements or, on slower timescales, for the efficient control of posture. Here, we used time-resolved small-angle X-ray diffraction (SAXD) to determine how muscle thin and thick filaments switch OFF in extensor digitorum longus (EDL) muscles of the mouse in response to decreases in either [Ca 2+ ] i or muscle load and to describe the distribution of muscle sarcomere lengths (SLs) during relaxation. We show that reducing load at high [Ca 2+ ] i is more effective in switching OFF both the thick and thin filaments than reducing [Ca 2+ ] i at high load in normal relaxation. In the latter case, the thick filaments initially remain fully ON, although the number of myosin motors bound to actin decreases and the force per attached motor increases. That initial slow phase of relaxation is abruptly terminated by yielding of one population of sarcomeres, triggering a redistribution of SLs that leads to the rapid completion of mechanical relaxation.

Sjögren’s syndrome increased risk of attempted suicide

For geological carbon sequestration to work, we need a geospatial planning policy

Innovative liposomal coumarin: A promising solution for enhancing soft white cheese quality

Background Coumarin is a natural bioactive compound found in many plants and acquires antibacterial, antioxidant and anticoagulant activities. The antibacterial activity of coumarin has never been tested after being encapsulated in liposomes. This study was carried out to screen the main functional components of Rubus canescens DC crude extract (CE), develop a coumarin nanoliposome, and test its anti-bacterial and antioxidant properties. Methods R. canescens DC CE was screened for its main functional compounds using liquid chromatography-mass spectrometry (LC-MS). Pure commercial coumarin was loaded into liposomes and characterized in terms of surface morphology, hydrodynamic diameter, zeta potential, and encapsulation efficiency (EE). The antioxidant activity of coumarin was evaluated against ascorbic acid. The antibacterial activity of both coumarin alone and liposome-encapsulated coumarin against Staphylococcus aureus, Salmonella typhimurium, and Pseudomonas aeruginosa inoculated in soft white cheese (SWC) was also evaluated. Results The predominant natural constituent of R. canescens DC CE, was coumarin. Comparing the DPPH scavenging activity of coumarin to that of ascorbic acid, coumarin exhibited an insignificant effect (p ≥ 0.05). The minimum inhibitory concentration (MIC) values for coumarin against P. aeruginosa, E. coli, Staph. aureus, S. typhimurium, and L. monocytogenes were 2.5, 2.5, 2.5, 1.25, and 1.25 µg/ml, respectively. The minimum bactericidal concentration (MBC) values for coumarin against these microorganisms were 5, 5, 5, 2.5, and 2.5 µg/ml, respectively. Coumarin was successfully loaded into nanoliposomes, which had a polydispersity index (PDI) of 0.36 ±  0.35 Đ, hydrodynamic diameter of 127.8 ±  0.3 nm, zeta-potential of -61.03 ±  2.9 mV, and EE of 40.93 ±  0.2%. Both the coumarin alone and the liposome loaded with coumarin showed antibacterial effects against the inoculated bacterial strains in SWC over a 30-day storage period at 4°C. Conclusions Coumarin was successfully formulated into a nanoliposome, and showed antibacterial activity against P. aeruginosa, S. aureus, and S. typhimurium.

Relation-based self-distillation method for 2D object detection

SOS1 inhibitor BI-3406 shows in vivo antitumor activity akin to genetic ablation and synergizes with a KRAS ^G12D inhibitor in KRAS LUAD

We evaluated the in vivo therapeutic efficacy and tolerability of BI-3406-mediated pharmacological inhibition of SOS1 in comparison to genetic ablation of this universal Ras-GEF in various KRAS-dependent experimental tumor settings. Contrary to the rapid lethality caused by SOS1 genetic ablation in SOS2 KO mice, SOS1 pharmacological inhibition by its specific inhibitor BI-3406 did not significantly affect animal weight/viability nor cause noteworthy systemic toxicity. Allograft assays using different KRAS mut cell lines showed that treatment with BI-3406 impaired RAS activation and RAS downstream signaling and decreased tumor burden and disease progression as a result of both tumor-intrinsic and -extrinsic therapeutic effects of the drug. Consistent with prior genetic evidence and the KRAS mut allografts assays in immunocompromised mice, our analyses using an in vivo model of KRAS G12D -driven lung adenocarcinoma (LUAD) in immunocompetent mice showed that single, systemic BI-3406 treatment impaired tumor growth and downmodulated protumorigenic components of the tumor microenvironment comparably to SOS1 genetic ablation or to treatment with the specific KRAS G12D inhibitor MRTX1133. Furthermore, markedly stronger, synergistic antitumor effects were observed upon concomitant treatment with BI-3406 and MRTX1133 in the same in vivo LUAD mouse model. Our data confirm SOS1 as an actionable therapy target in RAS-dependent cancers and suggest that BI-3406 treatment may yield clinical benefit both as monotherapy or as a potential combination partner for multiple RAS-targeting strategies.

Correction: A scoping review to examine health care professionals’ experiences as family caregivers

Measurement properties of the Polish version of the Cystic Fibrosis Questionnaire Revised 14+ in the adult population

Proteasomal processing of the viral replicase ORF1 facilitates HEV-induced liver fibrosis

Chronic infections with hepatitis E virus (HEV), especially those of genotype 3 (G3), frequently lead to liver fibrosis and cirrhosis in patients. However, the causation and mechanism of liver fibrosis triggered by chronic HEV infection remain poorly understood. Here, we found that the viral multiple-domain replicase (ORF1) undergoes unique ubiquitin–proteasomal processing leading to formation of the H EV- D erived S MAD A ctivator (HDSA), a viral polypeptide lacking putative helicase and RNA polymerase domains. The HDSA is stable, non-HSP90-bound, localizes to the nucleus, and is abundant in G3 HEV-infected hepatocytes of various origins. Markedly, the HDSA in hepatocytes potentiates the fibrogenic TGF-β/SMAD pathway by forming compact complexes with SMAD3 to facilitate its promoter binding and coactivator recruitment, leading to significant fibrosis in HEV-susceptible gerbils. Virus infection–induced liver fibrosis in HEV-susceptible gerbils could be prevented by mutating the residues P989C, A990C, and A991C (PAA-3C) within ORF1, which are required for proteasomal processing. Thus, we have identified a viral protein derived from host proteasomal processing, defined its notable role in liver fibrosis and highlighted the nature of an unanticipated host–HEV interaction that facilitates hepatitis E pathogenesis.