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Tenure and research trajectories
Tenure is a cornerstone of the US academic system, yet its relationship to faculty research trajectories remains poorly understood. Conceptually, tenure systems may act as a selection mechanism, screening in high-output researchers; a dynamic incentive mechanism, encouraging high output prior to tenure but low output after tenure; and a creative search mechanism, encouraging tenured individuals to undertake high-risk work. Here, we integrate data from seven different sources to trace US tenure-line faculty and their research outputs at a remarkable scale and scope, covering over 12,000 researchers across 15 disciplines. Our analysis reveals that faculty publication rates typically increase sharply during the tenure track and peak just before obtaining tenure. Post-tenure trends, however, vary across disciplines: In lab-based fields, such as biology and chemistry, research output typically remains high post-tenure, whereas in non-lab-based fields, such as mathematics and sociology, research output typically declines substantially post-tenure. Turning to creative search, faculty increasingly produce novel, high-risk research after securing tenure. However, this shift toward novelty and risk-taking comes with a decline in impact, with post-tenure research yielding fewer highly cited papers. Comparing outcomes across common career ages but different tenure years or comparing research trajectories in tenure-based and non-tenure-based research settings underscores that breaks in the research trajectories are sharply tied to the individual’s tenure year. Overall, these findings provide an empirical basis for understanding the tenure system, individual research trajectories, and the shape of scientific output.
Increased breathlessness in post-COVID syndrome despite normal breathing patterns in a rebreathing challenge
Abstract Severe symptoms in the absence of measurable body pathology are a frequent hallmark of post-COVID syndrome. From a Bayesian Brain perspective, such symptoms can be explained by incorrect internal models that the brain uses to interpret sensory signals. In this pre-registered study, we investigate whether induced breathlessness perception during a controlled CO2rebreathing challenge is reflected by altered respiratory measures (physiology and breathing patterns), and propose different computational mechanisms that could explain our findings in a Bayesian Brain framework. We analysed data from 40 patients with post-COVID syndrome and 40 healthy participants. Results from lung function, neurological and neurocognitive examination of all participants were within normal limits on the day of the experiment. Using a Bayesian repeated-measures ANOVA, we found that patients’ breathlessness was strongly increased (BF10,baseline =8.029, BF10,rebreathing =11636, BF10,recovery =43662) compared to controls. When excluding patients who hyperventilated (N = 8, 20%) during the experiment from the analysis, differences in breathlessness remained (BF10,baseline =1.283, BF10,rebreathing =126.812, BF10,recovery =751.282). For physiology and breathing patterns, all evidence pointed towards no difference between the two groups (0.307 > BF10 < 0.704). In summary, we found intact breathing patterns and physiology but increased symptom perception in patients with post-COVID syndrome.
Ras-mediated dynamic and biphasic regulation of cell migration
Ras has traditionally been regarded as a positive regulator and therapeutic target due to its role in cell proliferation, but recent findings indicate a more nuanced role in cell migration, where suppressed Ras activity can unexpectedly promote migration. To clarify this complexity, we systematically modulate Ras activity using various RasGEF and RasGAP proteins and assess their effects on migration dynamics. Leveraging optogenetics, we assess the immediate, nontranscriptional effects of Ras signaling on migration. Local RasGEF recruitment to the plasma membrane induces protrusions and new fronts to effectively guide migration, even in the absence of GPCR/G-protein signaling, whereas global recruitment causes immediate cell spreading halting cell migration. Local RasGAP recruitment suppresses protrusions, generates new backs, and repels cells, whereas global relocation either eliminates all protrusions to inhibit migration or preserves a single protrusion to maintain polarity. Consistent local and global increases or decreases in signal transduction and cytoskeletal activities accompany these morphological changes. Additionally, we performed cortical tension measurements and found that Ras activity is regulated by guanine nucleotide exchange factors generally increase cortical tension while Ras activity is regulated by GTPase-activating proteins decrease it. Our results reveal a biphasic relationship between Ras activity and cellular dynamics, reinforcing our previous findings that optimal Ras activity and cortical tension are critical for efficient migration.
A hybrid filtering and deep learning approach for early Alzheimer’s disease identification
Abstract Alzheimer’s disease is a progressive neurological disorder that profoundly affects cognitive functions and daily activities. Rapid and precise identification is essential for effective intervention and improved patient outcomes. This research introduces an innovative hybrid filtering approach with a deep transfer learning model for detecting Alzheimer’s disease utilizing brain imaging data. The hybrid filtering method integrates the Adaptive Non-Local Means filter with a Sharpening filter for image preprocessing. Furthermore, the deep learning model used in this study is constructed on the EfficientNetV2B3 architecture, augmented with additional layers and fine-tuning to guarantee effective classification among four categories: Mild, moderate, very mild, and non-demented. The work employs Grad-CAM++ to enhance interpretability by localizing disease-relevant characteristics in brain images. The experimental assessment, performed on a publicly accessible dataset, illustrates the ability of the model to achieve an accuracy of 99.45%. These findings underscore the capability of sophisticated deep learning methodologies to aid clinicians in accurately identifying Alzheimer’s disease.
Sound-evoked tonic motility of cochlear outer hair cells in mice with stereociliary defects
Mammalian hearing sensitivity depends on the amplification of sound-induced cochlear vibrations by outer hair cells (OHCs). OHCs transduce deflections of their stereociliary bundles into receptor potentials that drive changes in cell length. While fast, phasic OHC length changes are thought to generate the forces that underlie cochlear amplification, OHCs also exhibit large tonic length changes in response to sound. These tonic length changes could theoretically arise from asymmetries in the mechanotransduction process that lead to tonic changes in membrane potential, though their exact origins and functional significance are uncertain. Here, in vivo cochlear vibration measurements reveal that sound can elicit tonic OHC motility in mice with stereociliary defects that eliminate cochlear amplification and presumably impair mechanotransduction. Tonic OHC motility in impaired mice was physiologically vulnerable but only weakly correlated with any residual phasic motility, suggesting a possible dissociation between the underlying mechanisms. Nevertheless, a simple model demonstrates how realistic changes to the OHC mechanotransducer function in impaired mice can lead to small but strongly asymmetric receptor potentials, producing sizable tonic length changes in the absence of any detectable phasic motility. Tonic OHC motility is therefore not a unique feature of sensitive ears and is the dominant active mechanical response in ears with certain types of deafness. Whether such tonic responses play a functional role in the normal or impaired cochlea remains to be determined.
The value of acetylation reader YEATS2 in hepatocellular carcinoma management
Static allometries of caste-associated traits vary with genotype but not environment in the clonal raider ant
Polyphenic traits in animals often exhibit nonlinear scaling with body size. Static allometries (i.e., scaling relationships) themselves can exhibit plasticity, such that individuals of the same size and genotype differ in body proportions across different environments. In ants, both larval environment and genotype regulate the expression of caste-associated traits, including body size and ovariole number. However, it remains untested whether caste-associated traits are independently regulated by environmental variables or whether they covary due to coupled developmental mechanisms. If caste traits are regulated independently, developmental plasticity should affect both trait expression and the scaling relationships between traits. Using the clonal raider ant, Ooceraea biroi , we tested this by manipulating the rearing environment of genetically identical larvae. We found that caregiver genotype, temperature, and food quantity influenced caste morphology strictly in tandem with body size, producing similar static allometries across rearing conditions (i.e., no allometric plasticity was detected). In contrast, clonal genotypes differed in average body size and their static allometries. Thus, size-matched individuals of the same genotype from different rearing environments exhibited no differences in mean caste trait expression, while those of different genotypes did. This absence of plasticity in the static allometries of different caste traits suggests that they are developmentally coupled due to systemic regulatory factors. Our findings contrast with reports of allometric plasticity in other insects, suggesting that ant caste traits are exceptionally integrated and therefore constrained in their independent responses to environmental variation. We discuss how these results inform contemporary hypotheses for ant caste development and evolution.
Exploring the influence of vitamin C concentrations on the dynamics of RT-PCR assay reactions
OGG1 augments the transcriptional activation of <i>Foxp3</i> to promote iTreg differentiation for IBD alleviation
8-oxo-7,8-dihydroguanine (8-oxoG), the most frequent form of oxidative-DNA-base lesion caused by ROS, is recognized and repaired by 8-oxoguanine DNA glycosylase 1 (OGG1) through base excision repair (BER) pathway. Beyond its role in DNA repair, OGG1 has been shown to promote transcriptional activation of proinflammatory mediators and contribute to both acute and chronic lung inflammation. However, pioneering studies have shown an anti-inflammation role for OGG1 in inflammatory bowel disease (IBD), but its underlying molecular mechanism remains unclear. In the present study, we unveiled that OGG1 plays an important role in the differentiation of inducible regulatory T cells (iTregs). Binding of OGG1 to 8-oxoG facilitated the recruitment of Smad3 to the Foxp3 promoter, leading to the transcriptional activation. Moreover, OGG1 binding promoted demethylation of CpG sites in the conserved noncoding sequence 2 (CNS2) region of Foxp3 by decreasing Dnmt1 occupancy and enhancing recruitment of Tet1/2. Notably, the S326C variant—a naturally occurring polymorphism in humans—was more effective than the wild-type protein in promoting iTreg differentiation and showed a negative correlation with IBD incidence. Furthermore, treatment with O8, a selective OGG1 inhibitor that blocks base excision activity without affecting substrate binding, significantly alleviated IBD in a mouse model, suggesting a promising therapeutic strategy. Together, these findings extend the understanding of OGG1’s epigenetic role in transcriptional regulation and highlight its protective function in inflammatory diseases, potentially shaped by aerobic evolution.
Author Correction: Combination therapy of tyrosine kinase inhibitor sorafenib with the HSP90 inhibitor onalespib as a novel treatment regimen for thyroid cancer
An electron-bifurcating “plug” to a protein nanowire in tungsten-dependent aldehyde detoxification
Members of the tungsten-containing oxidoreductase (WOR) family, which contain a tungstopyranopterin (Tuco) cofactor, are typically either monomeric (WorL) or heterodimeric (WorLS). These enzymes oxidize aldehydes to the corresponding acids while reducing the redox protein ferredoxin. They have been structurally characterized mainly using WORs from hyperthermophilic archaea. The WORs of some bacteria contain three additional subunits of the BfuABC family and these chimeric WorABCSL enzymes catalyze an electron-bifurcating reaction in which aldehyde oxidation is coupled to the simultaneous reduction of ferredoxin and nicotinamide adenine dinucleotide. In human gut microbes, electron bifurcation by WorABSL is proposed to enable the detoxification of aldehydes generated from cooked foods and in the tungstocentric production of beneficial short chain fatty acids from lactate, potentially impacting health. Herein we present the high-resolution cryogenic electron microscopy (cryo-EM) structure of the WorABCSL purified from the bacterium Acetomicrobium mobile. The structure reveals a surprising 1:3 stoichiometry between WorABC and WorSL, with the WorSL units forming a nanowire-like architecture leading from three Tuco-containing catalytic sites in WorL via strings of multiple iron-sulfur clusters in WorS to a single bifurcating WorABC core. Our structure uncovers a distinct domain arrangement that links three Tuco-dependent aldehyde oxidation sites with the bifurcation process and potentially facilitates environmental aldehyde oxidation.
Safety and immunogenicity of fractional COVID-19 vaccine doses in Nigerian adults: A randomized non-inferiority trial
Abstract Fractional dosing of vaccines is a viable strategy to extend COVID-19 vaccine supplies in resource-constrained settings. We did a triple-blinded, multi-site, randomized non-inferiority trial in Nigeria (PACTR202206754734018). Adults 18–65 years received full, half, or quarter primary doses of ChAdOx1 or Ad26.COV2.S, or full vs half doses of BNT162b2. Primary study outcome was seroconversion defined as ≥ 2.5-fold rise in anti-Spike IgG geometric-mean fold rise (GMFR) at day 28. A total of 1894 participants were enrolled between June 21, 2022, and January 25, 2023. 320 participants in the fractional dose group and 220 in the standard dose group completed follow-up and were included in the analysis. Seropositivity at baseline was high, at 68% (365/539). Seroconversion was comparable between standard and fractional doses (p = 0.822). For ChAdOx1, 31% achieved seroconversion at standard dose (16/52), 28% at half-dose (15/53), and 34% in quarter-dose (18/53). For Ad26.COV2.S, the proportions were 27% (28/105), 32% (22/68), and 30% (21/71) respectively. For BNT162b2, the proportions were 43% (27/63) and 39% (29/75) for standard- and half-dose. Serum neutralization showed ≥ twofold response across dosing. There were no serious adverse events. Fractional vaccine doses generated non-inferior immune responses compared to standard doses in the context of previous COVID-19. Protocol Registration: The protocol was registered with the Pan African Clinical Trials Registry (PACTR) PACTR202206754734018.
Gibberellin-deactivating GA2OX enzymes act as a hub for auxin–gibberellin cross talk in <i>Arabidopsis thaliana</i> root growth regulation
Plant bodies are built from immobile cells, making the regulation of cell expansion essential for growth, development, and adaptation. In roots, cell elongation executes the movement of the root tips through the soil. This process is tightly controlled by numerous signaling pathways. Among these, gibberellin and auxin signaling stand out for their contrasting effects on root growth, interacting through complex cross talk at multiple regulatory levels. Here, we reveal the molecular basis of the auxin–gibberellin cross talk in the model plant Arabidopsis thaliana . We show that the auxin signaling pathway steers the expression of GIBBERELLIN 2-OXIDASES (GA2OXs) , key gibberellin-deactivating enzymes in the root elongation zone (EZ). GA2OXs are negative regulators of root cell elongation; GA2OX8 overexpression decreases gibberellin levels and inhibits root cell elongation; in contrast, the ga2ox heptuple mutant roots show elevated gibberellin levels in the EZ and grow longer roots. Intriguingly, shoot-derived auxin can regulate GA2OX6 and GA2OX8 expression in roots, linking systemic auxin signaling to local gibberellin level modulation. Together, our findings identify GA2OX6 and GA2OX8 enzymes as key mediators of auxin–gibberellin cross talk, providing insights into their roles in root elongation. These results expand our understanding of how auxin integrates with gibberellin signaling to coordinate root development and growth dynamics.
Retraction Note: Tiliroside as a CAXII inhibitor suppresses liver cancer development and modulates E2Fs/Caspase-3 axis
Central memory T cells with key TCR repertoires and gene expression profiles dominate influenza CD8+ T cell pools across the human lifespan
Central memory CD8 + T cells (T cm ) represent the prominent memory T cell subset in human blood, yet the persistence of T cell receptor (TCR) clonotypic and transcriptional features of epitope-specific T cm pools across the human lifespan remains unknown. We analyzed T cm CD8 + T cells specific for HLA-A*02:01-M1 58–66 (A2/M1 58 ; a prominent influenza epitope) in newborns, children, adults, and older adults directly ex vivo. Our data provide evidence that epitope-specific T cm CD8 + pools dominate influenza-specific memory A2/M1 58 + CD8 + T cell responses from the early childhood until old age. T cm gene signatures were largely maintained across the age groups, although self-renewal genes defined T cm pools in children, while older adult T cm A2/M1 58 + CD8 + T cells displayed detoxication and stress profiles. TCRαβ diversity within T cm A2/M1 58 + CD8 + T cell pools was greater in children and older adults, when compared to adults. The key public-associated TCRαβ clonotypes largely persisted across the human lifespan, although their highest frequency was detected in adults, reflecting lower TCRαβ diversity in this group. Older adults displayed increased TCRαβ heterogeneity, underpinned by large TCRαβ clonotype expansions of private TCRαβ clonotypes. Our study highlights the importance of largely preserved virus-specific T cm pools across the human lifespan and advocates for boosting persistent TCRαβ clonotypes within this key peripheral blood subset.
Swelling reduction in bentonite due to saline solutions via fractal modeling
Sharks and rays have the oldest vertebrate sex chromosome with unique sex determination mechanisms
Sex determination has been investigated across vertebrate lineages to reveal the stepwise evolution of sex chromosomes and the diversity of responsible molecular mechanisms. However, these studies rarely include cartilaginous fishes, which diverged from the other vertebrates 450 Mya, hindering the comprehensive view of vertebrate sex determination. Here, we produced chromosome-scale genome assemblies of egg-laying shark species and comparatively investigated genome sequences and transcriptome profiles across diverse cartilaginous fishes. Sex chromosome identification, supported by cytogenetic experiments, elucidated the homology of X chromosomes between sharks and rays as well as an extensively degenerated Y chromosome harboring no detectable male-specific genes. Orthologs of documented sex-determining genes were identified, but not on these sex chromosomes. Transcriptomic analyses combined with histology of embryonic gonads revealed female-biased expression of X-linked genes—including those implicated in the TGF-β and IGF signaling pathways—attributed to incomplete dosage compensation. Our findings indicate that sharks and rays share the oldest sex chromosomes among vertebrates that originated around 300 Mya and the dosage-dependent sex determination mechanism composed of distinct molecules from other vertebrates. This study highlights the antiquity of sex chromosomes and the uniqueness of sex determination mechanisms in sharks and rays, which advances our understanding of evolutionary plasticity in vertebrate sex determination.
A data-driven analysis of lumbar steroid injection satisfaction in patients with chronic low back pain
Abstract Chronic low back pain (CLBP) is a prevalent condition significantly reducing quality of life. Lumbar steroid injections are a widely used conservative treatment option, but their effectiveness varies among patients. This study aimed to develop a predictive framework that integrates clinical variables and patient demographics to evaluate post-treatment pain satisfaction in CLBP patients undergoing lumbar injection therapy. We performed a retrospective analysis of 212 CLBP patients to evaluate the treatment satisfaction and pain intensity changes using the Numerical Rating Scale (NRS). A Random Forest model, validated through nested cross-validation, achieved an average precision of 0.865 in predicting treatment satisfaction. SHapley Additive exPlanations (SHAP) analysis revealed pain self-efficacy features, particularly coping mechanisms and household activities, as key outcome predictors of post-treatment pain satisfaction. Clinically significant pain reduction thresholds were identified at an absolute change of 2.09 and a relative change of 30 % on the NRS. Our findings reveal the biological and social factors influencing post-treatment pain in CLBP patients. The identified pain reduction thresholds and predictors may help clinicians to develop individualized management strategies, optimizing treatment outcomes and improving patient care. Future research should refine the predictive model by incorporating additional multimodal variables to better capture CLBP heterogeneity.
Leveraging chromatin packing domains to target chemoevasion in vivo
Cancer cells exhibit a remarkable resilience to cytotoxic stress, often adapting through transcriptional changes linked to alterations in chromatin structure. In several types of cancer, these adaptations involve epigenetic modifications and restructuring of topologically associating domains. However, the underlying principles by which chromatin architecture facilitates such adaptability across different cancers remain poorly understood. To investigate the role of chromatin in this process, we developed a physics-based model that connects chromatin organization to cell fate decisions, such as survival following chemotherapy. Our model builds on the observation that chromatin forms packing domains, which influence transcriptional activity through macromolecular crowding. The model accurately predicts chemoevasion in vitro, suggesting that changes in packing domains affect the likelihood of survival. Consistent results across diverse cancer types indicate that the model captures fundamental principles of chromatin-mediated adaptation, independent of the specific cancer or chemotherapy mechanisms involved. Based on these insights, we hypothesized that compounds capable of modulating packing domains, termed Transcriptional Plasticity Regulators (TPRs), could prevent cellular adaptation to chemotherapy. We conducted a proof-of-concept compound screen using live-cell chromatin imaging to identify several TPRs that synergistically enhanced chemotherapy-induced cell death. The most effective TPR significantly improved therapeutic outcomes in a patient-derived xenograft model of ovarian cancer. These findings underscore the central role of chromatin in cellular adaptation to cytotoxic stress and present a framework for enhancing cancer therapies, with broad potential across multiple cancer types.