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Yeast centrosomes act as organizing centers to promote Polo kinase–mediated adaptation to persistent DNA damage

The ability of cells to overcome cell cycle arrest and adapt to the presence of unrepairable DNA damage is under the control of Polo-like kinases (PLKs) in eukaryotes. How DNA damage checkpoints are silenced or bypassed during the adaptation response is unknown, but the process requires enrichment of the Cdc5 PLK to microtubule organizing centers (MTOCs), such as the yeast centrosomes or spindle pole bodies (SPBs). Here, we found that SPBs play an active role as supramolecular organizing centers that coordinate Cdc5 recruitment and signaling to downstream effectors during the adaptation response to DNA damage. We show that SPB components Nud1, Spc110, and Spc72 are key effectors of Cdc5 recruitment to SPBs in the presence of sustained DNA damage. Following recruitment, Cdc5 transduces a phospho-signal to key structural subunits of the SPB, including Cnm67 and Mps3. We demonstrate these phosphorylation events are required to bypass cell cycle checkpoint arrest and enable effective adaptation to DNA damage. This response is specific because it cannot be recapitulated by a generic inactivation of MTOC activity. Collectively, our results indicate that centrosomes can act as supramolecular platforms to coordinate dynamic recruitment and substrate selection of PLKs during the DNA damage response (DDR).

The effects of high-altitude hypoxic environment on the pharmacokinetics and respiratory function of remimazolam: an experimental study in rats

The growth and collapse of autonomy at work

Humans hate being monitored. Autonomy is prized—including by research scientists. Yet little is known about a fundamental issue in the modern world: What is happening to job autonomy in today’s workplaces as people move from youth on to middle age and then on to older ages? It would be natural to believe that individuals in the second half of their careers would be the senior ones with high autonomy. We provide evidence that such a belief is wrong. This study uses longitudinal data on hundreds of thousands of randomly sampled individuals, in three rich countries, who are followed through their working lives (n > 400,000). Workers’ feelings of job autonomy trace out a smooth concave parabola, increasing up to midlife, until approximately the surprisingly early age of 40, and then collapsing over the ensuing twenty to 30 y of a person’s working life. This is apparently not an illusion. We show that objective measures of autonomy —signified by managerial and supervisory job titles, for example—behave in a matching, hump-shaped way. As a further check, consistent qualitative evidence is given: a survey we ran asking managers about their experiences. We believe this paper’s results represent a foundational, essentially unknown, and intrinsically cross-disciplinary puzzle.

New insights into the first cervical vertebrae of Otavipithecus and Nacholapithecus

Abstract Fossil hominoids are crucial to understand the selection pressures that played a role in the emergence of modern hominoid positional behaviors. Here we investigate the morphology of the atlas of Otavipithecus namibiensis (GSN BA 104’91, Namibia) and Nacholapithecus kerioi (KNM-BG 35250BE, Kenya) for identifying potential positional-related signals and discussing functional and evolutionary implications. Published data from GSN BA 13’21, a second Otavipithecus atlas from Namibia, were integrated. For comparative material, 105 atlases of extant catarrhines and platyrrhines were included. In addition to standard linear measurements, the morphology of GSN BA 104’91 and KNM-BG 35250BE was investigated by landmark-based geometric morphometric (GM) method and statistical analyses. The dimensions of the Miocene specimens fall within, or closely approximate to, the range of variation of Pan and Hylobates. Our GM analyses indicate that GSN BA 104’91 is more similar to Pan. When the right lateral mass only is considered, GSN BA 104’91 and KNM-BG 35250BE show similarities with hominoids and cercopithecoids. Our results possibly support a positional repertoire in Otavipithecus that would have been partly similar with extant hominoids, and in particular with Pan (e.g., terrestrial quadrupedalism, climbing), and the presence of a mix of hominoid-like and cercopithecoid-like traits in the axial skeleton of Nacholapithecus.

Experimental determination of tripartite quantum discord

Quantum discord is a measure of nonclassical correlations in quantum systems. While the bipartite version of quantum discord is experimentally well-studied, the multipartite version has never been convincingly measured. In this study, we experimentally investigate tripartite quantum discord using an NMR quantum information processor. Building on a theoretical framework for conditional projective measurements and quantum conditional mutual information, we quantify the tripartite quantum discord and its contributions in different three-qubit states such as the Greenberger-Horne-Zeilinger (GHZ) and Werner (W) states as well as classical mixtures of biseparable Bell states, and classical mixtures of product states. The experiments employed full quantum state tomography and temporal averaging to prepare mixed states, achieving fidelities exceeding 95%. Our results confirm that quantum discord persists even in the absence of entanglement, highlighting its utility as a broader indicator of quantum correlations. Furthermore, we validate the nonconvexity of discord, confirming that classical mixtures of zero-discord states can exhibit nonzero discord. This experimentally confirms that quantum discord does not fit into the framework of resource theory. This work establishes a robust methodology for measuring quantum discord, illuminating the structure and distribution of quantum correlations in multipartite systems.

Molecular analysis of the emergence of Allium cepa L. Seeds response to saline stress and treatment with essential oil of Cordia verbenacea

A <i>Mycobacterium tuberculosis</i> secreted virulence factor Rv1435c/hsr1 disrupts host snRNP biogenesis

Transcriptional adaptation drives the host responses to Mycobacterium tuberculosis ( Mtb ) infection. However, Mtb alters host RNA splicing to quench host antibacterial responses, the mechanism for which remains unknown. Here, we report a mechanism whereby a secreted Mtb protein interferes with the biogenesis of key spliceosomal components. A high-throughput yeast-2-hybrid screen identified several Mtb -secreted proteins interacting with the host RNA splicing factors (SFs). Through custom-designed in-cell assays, we show that one of those proteins, Rv1435c/hsr1 (host splicing regulator 1), targets specific exon-skipping events. The Mtb Rv14345c/hsr1 facilitates direct interaction between Mtb phagosomes and U5 snRNA and SNRPF, key components of the snRNPs. Genetic deletion of Rv1435c/hsr1 reverses the specific exon-skipping events caused by WT Mtb infection. The Δ hsr1 strain shows compromised growth during ex vivo infection in macrophages and in vivo infection in mice. Tissue sections from the WT Mtb or Δhsr1 -infected mice showed significant hsr1-dependent SNRPF staining, a phenomenon also noted in the human intestinal tuberculosis (ITB) biopsies. Thus, hsr1 is a virulence factor that disrupts host snRNP biogenesis for pathogenesis. The splicing regulators from the host and pathogen are novel targets for antituberculosis therapy.

The association between baseline physical and mental health and the risk of postacute sequelae of COVID-19 infection

Expanding the diversity of bacterial DNA partitioning: A CTP-independent ParAB <i>S</i> system for plasmid partitioning in <i>Streptomyces</i>

The ATP- and CTP-dependent ParA-ParB- parS segrosome is a macromolecular complex that segregates chromosomes/plasmids in most bacterial species. CTP binding and hydrolysis enable ParB to slide along DNA and to bridge and condense DNA, thereby dictating the size and dynamics of the tripartite ParAB S complex. Several other evolutionarily distinct systems can also segregate DNA, although the full diversity of bacterial DNA partition systems remains unknown. Here, we identify a CTP-independent ParAB S system that maintains the conjugative plasmid SCP2 in the filamentous bacterium Streptomyces coelicolor . We demonstrate that an SCP2 ParB-like protein, ParT, loads onto DNA at an 18-bp parS site and diffuses away to the adjacent DNA despite lacking an apparent CTPase domain and detectable NTPase activity. We further show that parS DNA facilitates ParT transition from loading to a diffusing state, allowing ParT to accumulate on DNA, and that ParT activates the ATPase activity of its cognate partner protein, ParA. Additionally, we identify numerous structural homologs of ParT, suggesting that CTP-independent diffusion on DNA might be more common than previously recognized. Overall, our findings reveal a CTP-independent DNA translocation as an alternative and unexpected mechanism for assembling a bacterial DNA segregation complex and suggest that CTP binding and hydrolysis are not universal features of ParAB S -like systems.

AI-enhanced patient-specific dosimetry in I-131 planar imaging with a single oblique view

Abstract This study aims to enhance the dosimetry accuracy in 131I planar imaging by utilizing a single oblique view and Monte Carlo (MC) validated dose point kernels (DPKs) alongside the integration of artificial intelligence (AI) for accurate dose prediction within planar imaging. Forty patients with thyroid cancers post-thyroidectomy surgery and 30 with neuroendocrine tumors underwent planar and SPECT/CT imaging. Using whole-body (WB) planar images with an additional oblique view, organ thicknesses were estimated. DPKs and organ-specific S-values were used to estimate the absorbed doses. Four AI algorithms- multilayer perceptron (MLP), linear regression, support vector regression model, decision tree, convolution neural network, and U-Net were used for dose estimation. Planar image counts, body thickness, patient BMI, age, S-values, and tissue attenuation coefficients were imported as input into the AI algorithm. To provide the ground truth, the CT-based segmentation generated binary masks for each organ, and the corresponding SPECT images were used for GATE MC dosimetry. The MLP-predicted dose values across all organs represented superior performance with the lowest mean absolute error in the liver but higher in the spleen and salivary glands. Notably, MLP-based dose estimations closely matched ground truth data with &lt; 15% differences in most tissues. The MLP-estimated dose values present a robust patient-specific dosimetry approach capable of swiftly predicting absorbed doses in different organs using WB planar images and a single oblique view. This approach facilitates the implementation of 2D planar imaging as a pre-therapeutic technique for a more accurate assessment of the administrated activity.

UFMylation: A supervisor of the HIF1α pathway and a potential therapeutic target for anti-PD-1 combination therapy in hypoxic tumors

Activation of hypoxia signaling has been identified as an innate resistance signature against anti-PD-1 therapy, suggesting its potential as a target for combination treatments. Here, we demonstrate that UFMylation modification of HIF1α stabilizes the protein by antagonizing its ubiquitination and proteasomal degradation under hypoxic conditions. Mechanistically, depletion of UFL1 or defective UFMylation increases HIF1α binding to p53, promoting its degradation. Depletion of UFL1 or UBA5 , or defective UFMylation of HIF1α, destabilizes HIF1α, significantly inhibiting tumor growth and development in vitro and in xenograft mouse models. Defective UFMylation of HIF1α enhances the response to anti-PD-1 therapy in xenograft models. Clinically, UBA5 expression is upregulated in breast cancer tissues, and a selective UBA5 inhibitor reduces UFMylation activity and HIF1α protein levels, thereby enhancing anti-PD-1 combination therapy in mouse tumor models. Our findings highlight UFMylation as a critical posttranslational modification for the HIF1α pathway and a promising therapeutic target in hypoxic tumors.

Physical characterization and biodegradation of fibers produced by melt-spinning of aliphatic polyesters

Abstract The increasing environmental concerns surrounding synthetic fibers, particularly their contribution to microplastic pollution are driving research toward sustainable alternatives. This study explores the processing, thermal, mechanical, and environmental characteristics of melt-spun biodegradable fibers derived from various biodegradable polymers, including polylactic acid (PLA), polyglycolic acid (PGA), polyhydroxyalkanoates (PHA), polybutylene succinate (PBS), polycaprolactone (PCL), and some copolymers. The melt-spinning process was optimized to address challenges such as thermal degradation, low melt strength, and crystallization limitations. The resulting fibers were analyzed for their mechanical properties, thermal behavior, and biodegradation potential under different environmental conditions, including composting and weathering assessments. The findings indicate that fiber performance is highly dependent on the polymer structure and processing parameters, with PLA and PGA demonstrating superior tensile properties and crystallization behavior, whereas PHA and most copolymers exhibited processing limitations or low-tenacity fibers. The results provide some insights into the development of high-performance biodegradable fibers suitable for textile and technical applications, paving the way for sustainable alternatives to conventional synthetic fibers.

Vamp3/syntaxin 4 mediates the basolateral membrane fusion of TfR transcytosis across the BBB and is exploited by pathogenic <i>Escherichia coli</i>

Transcytosis across the blood–brain barrier (BBB), composed of brain microvascular endothelial cells (HBMECs), is tightly controlled to prevent the entry of macromolecules, microorganisms, and toxins into the brain. Transferrin receptor (TfR) transcytosis, one of the few active transcytosis pathways in HBMECs, is extensively utilized for drug transport across the BBB and employed by meningitis-causing bacteria to penetrate into the brain. However, the molecular mechanism facilitating the fusion of TfR vesicles with the basolateral membrane of HBMECs, the final step of transcytosis, has not been experimentally studied. Here, we found that the interaction between the v-SNARE protein VAMP3 on TfR vesicles and the t-SNARE protein syntaxin 4 that is limited to the basolateral membrane in HBMECs mediates the fusion. We also provided evidence that this step is critical for the efficiency of TfR transcytosis. Furthermore, we showed that neonatal meningitis Escherichia coli (NMEC) infection significantly boosts the efficiency of this transcytosis by enhancing the expression of VAMP3 and syntaxin 4 through the TLR4-TRAM-TRIF-TRAF3-IKK-IRF3 signaling pathway in HBMECs. Silence or overexpression of VAMP3 and syntaxin 4 reduces or enhances the transcytosis of transferrin and NMEC in a human BBB model in vitro . Consistently, the penetration of transferrin and NMEC into the brain was significantly inhibited in VAMP3-deficient mice. These findings provide insights for improving strategies to deliver drugs into the brain and developing effective therapy for meningitis caused by NMEC.

Comparative QSPR study of food preservatives using topological indices and regression models

Abstract Food preservatives play a crucial role in extending the shelf life of food products. Understanding their physicochemical properties can help in designing more effective and safer preservatives. In this study, we use a Quantitative Structure Property Relationship (QSPR) approach based on topological indices to develop a predictive model for certain physicochemical properties of food preservatives. We compare the performance of linear and curvilinear regression models to understand which provides the best prediction model. Among the tested models, the cubic regression model demonstrated superior predictive performance. Of all the models tested, the cubic regression model had the best predictive capabilities such as $$R^2 = 0.9998$$ for vapour density and $$R^2 = 0.9039$$ for molecular weight. To validate our findings, we employ the developed model to estimate the properties of an existing food preservative, the propionic acid. Our results offer valuable insights that can aid in the development of new and improved food preservatives.

Tunable shear thickening, aging, and rejuvenation in suspensions of shape-memory-endowed liquid crystalline particles

The morphological features of particles, notably shape anisotropy, critically influence the rheological properties of dense suspensions, spanning both natural and engineered systems. This work explores the potential of using shape memory particles to dynamically regulate suspension fluid flow through controllable shape transformations. First, we synthesize shape-memory particles with programmable anisotropy from liquid crystal elastomers, such that the stiffness and shapes of the particles can be tuned by manipulating temperature. Our findings reveal that suspensions from such particles exhibit significant tunability in shear thickening behavior, transitioning from discontinuous shear thickening to a Newtonian-like response within a narrow temperature range of 60 ° C. This capability to modulate rheological responses in situ presents an approach for addressing processing challenges in many applications where control over flow behavior is paramount. Furthermore, we also show that suspensions composed of these anisotropic particles can undergo physical aging, and evolve into a glassy state. This state can be escaped upon activation of the shape memory effect. This reversibility underscores the potential for using such materials to engineer systems that can enter or come out of kinetic arrest by leveraging internal mechanical responses to external stimuli. The insights gained here not only broaden our understanding of the interplay between particle geometry and suspension dynamics but also pave the way for leveraging ensembles of stimuli-responsive objects to precisely control collective behaviors in many-body systems.

A new golden ratio for foramen magnum in pre- and post-adolescent children

Akt isoform specificity drives intrinsic immune regulation during HSV-1 infection

Akt isoforms are generally considered functionally redundant, contributing to total Akt activity. However, during HSV-1 infection, Akt1 and Akt2 knockout animals exhibited distinct antiviral responses. Unexpectedly, in the absence of Akt1, Akt2 played a unique role in regulating cytokine production and inactivating proapoptotic transcription factor FoxO3a, a mechanism not shared by Akt1. These findings provide the clearest in vivo evidence yet that Akt isoforms are not functionally redundant, revealing distinct immune-regulatory roles for each isoform and suggesting a broader principle for fine-tuning immunity and cell death across diverse pathological settings.

Automated underwater plectropomus leopardus phenotype measurement through cylinder

Abstract Accurate and non-invasive measurement of fish phenotypic characteristics in underwater environments is crucial for advancing aquaculture. Traditional manual methods require significant labor to anesthetize and capture fish, which not only raises ethical concerns but also risks causing injury to the animals. Alternative hardware-based approaches, such as acoustic technology and active structured light techniques, are often costly and may suffer from limited measurement accuracy. In contrast, image-based methods utilizing low-cost binocular cameras present a more affordable solution, although they face challenges such as light refraction between water and the waterproof enclosure, which can cause discrepancies between image coordinates and actual positions. To address these challenges, we have developed a fish keypoint detection dataset and trained both a fish object detection model and a keypoint detection model using the RTMDet and RTMPose architectures to identify keypoints on Plectropomus leopardus. Since the binocular camera must be housed in a waterproof enclosure, we correct for birefringence caused by the water and the enclosure by applying refraction corrections to the detected keypoint coordinates. This ensures that the keypoint coordinates obtained underwater are consistent with those in air, thereby improving the accuracy of subsequent stereo matching. Once the corrected keypoint coordinates are obtained, we apply the least squares method, in conjunction with binocular stereo imaging principles, to perform stereo matching and derive the actual 3D coordinates of the keypoints. We calculate the fish body length by measuring the 3D coordinates of the snout and tail. Our model achieved 98.6% accuracy in keypoints detection (AP@0.5:0.95). Underwater tests showed an average measurement error of approximately 3.2 mm (MRPE=3.50%) for fish in a tank, with real-time processing at 28 FPS on an NVIDIA GTX 1060 GPU. These results confirm that our method effectively detects keypoints on fish bodies and measures their length without physical contact or removal from the tank. By eliminating invasive procedures, our approach not only improves measurement efficiency but also aligns with ethical standards in aquaculture. Compared to existing techniques, our method offers enhanced accuracy (reducing MRPE by 53.8% compared to baseline methods) and practicality, making it a valuable tool for the aquaculture industry.

Molecular basis for substrate recognition and transport of mammalian taurine transporters

The taurine transporter (TAUT) mediates cellular taurine uptake, playing a critical role in human health and longevity. In this study, we present cryogenic electron microscopy structures of both mouse and human TAUT in various conformational states. The taurine-bound, occluded forms of mouse and human TAUT reveal the substrate binding pocket and the ion binding sites. The amino group of taurine interacts with Glu406 at the binding site, constituting a key structural feature determining substrate preference. While both imidazole acetic acid and guanidinoethyl sulfonate (GES) inhibit TAUT by competing with taurine for the binding site, GES also functions as a substrate of TAUT. Moreover, mouse TAUT is captured in an inward-open apo conformation, where the tilted movement of transmembrane helix (TM) 1a opens the intracellular gate. Notably, TM6 exhibits two distinct conformational states: the canonical form consisting of two half-helices and a continuous straight helix. In the latter conformation, TM6 partially occupies the substrate binding site, likely promoting taurine release. Together, our findings provide critical insights into the molecular mechanisms by which TAUT recognizes and transports taurine.