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Construction and verification of a nomogram model for the risk of death in sepsis patients

Microtubule inner proteins of <i>Plasmodium</i> are essential for transmission of malaria parasites

Microtubule inner proteins (MIPs) are microtubule-associated proteins that bind to tubulin from the luminal side. MIPs can be found in axonemes to stabilize flagellar beat or within cytoplasmic microtubules. Plasmodium spp. are the causative agents of malaria that feature different parasite forms across a complex life cycle with both unique and divergent microtubule-based arrays. Here, we investigate four MIPs in a rodent malaria parasite for their role in transmission to and from the mosquito. We show by single and double gene deletions that SPM1 and TrxL1, MIPs associated with subpellicular microtubules, are dispensable for transmission from the vertebrate host to the mosquito and back. In contrast, FAP20 and FAP52, MIPs associated with the axonemes of gametes, are essential for transmission to mosquitoes but only if both genes are deleted. In the absence of both FAP20 and FAP52, the B-tubule of the axoneme partly detaches from the A-tubule, resulting in the deficiency of axonemal beating and hence gamete formation and egress. Our data suggest that a high level of redundancy ensures microtubule stability in the transmissive stages of Plasmodium , which is important for parasite transmission.

MedFuseNet: fusing local and global deep feature representations with hybrid attention mechanisms for medical image segmentation

Circadian clock control of interactions between eIF2α kinase CPC-3 and GCN1 with ribosomes regulates rhythmic translation initiation

Misregulation of the activity of GCN2, the kinase that phosphorylates and inactivates translation initiation factor eIF2α, has been implicated in several health disorders, underscoring the need to determine the mechanisms controlling GCN2 activation. During nutrient starvation, increased uncharged tRNA levels trigger GCN1 and GCN20 proteins to mediate the binding of uncharged tRNA to GCN2 to activate the kinase to phosphorylate eIF2α. Under constant conditions, activation of the Neurospora crassa homolog of GCN2, CPC-3, is controlled by the circadian clock. However, how the circadian clock controls the rhythmic activity of CPC-3 was not known. We found that the clock regulates CPC-3 and GCN1 interaction with ribosomes and show that these interactions are necessary for clock regulation of CPC-3 activity. CPC-3 activity rhythms, and the rhythmic interaction of CPC-3 and GCN1 with ribosomes, are abolished in a temperature-sensitive valyl-tRNA synthetase mutant ( un-3 ts ) that has high levels of uncharged tRNA Val at all times of the day. Disrupting the interaction between GCN1 and uncharged tRNA in the absence of GCN20 altered rhythmic CPC-3 activity, indicating that the clock controls the interaction between uncharged tRNA and GCN1. Together, these data support that circadian rhythms in mRNA translation through CPC-3 activity require rhythms in uncharged tRNA levels that drive the rhythmic interaction between CPC-3 and GCN1 with ribosomes. This regulation uncovers a fundamental mechanism to ensure temporal coordination between peak cellular energy levels and the energetically demanding process of mRNA translation.

Ancient levantine demography follows ecological stochasticity

Variable transduction of thyroid hormone signaling in structures of the mouse brain

L-thyroxine (L-T4) monotherapy is the standard treatment for hypothyroidism, administered daily to normalize TSH levels. Once absorbed, T4 is converted to T3 to alleviate most symptoms. However, this treatment abnormally elevates plasma T4 levels in over 50% of patients. Using L-T4-treated Thyroid Hormone (TH) Action Indicator mice, which express a T3-regulated luciferase (Luc) reporter, we examined whether these T4 elevations disrupt TH signaling. Hypothyroid mice exhibited reduced Luc expression across brain regions, and L-T4 treatment failed to restore T3 signaling uniformly. There was also variability in the activity of type 2 deiodinase (D2), the enzyme that generates most brain T3. Intracerebroventricular T4 administration achieved higher elevation of Luc expression in the mediobasal hypothalamus compared to the cortex, and studies on cultured cortical astrocytes and hypothalamic tanycytes revealed cell-type-specific responses to T4. In tanycytes, exposure to T4 sustained D2 activity, leading to progressive T3 signaling, whereas in astrocytes, T4 exposure triggered a drop in D2 activity, limiting T3 production through a ubiquitin-dependent, self-limiting mechanism. The sustained D2 activity in tanycytes was linked to rapid deubiquitination by USP33, as confirmed using a ubiquitin-specific protease (USP) pan-inhibitor and USP33 knockout mice. In conclusion, the brain’s response to L-T4 treatment is heterogeneous, influenced by cell-specific regulation of D2-mediated T3 production. While cortical astrocytes exhibit limited T3 signaling due to D2 ubiquitination, tanycytes coexpressing USP33 amplify T3 signaling by rescuing ubiquitinated D2 from proteasomal degradation. These findings provide mechanistic insights into the limitations of L-T4 therapy and highlight the need for tailored approaches to managing hypothyroidism.

Spectrochemical differentiation in endometriosis based on infrared spectroscopy advanced data fusion and multivariate analysis

Spatial propagation of temperate phages within and among biofilms

Bacteria form groups composed of cells and a secreted polymeric matrix that controls their spatial organization. These groups—termed biofilms—can act as refuges from environmental disturbances and from biotic threats, including phages. Despite the ubiquity of temperate phages and bacterial biofilms, live propagation of temperate phages within biofilms has not been characterized on cellular spatial scales. Here, we leverage several approaches to track temperate phages and distinguish between lytic and lysogenic host infections. We determine that lysogeny within Escherichia coli biofilms initially occurs within a predictable region of cell group packing architecture on the biofilm periphery. Because lysogens are generally found on the periphery of large cell groups, where lytic viral infections also reduce local biofilm structural integrity, lysogens are predisposed to disperse into the passing liquid and are overrepresented in downstream biofilms formed from the dispersal pool of the original biofilm-phage system. Comparing our results with those for virulent phages reveals that temperate phages have unique advantages in propagating over long spatial and time scales within and among bacterial biofilms.

The sustained-release agent of total flavonoids of Rhizoma drynariae prepared by nano-mesoporous silica can still promote osteogenesis and angiogenesis in vitro

Black and Latinx workers reap lower rewards than White workers from years spent working in big cities

The large labor markets of big cities offer greater possibilities for workers to gain skills and experience through successively better employment opportunities. This “experience effect” contributes to the higher average wages that are found in big cities compared to the economy as a whole. Racial wage inequality is also higher in bigger cities than in the economy on average. We offer an explanation for this pattern, demonstrating that there is substantial racial inequality in the economic returns to work experience acquired in big cities. Using data from the National Longitudinal Survey of Youth, 1979 we find that each year of work experience in a big city increases Black and Latinx workers’ wages by about one quarter to half as much as White workers’ wages. A substantial amount of this inequality can be explained by further racial disparities in the benefits of high-skill work experience. This research identifies a heretofore unknown source of inequality that is distinctly urban in nature, and expands our knowledge of the challenges to reaching interracial wage equality.

Integrating type-2 fuzzy logic controllers with digital twin and neural networks for advanced hydropower system management

Activation-induced thrombospondin-4 works with thrombospondin-1 to build cytotoxic supramolecular attack particles

Cytotoxic attack particles released by CTLs and NK cells include diverse phospholipid membrane and glycoprotein encapsulated entities that contribute to target cell killing. Supramolecular attack particles (SMAPs) are one type of particle characterized by a cytotoxic core enriched in granzymes and perforin surrounded by a proteinaceous shell including thrombospondin (TSP)-1. TSP-4 was also detected in bulk analysis of SMAPs released by CTLs; however, it has not been investigated whether TSP-4 contributes to distinct SMAP types or the same SMAP type as TSP-1 and, if in the same type of SMAP, whether TSP-4 and TSP-1 cooperate or compete. Here, we observed that TSP-4 expression increased upon CD8 + T cell activation while, surprisingly, TSP-1 was down-regulated. Correlative Light and Electron Microscopy and Stimulated Emission Depletion microscopy localized TSP-4 and TSP-1 in SMAP-containing multicore granules. Superresolution dSTORM revealed that TSP-4 and TSP-1 are usually enriched in the same SMAPs while particles with single-positive shells are rare. Retention Using Selective Hooks assays showed that TSP-4 localizes to the lytic granules faster than TSP-1 and promotes its accumulation therein. TSP-4 contributed to direct CTL-mediated killing, as previously shown for TSP-1. TSP-4 and TSP-1 were both required for latent SMAP-mediated cell killing, in which released SMAPs kill targets after removal of the CTLs. Of note, we found that chronic lymphocytic leukemia (CLL) cell culture supernatants suppressed expression of TSP-4 in CTL and latent SMAP-mediated killing. These results identify TSP-4 as a functionally important component of SMAPs and suggest that SMAPs may be targeted for immune suppression by CLL.

Application of drug-induced growth rate inhibition and intracellular drug exposures for comprehensive evaluation of cellular drug sensitivity

Uncovering the hidden RNA virus diversity in Lake Nam Co: Evolutionary insights from an extreme high-altitude environment

Alpine lakes, characterized by isolation, low temperatures, oligotrophic conditions, and intense ultraviolet radiation, remain a poorly explored ecosystem for RNA viruses. Here, we present the first comprehensive metatranscriptomic study of RNA viruses in Lake Nam Co, a high-altitude alkaline saline lake on the Tibetan Plateau. Using a combination of sequence- and structure-based homology searches, we identified 742 RNA virus species, including 383 novel genus-level groups and 84 novel family-level groups exclusively found in Lake Nam Co. These findings significantly expand the known diversity of the Orthornavirae , uncovering evolutionary adaptations such as permutated RNA-dependent RNA polymerase motifs and distinct RNA secondary structures. Notably, 14 additional RNA virus families potentially infecting prokaryotes were predicted, broadening the known host range of RNA viruses and questioning the traditional assumption that RNA viruses predominantly target eukaryotes. The presence of auxiliary metabolic genes in viral genomes suggested that RNA viruses (families f . 0102 and Nam-Co_family_51) exploit host energy production mechanisms in energy-limited alpine lakes. Low nucleotide diversity, single nucleotide polymorphism frequencies, and pN/pS ratios indicate strong purifying selection in Nam Co viral populations. Our findings offer insights into RNA virus evolution and ecology, highlighting the importance of extreme environments in uncovering hidden viral diversity and further shed light into their potential ecological implications, particularly in the context of climate change.

Ensemble probabilistic quantization encoding for information preservation of numerical variables in convolutional neural networks

Fixational eye movements as active sensation for high visual acuity

Perception and action are inherently entangled: our world view is shaped by how we explore our environment through complex and variable self-motion. Even when fixating stable stimuli, our eyes undergo small, involuntary movements. Fixational eye movements (FEM) render a stable world jittery on our retinae, which can be expected to harm neural coding. Yet, empirical evidence suggests that FEM help rather than harm human perception of fine detail. Here, we elucidate this paradox by uncovering under which conditions FEM improve or impair retinal coding and human acuity. We combine theory and experiment: model accuracy is directly compared to that of healthy human subjects in a visual acuity task. Acuity is modeled by applying an ideal Bayesian classifier to simulations of retinal spiking activity in the presence of FEM. In addition, empirical FEM are monitored using high-resolution eye-tracking by an adaptive optics scanning laser ophthalmoscope. FEM introduce variability in retinal ganglion cell activity, but they also effectively preprocess inputs to facilitate retinal information encoding. Based on an interplay of these mechanisms, our model predicts a relation between visual acuity, FEM amplitude, and single-trial stimulus size that quantitatively accounts for experimental observations and captures the beneficial effect of FEM. Moreover, we observe that while human subjects’ FEM statistics vary with stimulus size, our model suggests that subjects’ FEM amplitude remains within a near-optimal range, where acuity is enhanced compared to much larger or smaller amplitudes. Overall, our findings indicate that perception benefits from action even at the fine spatiotemporal scale of FEM.

A pocket-integrated miniature, dual-band, and high gain textile MIMO antenna for 5G and WiFi wearable applications

Spatial Patterning Analysis of Cellular Ensembles (SPACE) finds complex spatial organization at the cell and tissue levels

Spatial patterns of cells and other biological elements drive physiologic and pathologic processes within tissues. While many imaging and transcriptomic methods document tissue organization, discerning these patterns is challenging, especially when they involve multiple elements in complex arrangements. To address this challenge, we present Spatial Patterning Analysis of Cellular Ensembles (SPACE), an R package for analysis of high-plex spatial data. SPACE is compatible with any data collection modality that records values (i.e., categorical cell/structure types or quantitative expression levels) at fixed spatial coordinates (i.e., 2d pixels or 3d voxels). SPACE detects not only broad patterns of co-occurrence but also context-dependent associations, quantitative gradients and orientations, and other organizational complexities. Via a robust information theoretic framework, SPACE explores all possible ensembles of tissue elements—single elements, pairs, triplets, and so on—and ranks the most strongly patterned ensembles. For single images, rankings reflect differences from random assortment. For sets of images, rankings reflect differences across sample groups (e.g., genotypes, treatments, timepoints, etc.). Further tools then characterize the nature of each pattern for intuitive interpretation. We validate SPACE and demonstrate its advantages using murine lymph node images for which ground truth has been defined. We then detect new patterns across varied datasets, including tumors and tuberculosis granulomas.

Carbon benefits through agroforestry transitions on unmanaged fallow agricultural land in Hawaiʻi

Observed declines in upper ocean phosphate-to-nitrate availability

Climate warming is increasing ocean stratification, which in turn should decrease the nutrient flux to the upper ocean. This may slow marine primary productivity, causing cascading effects throughout food webs. However, observing changes in upper ocean nutrients is challenging because surface concentrations are often below detection limits. We show that the nutricline depth, where nutrient concentrations reach well-detected levels, is tied to productivity and upper ocean nutrient availability. Next, we quantify nutricline depths from a global database of observed vertical nitrate and phosphate profiles to assess contemporary trends in global nutrient availability (1972–2022). We find strong evidence that the P-nutricline (phosphacline) is mostly deepening, especially throughout the southern hemisphere, but the N-nutricline (nitracline) remains mostly stable. Earth System Model (ESM) simulations support the hypothesis that reduced iron stress and increased nitrogen fixation buffer the nitracline, but not phosphacline, against increasing stratification. These contemporary trends are expected to continue in the coming decades, leading to increasing phosphorus but not nitrogen stress for marine phytoplankton, with important ramifications for ocean biogeochemistry and food web dynamics.