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Effect of mRNA formulated with lipid nanoparticles on the transcriptomic and epigenetic profiles of F4/80+ liver-associated macrophages

PsDMAP1/PsTIP60-regulated H4K16ac is required for ROS-dependent virulence adaptation of <i>Phytophthora sojae</i> on host plants

Host plants and various fungicides inhibit plant pathogens by inducing the release of excessive reactive oxygen species (ROS) and causing DNA damage, either directly or indirectly leading to cell death. The mechanisms by which the oomycete Phytophthora sojae manages ROS stress resulting from plant immune responses and fungicides remains unclear. This study elucidates the role of histone acetylation in ROS-induced DNA damage responses (DDR) to adapt to stress. Mechanistically, the P. sojae DNA methyltransferase 1-associated protein (PsDMAP1) binds Tat-interactive protein 60 (PsTIP60) to comediate histone H4 acetylation on lysine 16 (H4K16ac). This regulation affects RNA polymerase II (pol II) recruitment, transcriptional induction of DDR-related genes, and the enrichment of histone H2Ax phosphorylated on serine 137 (γH2Ax) in response to both plant immunity and fungicide stress. The resulting H4K16ac serves as a crucial transgenerational epigenetic signal for virulence adaptation of P. sojae on plants, as a result of adaptation to ROS stress.

Use of multispecies (Nannochloropsis oceanica, Artemia franciscana, and Arbacia nigra) approach to assess the quality of marine water from Callao Bay, Peru

Metabolic enhancement contributed by horizontal gene transfer is essential for dietary specialization in leaf beetles

Horizontal gene transfer (HGT) from bacteria to insects is widely reported and often associated with the adaptation and diversification of insects. However, compelling evidence demonstrating how HGT-conferred metabolic adjustments enable species to adapt to surrounding environment remains scarce. Dietary specialization is an important ecological strategy adopted by animals to reduce inter- and intraspecific competition for limited resources. Adults of the leaf beetle Plagiodera versicolora (Coleoptera) preferentially consume new leaves; nevertheless, we found that they selectively oviposit on mature leaves, thereby establishing a distinct dietary niche separation between adults and larvae. Based on the de novo assembled chromosome-level genome, we identified two horizontally transferred genes with cellulose degradation potential, belonging to the glycosyl hydrolase 48 family ( GH48-1 and GH48-2 ). Prokaryotic expression of the HGTs confirmed the cellulose degradation capability of the two genes. Knockdown of GH48 significantly hampered the growth and survival rate of larvae feeding on mature leaves compared to wild-type larvae, with no similar effect observed in adults. Replenishing the GH48-expressing bacteria compensated for the knockdown of these two genes and recurred larval adaptability to mature leaves. Taken together, our results highlight the advantage and metabolic enhancement conferred by the two cellulose-degrading HGTs in P. versicolora larvae, enabling their development on cellulose-enriched mature leaves and underscoring the indispensable role of HGTs in facilitating the adaptation of leaf beetles to plants.

Deep learning-based encryption scheme for medical images using DCGAN and virtual planet domain

AbstractThe motivation for this article stems from the fact that medical image security is crucial for maintaining patient confidentiality and protecting against unauthorized access or manipulation. This paper presents a novel encryption technique that integrates the Deep Convolutional Generative Adversarial Networks (DCGAN) and Virtual Planet Domain (VPD) approach to enhance the protection of medical images. The method uses a Deep Learning (DL) framework to generate a decoy image, which forms the basis for generating encryption keys using a timestamp, nonce, and 1-D Exponential Chebyshev map (1-DEC). Experimental results validate the efficacy of the approach in safeguarding medical images from various security threats, including unauthorized access, tampering, and adversarial attacks. The randomness of the keys and encrypted images are demonstrated through the National Institute of Standards and Technology (NIST) SP 800-22 Statistical test suite provided in Tables 4 and 14, respectively. The robustness against key sensitivity, noise, cropping attacks, and adversarial attacks are shown in Figs. 15–18, 22–23, and 24. The data presented in Tables 5, 6, and 7 shows the proposed algorithm is robust and efficient in terms of time and key space complexity. Security analysis results are shown (such as histogram plots in Figs. 11–14 and correlation plots in Figs. 19–21). Information Entropy ($$7.9993 \pm 0.0001$$), correlation coefficient ($$\pm 0.09$$), Mean Square Error (MSE) ($$4166.3107 \pm 1645.2980$$), Peak Signal to Noise Ratio (PSNR) ($$12.2643 \pm 1.7032$$), Number of Pixel Change Rate (NPCR) ($$99.60\% \pm 0.2\%$$), and Unified Average Changing Intensity (UACI) ($$33.47\% \pm 0.1\%$$) underscore the high security and reliability of the encrypted images, are shown in Tables 8–11. Further, statistical NPCR and UACI are calculated in Tables 12 and 13, respectively. The proposed algorithm is also compared with existing algorithms, and compared values are provided in Table 15. The data presented in Tables 3–15 suggest that the proposed algorithm can opt for practical use.

Computational study on water based hybrid photovoltaic systems with different absorber configurations

Hydroxychloroquine prevents resistance and potentiates the antitumor effect of SHP2 inhibition in NF1-associated malignant peripheral nerve sheath tumors

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas and the primary cause of mortality in patients with neurofibromatosis type 1 (NF1). These malignancies develop within preexisting benign lesions called plexiform neurofibromas (PNs). PNs are solely driven by biallelic NF1 loss eliciting RAS pathway activation, and they respond favorably to MEK inhibitor therapy. MPNSTs harbor additional mutations and respond poorly to MEK inhibition. Our analysis of genetically engineered and orthotopic patient-derived xenograft MPNST models indicates that MEK inhibition has poor antitumor efficacy. By contrast, upstream inhibition of RAS through the protein-tyrosine phosphatase SHP2 reduced downstream signaling and suppressed NF1 MPNST growth, although resistance eventually emerged. To investigate possible mechanisms of acquired resistance, kinomic analyses of resistant tumors were performed, and data analysis identified enrichment of activated autophagy pathway protein kinases. Combining SHP2 inhibition with hydroxychloroquine (HQ) resulted in durable responses in NF1 MPNSTs in both genetic and orthotopic xenograft mouse models. Our studies could be rapidly translated into a clinical trial to evaluate SHP2 inhibition in conjunction with HQ as a unique treatment approach for NF1 MPNSTs.

Digitalised multidisciplinary conferences effectively identify and prevent imaging-related medical error in intensive care patients during the COVID-19 pandemic

Abstract This study aims to assess the effectiveness of digital multidisciplinary conferences (MDCs) in preventing imaging-related quality management (QM) events during the coronavirus-disease-19 (COVID-19) pandemic. COVID-19 challenged interdisciplinary exchange and QM measures for patient safety. Regular MDCs between radiologists and intensive care unit (ICU) physicians, introduced in our hospital in 2018, enable re-evaluation of imaging examinations and bilateral feedback. MDC protocols from 2020 to 2021 were analysed regarding imaging-related QM events. Epidemiological data on COVID-19 were matched with MDCs. 333 MDCs including 1324 radiological examinations in 857 patients (median age = 64 (IQR = 55–73) years, 66.7% male) were analysed. MDCs were held within a median of 1 day after imaging (IQR = 1–3). QM events were identified in 2.7% (n = 36/1324) of examinations. This represented a significant decrease compared to a control group from 2018/2019 (QM events identified in 14.0%, p &lt; 0.001). QM incidence remained consistent in the pandemic cohort (regression coefficient estimate = -0.01, 95% confidence interval = [0.000, 0.000], p = 0.68). 81% (n = 29/36) of QM events were report-related, 19% process-related (n = 6/36), and 2.8% indication-related (n = 1/36). In 7.3% (n = 97/1324) of examinations, the patient was affected by COVID-19. With MDCs as an effective feedback mechanism in place, the challenges of the COVID-19 pandemic led to no increase in QM incidence. Notably, COVID status did not impact QM event occurrence.

Population encoding of observed and actual somatosensations in the human posterior parietal cortex

Cognition relies on transforming sensory inputs into a generalizable understanding of the world. Mirror neurons have been proposed to underlie this process, mapping visual representations of others’ actions and sensations onto neurons that mediate our own, providing a conduit for understanding. However, this theory has limitations. Here, we hypothesize that mirror-like responses represent one facet of a broader framework in which our brains engage internal models for cognition. We recorded populations of single neurons in the human posterior parietal cortex (PPC) of a brain–machine interface clinical trial participant implanted with a microelectrode array while she either experienced actual touch, or observed diverse tactile stimuli applied to other individuals. Two body locations were tested, on each of the participant and other individuals. Some neurons exhibited mirror-like properties, consistent with earlier literature. However, they were fragile, breaking with increased task complexity. Population responses were better characterized by generalizable and compositional basic-level features encoded within neural subspaces. These features enable the population to respond to diverse actual and observed touch stimuli and are recruited similarly for similar forms of touch. Mirror-like neurons belong within these subspaces, contributing more globally to compositionality and generalizability. We speculate that at a population-level, human PPC manifests an internal model for touch, and that cognition unfolds in the high-level human cortex by versatility in its representational building blocks. In a broad sense, we speculate that the population features we demonstrate support a broad mechanism by which the high-level human cortex enables understanding.

Comparative transcriptome analyses of different orthosiphon aristatus tissues reveal differentially expressed genes associated with flavonoid biosynthesis

Dissecting the cellular architecture and genetic circuitry of the soybean seed

Seeds are complex structures composed of three regions, embryo, endosperm, and seed coat, with each further divided into subregions that consist of tissues, cell layers, and cell types. Although the seed is well characterized anatomically, much less is known about the genetic circuitry that dictates its spatial complexity. To address this issue, we profiled mRNAs from anatomically distinct seed subregions at several developmental stages. Analyses of these profiles showed that all subregions express similar diverse gene numbers and that the small gene numbers expressed subregion specifically provide information about the biological processes that occur in these seed compartments. In parallel, we profiled RNAs in individual nuclei and identified nuclei clusters representing distinct cell identities. Integrating single-nucleus RNA and subregion mRNA transcriptomes allowed most cell identities to be assigned to specific subregions and cell types and/or cell states. The number of cell identities exceeds the number of anatomically distinguishable cell types, emphasizing the spatial complexity of seeds. We defined gene coexpression networks that underlie distinct biological processes during seed development. We showed that network distribution among subregions and cell identities is highly variable. Some networks operate in single subregions and/or cell identities, and many coexpression networks operate in multiple subregions and/or cell identities. We also showed that single subregions and cell identities possess several networks. Together, our studies provide unique insights into the biological processes and genetic circuitry that underlie the spatial landscape of the seed.

Curcumin reverses cognitive deficits through promoting neurogenesis and synapse plasticity via the upregulation of PSD95 and BDNF in mice

Climate change could amplify weak synchrony in large marine ecosystems

Climate change is increasing the frequency of large-scale, extreme environmental events and flattening environmental gradients. Whether such changes will cause spatially synchronous, large-scale population declines depends on mechanisms that limit metapopulation synchrony, thereby promoting rescue effects and stability. Using long-term data and empirical dynamic models, we quantified spatial heterogeneity in density dependence, spatial heterogeneity in environmental responses, and environmental gradients to assess their role in inhibiting synchrony across 36 marine fish and invertebrate species. Overall, spatial heterogeneity in population dynamics was as important as environmental drivers in explaining population variation. This heterogeneity leads to weak synchrony in the California Current Ecosystem, where populations exhibit diverse responses to shared, large-scale environmental change. In contrast, in the Northeast U.S. Shelf Ecosystem, gradients in average environmental conditions among locations, filtered through nonlinear environmental response curves, limit synchrony. Simulations predict that environmental gradients and response diversity will continue to inhibit synchrony even if large-scale environmental extremes become common. However, if environmental gradients weaken, synchrony and periods of large-scale population decline may rise sharply among commercially important species on the Northeast Shelf. Our approach thus allows ecologists to 1) quantify how differences among local communities underpin landscape-scale resilience and 2) identify the kinds of future climatic changes most likely to amplify synchrony and erode species stability.

Autoregulation of the glial gene reversed polarity in Drosophila

Computational-aided rational mutation design of pertuzumab to overcome active HER2 mutation S310F through antibody–drug conjugates

Recurrent missense mutations in the human epidermal growth factor receptor 2 (HER2) have been identified across various human cancers. Among these mutations, the active S310F mutation in the HER2 extracellular domain stands out as not only oncogenic but also confers resistance to pertuzumab, an antibody drug widely used in clinical cancer therapy, by impeding its binding. In this study, we have successfully employed computational-aided rational design to undertake directed evolution of pertuzumab, resulting in the creation of an evolved pertuzumab variant named Ptz-SA. This variant, with only two mutations (T30S/D31A) located on its heavy chain, effectively reinstates binding to the mutated antigen, at the expense of a 35-fold reduction in binding affinity to HER2 (S310F) compared to the wild-type pair. Subsequently, Ptz-SA demonstrates potent killing capacity through antigen-dependent cytotoxicity. Moreover, upon engineering Ptz-SA into antibody–drug conjugates, such as Ptz-SA-MMAE, it manifests notable in vitro and in vivo antitumor efficacy by efficiently delivering cytotoxic payload into tumor cells expressing HER2 (S310F). Cryoelectron microscopy studies elucidate the molecular mechanism underlying the restored binding ability of Ptz-SA toward the S310F mutation. The steric hindrance induced by the S310F mutation is efficiently circumvented by the T30S and D31A mutations, which provides adequate space to accommodate the larger phenylalanine. Additionally, Ptz-SA also exhibits binding capacity to HER2 (S310Y), another mutation occurring at the S310 site of HER2 with high frequency. The computational-aided evolution of pertuzumab provides an alternative strategy for overcoming point mutation-mediated resistance to therapeutic antibodies.

Healthcare professionals and the public sentiment analysis of ChatGPT in clinical practice

<i>Salmonella</i> infection accelerates postnatal maturation of the intestinal epithelium

Postnatal establishment of enteric metabolic, host–microbial and immune homeostasis is the result of precisely timed and tightly regulated developmental and adaptive processes. Here, we show that infection with the invasive enteropathogen Salmonella Typhimurium results in accelerated maturation of the neonatal epithelium with premature appearance of antimicrobial, metabolic, developmental, and regenerative features of the adult tissue. Using conditional Myd88-deficient mice, we identify the critical contribution of immune cell-derived mediators. Cytokine stimulation of neonatal intestinal epithelial stem cell organoids suggests a network of synergistic and antagonistic cytokine effects with a significant contribution of IL-22, IL-4/IL-13, TNF, and IL-6 to infection-induced enterocyte reprogramming. Our findings demonstrate that the infection-associated immune cell activation disrupts physiological postnatal tissue maturation and may thereby worsen clinical outcomes and alter the neonatal-adult transition.

Systemic lupus erythematosus is associated with an increased risk of cervical artery dissection

AbstractLimited evidence suggests that autoimmune diseases are associated with an increased risk of cervical artery dissection (CeAD). We hypothesized individuals with systemic lupus erythematosus (SLE) would have an increased risk of CeAD following SLE diagnosis compared to matched non-lupus controls. We queried a de-identified United States electronic medical records network (TriNetX, Inc.) for individuals aged 10 and older from 2012 to 2020, for two cohorts: (1) SLE and (2) non-lupus controls, excluding those with prior CeAD. We used propensity matching to control for confounding variables and calculated the risk ratio (RR) for CeAD occurring over four years’ follow-up, secondarily exploring cumulative incidence. After matching, both cohorts contained 77,008 patients, who were mostly female (89%). The incidence and risk of CeAD was significantly greater among those with SLE compared to matched non-lupus controls [95% CI] (0.08% vs. 0.04%; RR = 2.33 [1.49;3.66]; P &lt; 0.0001). These findings support the hypothesis that SLE is a risk factor for CeAD. Additional research is needed to identify the mechanisms that may underly the SLE-CeAD association and examine the potential association between other autoimmune diseases and CeAD.

A lever hypothesis for Synaptotagmin-1 action in neurotransmitter release

Neurotransmitter release is triggered in microseconds by Ca 2+ -binding to the Synaptotagmin-1 C 2 -domains and by SNARE complexes that form four-helix bundles between synaptic vesicles and plasma membranes, but the coupling mechanism between Ca 2+ -sensing and membrane fusion is unknown. Release requires extension of SNARE helices into juxtamembrane linkers that precede transmembrane regions (linker zippering) and binding of the Synaptotagmin-1 C 2 B domain to SNARE complexes through a “primary interface” comprising two regions (I and II). The Synaptotagmin-1 Ca 2+ -binding loops were believed to accelerate membrane fusion by inducing membrane curvature, perturbing lipid bilayers, or helping bridge the membranes, but SNARE complex binding through the primary interface orients the Ca 2+ -binding loops away from the fusion site, hindering these putative activities. To clarify this paradox, we have used NMR and fluorescence spectroscopy. NMR experiments reveal that binding of C 2 B domain arginines to SNARE acidic residues at region II remains after disruption of region I, and that a mutation that impairs spontaneous and Ca 2+ -triggered neurotransmitter release enhances binding through region I. Moreover, fluorescence assays show that Ca 2+ does not induce dissociation of Synaptotagmin-1 from membrane-anchored SNARE complex but causes reorientation of the C 2 B domain. Based on these results and electrophysiological data described by Toulme et al. ( https://doi.org/10.1073/pnas.2409636121 ), we propose that upon Ca 2+ binding the Synaptotagmin-1 C 2 B domain reorients on the membrane and dissociates from the SNAREs at region I but not region II, acting remotely as a lever that pulls the SNARE complex and facilitates linker zippering or other SNARE structural changes required for fast membrane fusion.

Real-time monitoring and prediction of remote operator fatigue in plateau deep mining based on dynamic Bayesian networks