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Scale dichotomization reduces customer racial discrimination and income inequality
FAN1-mediated translesion synthesis and POLQ/HELQ-mediated end joining generate interstrand crosslink-induced mutations
Functional role for Taz during hindbrain ventricle morphogenesis
The brain ventricle system, composed of the ventricular cavities and the cerebral spinal fluid within, performs critical functions including circulation of nutrients, removal of wastes, and cushioning of neural tissues. Development of the hindbrain ventricle requires a series of factors that coordinate its initial formation and subsequent inflation. Previous work has demonstrated that the transcriptional co-activator Taz (also known as WW domain-containing transcription regulator protein 1, Wwtr1), a component of Hippo signalling, is active at hindbrain rhombomere boundaries where it is regulated by mechanotransduction and promotes proliferation. Here, we demonstrate that Taz is also a critical regulator of hindbrain ventricle development. Zebrafish embryos that lack Taz protein fail to undergo initial midline separation of the hindbrain ventricle. Furthermore, the ventricle phenotype is a result of disorganized cytoskeletal F-actin and apicobasal polarity components. In addition, we have demonstrated that the hindbrain rhombomere boundaries are a location of active Wnt-Hippo crosstalk. Through our work, we propose a model where Taz protein is stabilized at rhombomere boundaries and promotes proper cell polarity necessary for formation of the brain ventricle.
Expression of tumor endothelial marker 1 in cardiac fibroblast contributes to atrial fibrosis in atrial fibrillation
Engineered enzymes for enantioselective nucleophilic aromatic substitutions
Abstract Nucleophilic aromatic substitutions (SNAr) are among the most widely used processes in the pharmaceutical and agrochemical industries1–4, allowing convergent assembly of complex molecules through C–C and C–X (X = O, N, S) bond formation. SNAr reactions are typically carried out using forcing conditions, involving polar aprotic solvents, stoichiometric bases and elevated temperatures, which do not allow for control over reaction selectivity. Despite the importance of SNAr chemistry, there are only a handful of selective catalytic methods reported that rely on small organic hydrogen-bonding or phase-transfer catalysts5–11. Here we establish a biocatalytic approach to stereoselective SNAr chemistry by uncovering promiscuous SNAr activity in a designed enzyme featuring an activated arginine12. This activity was optimized over successive rounds of directed evolution to afford an engineered biocatalyst, SNAr1.3, that is 160-fold more efficient than the parent and promotes the coupling of electron-deficient arenes with carbon nucleophiles with near-perfect stereocontrol (>99% enantiomeric excess (e.e.)). SNAr1.3 can operate at a rate of 0.15 s−1, perform more than 4,000 turnovers and can accept a broad range of electrophilic and nucleophilic coupling partners, including those that allow construction of challenging 1,1-diaryl quaternary stereocentres. Biochemical, structural and computational studies provide insights into the catalytic mechanism of SNAr1.3, including the emergence of a halide binding pocket shaped by key catalytic residues Arg124 and Asp125. This study brings a landmark synthetic reaction into the realm of biocatalysis to provide an efficient and versatile platform for catalytic SNAr chemistry.
Dissipative charge transport in organic mixed ionic-electronic conductor channels
Digital PCR characterizes epithelial cell populations in murine duodenal organoids
Three-dimensional cultures are powerful tools to recapitulate animal and human tissues. Under the influence of specific growth factors, adult stem cells differentiate and organize into 3D cultures named organoids. The molecular phenotyping of these structures is an essential step for validating an organoid model. However, the limited number of organoids generated in culture yields very low amounts of genetic material, making phenotyping difficult. Recently, digital PCR (dPCR) techniques have become available for the highly sensitive detection of genetic material at low concentrations. The aim of this work was to apply dPCR to the identification of the various cell populations expected to be present in murine duodenal organoids. Results show the potential use of dPCR as a genetic characterization tool for organoids.
Enhancing parkinson disease detection through feature based deep learning with autoencoders and neural networks
Four ways COVID changed virology: lessons from the most sequenced virus of all time
Sustainable bioactive hydrogels for organic contaminant elimination in wastewater
Aging aggravates cognitive dysfunction in spontaneously hypertensive rats by inducing cerebral microvascular endothelial dysfunction
Hypertension in the elderly can seriously lead to cerebral microvascular damage and promote the development of vascular cognitive impairment. While endothelial function is crucial in cerebral microvascular protection, it is unclear whether aging exacerbates hypertension-induced cognitive dysfunction through endothelial dysfunction. In this study, we injected D-galactose (D-gal) into 24 spontaneous hypertension rats (SHR) and 24 Wistar-Kyoto rats (WKY) for 12 weeks to induce aging. Firstly, the results of behavioral experiments showed that compared with WKY and SHRs injected with D-gal for 0 week, SHRs injected with D-gal for 12 weeks had more severe cognitive dysfunction and memory impairment. Subsequently, the pathological results showed that the pathological changes of brain microvessels and their structural and functional damage were more significant. After that, the results of molecular experiments showed enormous changes in endothelial damage indicators (nitric oxide (NO), endothelin (ET-1), platelet endothelial cell adhesion molecule-1(CD31) and endothelial tight junction protein), aggravation of blood-brain barrier (BBB) damage, microglial activation and upregulation of pro-inflammatory cytokines. Ultimately, the combination treatment of nimodipine and butylphthalide in WKY and SHRs injected with D-gal for 12 weeks showed that the two drugs could hugely improve the cognitive dysfunction in SHRs. In summary, we elaborated that aging exacerbates cognitive dysfunction in SHRs, which may be due to cerebral microvascular endothelial dysfunction, and even BBB damage and neuroinflammation, while the combination of nimodipine and butylphthalide can improve cognitive dysfunction in SHRs, providing a theoretical basis for the treatment of aging and hypertension-related diseases.
Empowering telecommunication towers employing improved war strategy optimization method
Pyrrolidine synthesis via ring contraction of pyridines
Modelling Temperature-dependent Schistosomiasis Dynamics for Single and Co-infections with S. mansoni and S. haematobium
Schistosomiasis, a prevalent public health issue specifically in sub-Saharan Africa, is primarily attributed to Schistosoma haematobium and Schistosoma mansoni, often occurring concurrently. These schistosome species share similarities in life cycles and transmission, manifesting comparable infection patterns and susceptibility to temperature variations. This study investigates the influence of temperature control not only on the transmission of individual species but also on their mutual interactions and co-infection dynamics using a mathematical model. Sub-models and co-dynamic properties, including reproduction numbers, equilibrium states, and stability conditions, are derived. Sensitivity analysis is performed to clarify the impact of parameter variations on model stability. Results suggest that temperature variation increases the spread of S. haematobium, which enhances susceptibility to S. mansoni co-infection, possibly by altering the immune response. At moderate temperatures (20°C and 25°C), infection levels in both single and co-infected individuals are higher, while recovery rates increase with temperature, peaking at 25°C and 35°C as infections significantly decrease. Biomphalaria snails exhibit greater population growth and susceptibility to infection than Bulinus snails, particularly below 25°C. Above this temperature, Biomphalaria population decreases while Bulinus species are more likely to experience faster mortality. These temperature-related variations differently impact mortality rates of intermediate snails and snail-to-human transmissibility rates for schistosome species, holding significant health implications. Targeting snails during seasons below 25°C, when susceptibility is higher, and intensifying human treatment interventions around 25°C–35°C, where recovery rates peak, may yield optimal results, particularly during seasons with intermediate temperatures around 25°C for both snails and humans. The results underscore the importance of integrating temperature into models for predicting and managing schistosomiasis dynamics for both genera. Therefore, this model is applicable not only to sub-Saharan Africa, but also to other regions where the described temperature ranges match with the local climate.
An interpretable dimensional reduction technique with an explainable model for detecting attacks in Internet of Medical Things devices
Discovery of mammalian collagens I and III within ancient poriferan biopolymer spongin
Abstract Spongin is a fundamental biopolymer that has played a crucial role in the skeletogenesis of keratosan sponges for over 800 million years. This biomaterial had so far remained chemically unidentified and believed to be an enigmatic type of halogenated collagen-keratin-based bioelastomer. Here we show collagen I and III as the main structural components of spongin. Proteomics, 13C solid state NMR and Raman spectroscopy confirm the identity of collagenous domains in spongin with collagen from mammals. Using an HPLC-MS analysis, we found halogenated di- and tri-tyrosines as crosslinking agents in spongin. Using molecular dynamics modeling, we solvated the crystal structures of collagen mimetic peptides for type I and type III collagens in four different systems, including selected brominated crosslinks. The results underscore the complex interplay between the collagen structures and crosslinks, raising intriguing questions about the molecular mechanisms underlying collagen chemistry within spongin as an ancient biocomposite.
Revisiting the physical limits to economic growth, with a focus on the waste heat limit
Whether there are imminent physical limits to economic growth has been the focus of a long-standing debate, often (but not exclusively) pitting natural scientists against economists. One side of the debate posits that finite resources constrain human economic growth, the other that productivity improvements and substitution can relax those resource constraints. However, the two sides lack a common framework to resolve their disagreement. We provide this framework and mediate this dispute using a combination of low-order economic and physical models, focusing especially on the waste heat limit. To start, we use a simple accounting identity to show that historical rates of growth in average productivity can support modest economic and population growth (totaling 1.2%). We model the future trajectory of productivity growth by combining a canonical production function (Cobb-Douglas) with a flexible model where population growth drives total-factor-productivity growth. We find remarkable parameter sensitivity: across a plausible range of parameters waste heat either never constrains economic growth in the model or does so in a few hundred years. Interestingly, either decreasing or increasing population growth can dramatically extend the time to heat constraint in the model, the latter due to increases in innovation. Finally, we use a more flexible (constant elasticity of substitution) production function and historical changes in the relative use of different resources to show that humans have the ability to substitute away from resources in shorter supply. Although there are vast uncertainties in this type of projection, our work highlights the potential for an optimistic future for humanity in which economic growth continues on a millennial timescale.