Notes

Will not give up right now: the actual hold is getting ready to switch.
We identify relevant characteristics that result from this joint optimization, particularly the frequency with which subjects and objects are expressed together for the same verb. Our findings suggest that syntactic structure and usage across languages coadapt to support efficient communication under limited cognitive resources.Nonequilibrium interfacial thermodynamics has important implications for crucial biological, physical, and industrial-scale transport processes. Here, we discuss a theory of local equilibrium for multiphase multicomponent interfaces that builds upon the "sharp" interface concept first introduced by Gibbs, allowing for a description of nonequilibrium interfacial processes such as those arising in evaporation, condensation, adsorption, etc. By requiring that the thermodynamics be insensitive to the precise location of the dividing surface, one can identify conditions for local equilibrium and develop methods for measuring the values of intensive variables at the interface. We then use extensive, high-precision nonequilibrium molecular dynamics (NEMD) simulations to verify the theory and establish the validity of the local equilibrium hypothesis. Selleck PACAP 1-38 In particular, we demonstrate that equilibrium equations of state are also valid out of equilibrium, and can be used to determine interfacial temperature and chemical potential(s) that are consistent with nonequilibrium generalizations of the Clapeyron and Gibbs adsorption equations. We also show, for example, that, far from equilibrium, temperature or chemical potential differences need not be uniform across an interface and may instead exhibit pronounced discontinuities. However, even in these circumstances, we demonstrate that the local equilibrium hypothesis and its implications remain valid. These results provide a thermodynamic foundation and computational tools for studying or revisiting a wide variety of interfacial transport phenomena.Muscle attachment sites (MASs, apodemes) in insects and other arthropods involve specialized epithelial cells, called tendon cells or tenocytes, that adhere to apical extracellular matrices containing chitin. Here, we have uncovered a function for chitin deacetylases (CDAs) in arthropod locomotion and muscle attachment using a double-stranded RNA-mediated gene-silencing approach targeted toward specific CDA isoforms in the red flour beetle, Tribolium castaneum (Tc). Depletion of TcCDA1 or the alternatively spliced TcCDA2 isoform, TcCDA2a, resulted in internal tendon cuticle breakage at the femur-tibia joint, muscle detachment from both internal and external tendon cells, and defective locomotion. TcCDA deficiency did not affect early muscle development and myofiber growth toward the cuticular MASs but instead resulted in aborted microtubule development, loss of hemiadherens junctions, and abnormal morphology of tendon cells, all features consistent with a loss of tension within and between cells. Moreover, simultaneous depletion of TcCDA1 or TcCDA2a and the zona pellucida domain protein, TcDumpy, prevented the internal tendon cuticle break, further supporting a role for force-dependent interactions between muscle and tendon cells. We propose that in T. castaneum, the absence of N-acetylglucosamine deacetylation within chitin leads to a loss of microtubule organization and reduced membrane contacts at MASs in the femur, which adversely affect musculoskeletal connectivity, force transmission, and physical mobility.Schwannomas are slow-growing benign neoplasms that develop throughout the body causing pain, sensory/motor dysfunction, and death. Because bacterial immunotherapy has been used in the treatment of some malignant neoplasms, we evaluated attenuated Salmonella typhimurium strains as immunotherapies for benign murine schwannomas. Several bacterial strains were tested, including VNP20009, a highly attenuated strain that was previously shown to be safe in human subjects with advanced malignant neoplasms, and a VNP20009 mutant that was altered in motility and other properties that included adherence and invasion of cultured mammalian cells. VNP20009 controlled tumor growth in two murine schwannoma models and induced changes in cytokine and immune effector cell profiles that were consistent with induction of enhanced innate and adaptive host immune responses compared with controls. Intratumoral (i.t.) injection of S. typhimurium led to tumor cell apoptosis, decreased tumor angiogenesis, and lower growth of the injected schwannoma tumors. Invasive VNP20009 was significantly more efficacious than was a noninvasive derivative in controlling the growth of injected tumors. Bacterial treatment apparently induced systemic antitumor immunity in that the growth of rechallenge schwannomas implanted following primary bacterial treatment was also reduced. Checkpoint programmed death-1 (PD-1) blockade induced by systemic administration of anti-PD-1 antibodies controlled tumor growth to the same degree as i.t. injection of S. typhimurium, and together, these two therapies had an additive effect on suppressing schwannoma growth. These experiments represent validation of a bacterial therapy for a benign neoplasm and support development of S. typhimurium VNP20009, potentially in combination with PD-1 inhibition, as a schwannoma immunotherapy.Viruses transmitted by Aedes mosquitoes are an increasingly important global cause of disease. Defining common determinants of host susceptibility to this large group of heterogenous pathogens is key for informing the rational design of panviral medicines. Infection of the vertebrate host with these viruses is enhanced by mosquito saliva, a complex mixture of salivary-gland-derived factors and microbiota. We show that the enhancement of infection by saliva was dependent on vascular function and was independent of most antisaliva immune responses, including salivary microbiota. Instead, the Aedes gene product sialokinin mediated the enhancement of virus infection through a rapid reduction in endothelial barrier integrity. Sialokinin is unique within the insect world as having a vertebrate-like tachykinin sequence and is absent from Anopheles mosquitoes, which are incompetent for most arthropod-borne viruses, whose saliva was not proviral and did not induce similar vascular permeability. Therapeutic strategies targeting sialokinin have the potential to limit disease severity following infection with Aedes-mosquito-borne viruses.Coordinated cell function requires a variety of subcellular organelles to exchange proteins and lipids across physical contacts that are also referred to as membrane contact sites. Such organelle-to-organelle contacts also evoke interest because they can appear in response to metabolic changes, immune activation, and possibly other stimuli. The microscopic size and complex, crowded geometry of these contacts, however, makes them difficult to visualize, manipulate, and understand inside cells. To address this shortcoming, we deposited endoplasmic reticulum (ER)-enriched microsomes purified from rat liver or from cultured cells on a coverslip in the form of a proteinaceous planar membrane. We visualized real-time lipid and protein exchange across contacts that form between this ER-mimicking membrane and lipid droplets (LDs) purified from the liver of rat. The high-throughput imaging possible in this geometry reveals that in vitro LD-ER contacts increase dramatically when the metabolic state is changed by feeding the animal and also when the immune system is activated. Contact formation in both cases requires Rab18 GTPase and phosphatidic acid, thus revealing common molecular targets operative in two very different biological pathways. An optical trap is used to demonstrate physical tethering of individual LDs to the ER-mimicking membrane and to estimate the strength of this tether. These methodologies can potentially be adapted to understand and target abnormal contact formation between different cellular organelles in the context of neurological and metabolic disorders or pathogen infection.Rechargeable Zn metal batteries (RZMBs) may provide a more sustainable and lower-cost alternative to established battery technologies in meeting energy storage applications of the future. However, the most promising electrolytes for RZMBs are generally aqueous and require high concentrations of salt(s) to bring efficiencies toward commercially viable levels and mitigate water-originated parasitic reactions including hydrogen evolution and corrosion. Electrolytes based on nonaqueous solvents are promising for avoiding these issues, but full cell performance demonstrations with solvents other than water have been very limited. To address these challenges, we investigated MeOH as an alternative electrolyte solvent. These MeOH-based electrolytes exhibited exceptional Zn reversibility over a wide temperature range, with a Coulombic efficiency > 99.5% at 50% Zn utilization without cell short-circuit behavior for > 1,800 h. More important, this remarkable performance translates well to Zn || metal-free organic cathode full cells, supporting 800 cycles at -40 °C.
Prostate cancer is the second most common cause of cancer mortality in men worldwide. Applying a novel genetically engineered mouse model (GEMM) of aggressive prostate cancer driven by deficiency of the tumor suppressors PTEN and Sprouty2 (SPRY2), we identified enhanced creatine metabolism as a central component of progressive disease. Creatine treatment was associated with enhanced cellular basal respiration in vitro and increased tumor cell proliferation in vivo. Stable isotope tracing revealed that intracellular levels of creatine in prostate cancer cells are predominantly dictated by exogenous availability rather than by de novo synthesis from arginine. Genetic silencing of creatine transporter SLC6A8 depleted intracellular creatine levels and reduced the colony-forming capacity of human prostate cancer cells. Accordingly, in vitro treatment of prostate cancer cells with cyclocreatine, a creatine analog, dramatically reduced intracellular levels of creatine and its derivatives phosphocreatine and creatinine and suppressed proliferation. Supplementation with cyclocreatine impaired cancer progression in the PTEN- and SPRY2-deficient prostate cancer GEMMs and in a xenograft liver metastasis model. Collectively, these results identify a metabolic vulnerability in prostate cancer and demonstrate a rational therapeutic strategy to exploit this vulnerability to impede tumor progression.

Enhanced creatine uptake drives prostate cancer progression and confers a metabolic vulnerability to treatment with the creatine analog cyclocreatine.
Enhanced creatine uptake drives prostate cancer progression and confers a metabolic vulnerability to treatment with the creatine analog cyclocreatine.We present an interesting case of concomitant congenital anomalies with an iatrogenic defect. The female patient underwent a percutaneous mitral balloon valvuloplasty due to rheumatic mitral stenosis. Unfortunately, an iatrogenic atrial septal defect (ASD) transpired during the procedure. Upon post-procedure examination, partial anomalous pulmonary venous (PAPVR) return was observed. The patient was symptomatic; on imaging, dilatation of the right heart chambers were detected. In addition, another crucial point was that the patient was planning a pregnancy, thus robotic surgery for iatrogenic ASD and PAPVR return was recommended. After a successful operation, the patient was asymptomatic and the size of right heart chambers were normalized.
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