Holcombtravis0136

Non-enzymatic chitinase-3 like-protein-1 (CHI3L1) belongs to glycoside hydrolase family 18. It binds to chitin, heparin, and hyaluronic acid, and is regulated by extracellular matrix changes, cytokines, growth factors, drugs, and stress. CHI3L1 is synthesized and secreted by a multitude of cells including macrophages, neutrophils, synoviocytes, chondrocytes, fibroblast-like cells, smooth muscle cells, and tumor cells. It plays a major role in tissue injury, inflammation, tissue repair, and remodeling responses. CHI3L1 has been strongly associated with diseases including asthma, arthritis, sepsis, diabetes, liver fibrosis, and coronary artery disease. Moreover, following its initial identification in the culture supernatant of the MG63 osteosarcoma cell line, CHI3L1 has been shown to be overexpressed in a wealth of both human cancers and animal tumor models. To date, interleukin-13 receptor subunit alpha-2, transmembrane protein 219, galectin-3, chemo-attractant receptor-homologous 2, and CD44 have been identified as CHI3L1 receptors. CHI3L1 signaling plays a critical role in cancer cell growth, proliferation, invasion, metastasis, angiogenesis, activation of tumor-associated macrophages, and Th2 polarization of CD4+ T cells. Interestingly, CHI3L1-based targeted therapy has been increasingly applied to the treatment of tumors including glioma and colon cancer as well as rheumatoid arthritis. This review summarizes the potential roles and mechanisms of CHI3L1 in oncogenesis and disease pathogenesis, then posits investigational strategies for targeted therapies.From starlight to sunlight, adaptation alters retinal output, changing both the signal and noise among populations of retinal ganglion cells (RGCs). Here we determine how these light level-dependent changes impact decoding of retinal output, testing the importance of accounting for RGC noise correlations to optimally read out retinal activity. We find that at moonlight conditions, correlated noise is greater and assuming independent noise severely diminishes decoding performance. In fact, assuming independence among a local population of RGCs produces worse decoding than using a single RGC, demonstrating a failure of population codes when correlated noise is substantial and ignored. We generalize these results with a simple model to determine what conditions dictate this failure of population processing. This work elucidates the circumstances in which accounting for noise correlations is necessary to take advantage of population-level codes and shows that sensory adaptation can strongly impact decoding requirements on downstream brain areas.Pancreatic ductal adenocarcinoma (PDAC) and cancer-associated cachexia (CAC) are multifactorial and characterized by dysregulated inflammatory networks. Beta-Lapachone price Whether the proinflammatory cytokine IL-20 is involved in the complex networks of PDAC and CAC remains unclear. Here, we report that elevated IL-20 levels in tumor tissue correlate with poor overall survival in 72 patients with PDAC. In vivo, we establish a transgenic mouse model (KPC) and an orthotopic PDAC model and examine the therapeutic efficacy of an anti-IL-20 monoclonal antibody (7E). Targeting IL-20 not only prolongs survival and attenuates PD-L1 expression in both murine models but also inhibits tumor growth and mitigates M2-like polarization in the orthotopic PDAC model. Combination treatment with 7E and an anti-PD-1 antibody shows better efficacy in inhibiting tumor growth than either treatment alone in the orthotopic PDAC model. Finally, 7E mitigates cachexic symptoms in CAC models. Together, we conclude IL-20 is a critical mediator in PDAC progression.Human behaviors are extremely sophisticated, relying on the adaptive, plastic and event-driven network of sensory neurons. Such neuronal system analyzes multiple sensory cues efficiently to establish accurate depiction of the environment. Here, we develop a bimodal artificial sensory neuron to implement the sensory fusion processes. Such a bimodal artificial sensory neuron collects optic and pressure information from the photodetector and pressure sensors respectively, transmits the bimodal information through an ionic cable, and integrates them into post-synaptic currents by a synaptic transistor. The sensory neuron can be excited in multiple levels by synchronizing the two sensory cues, which enables the manipulating of skeletal myotubes and a robotic hand. Furthermore, enhanced recognition capability achieved on fused visual/haptic cues is confirmed by simulation of a multi-transparency pattern recognition task. Our biomimetic design has the potential to advance technologies in cyborg and neuromorphic systems by endowing them with supramodal perceptual capabilities.Gene-targeted animal models that are generated by injecting Cas9 and sgRNAs into zygotes are often accompanied by undesired double-strand break (DSB)-induced byproducts and random biallelic targeting due to uncontrollable Cas9 targeting activity. Here, we establish a parental allele-specific gene-targeting (Past-CRISPR) method, based on the detailed observation that pronuclear transfer-mediated cytoplasmic dilution can effectively terminate Cas9 activity. We apply this method in embryos to efficiently target the given parental alleles of a gene of interest and observed little genomic mosaicism because of the spatiotemporal control of Cas9 activity. This method allows us to rapidly explore the function of individual parent-of-origin effects and to construct animal models with a single genomic change. More importantly, Past-CRISPR could also be used for therapeutic applications or disease model construction.The suprachiasmatic nucleus (SCN) is a complex structure dependent upon multiple mechanisms to ensure rhythmic electrical activity that varies between day and night, to determine circadian adaptation and behaviours. SCN neurons are exposed to glutamate from multiple sources including from the retino-hypothalamic tract and from astrocytes. However, the mechanism preventing inappropriate post-synaptic glutamatergic effects is unexplored and unknown. Unexpectedly we discovered that TRESK, a calcium regulated two-pore potassium channel, plays a crucial role in this system. We propose that glutamate activates TRESK through NMDA and AMPA mediated calcium influx and calcineurin activation to then oppose further membrane depolarisation and rising intracellular calcium. Hence, in the absence of TRESK, glutamatergic activity is unregulated leading to membrane depolarisation, increased nocturnal SCN firing, inverted basal calcium levels and impaired sensitivity in light induced phase delays. Our data reveals TRESK plays an essential part in SCN regulatory mechanisms and light induced adaptive behaviours.Protected areas (PAs) are the cornerstones of global biodiversity conservation efforts, but to fulfil this role they must be effective at conserving the ecosystems and species that occur within their boundaries. Adequate monitoring datasets that allow comparing biodiversity between protected and unprotected sites are lacking in tropical regions. Here we use the largest citizen science biodiversity dataset - eBird - to quantify the extent to which protected areas in eight tropical forest biodiversity hotspots are effective at retaining bird diversity. We find generally positive effects of protection on the diversity of bird species that are forest-dependent, endemic to the hotspots, or threatened or Near Threatened, but not on overall bird species richness. Furthermore, we show that in most of the hotspots examined this benefit is driven by protected areas preventing both forest loss and degradation. Our results provide evidence that, on average, protected areas contribute measurably to conserving bird species in some of the world's most diverse and threatened terrestrial ecosystems.An adaptive memory system rarely learns information tabula rasa, but rather builds on prior knowledge to facilitate learning. How prior knowledge influences the neural representation of novel associations remains unknown. Here, participants associated pairs of faces in two conditions a famous, highly familiar face with a novel face or two novel faces while undergoing fMRI. We examine multivoxel activity patterns corresponding to individual faces before and after learning. The activity patterns representing members of famous-novel pairs becomes separated in the hippocampus, that is, more distinct from one another through learning, in striking contrast to paired novel faces that become similar. In the left inferior frontal gyrus, however, prior knowledge leads to integration, and in a specific direction the representation of the novel face becomes similar to that of the famous face after learning, suggesting assimilation of new into old memories. We propose that hippocampal separation might resolve interference between existing and newly learned information, allowing cortical assimilation. Thus, associative learning with versus without prior knowledge relies on radically different computations.Compared to other Arctic ice masses, Svalbard glaciers are low-elevated with flat interior accumulation areas, resulting in a marked peak in their current hypsometry (area-elevation distribution) at ~450 m above sea level. Since summer melt consistently exceeds winter snowfall, these low-lying glaciers can only survive by refreezing a considerable fraction of surface melt and rain in the porous firn layer covering their accumulation zones. We use a high-resolution climate model to show that modest atmospheric warming in the mid-1980s forced the firn zone to retreat upward by ~100 m to coincide with the hypsometry peak. This led to a rapid areal reduction of firn cover available for refreezing, and strongly increased runoff from dark, bare ice areas, amplifying mass loss from all elevations. As the firn line fluctuates around the hypsometry peak in the current climate, Svalbard glaciers will continue to lose mass and show high sensitivity to temperature perturbations.High harmonic generation (HHG) is an extremely nonlinear effect generating coherent broadband radiation and pulse durations reaching attosecond timescales. Conventional models of HHG that treat the driving and emitted fields classically are usually very successful but inherently cannot capture the quantum-optical nature of the process. Although prior work considered quantum HHG, it remains unknown in what conditions the spectral and statistical properties of the radiation depart considerably from the known phenomenology of HHG. The discovery of such conditions could lead to novel sources of attosecond light having squeezing and entanglement. Here, we present a fully-quantum theory of extreme nonlinear optics, predicting quantum effects that alter both the spectrum and photon statistics of HHG, thus departing from all previous approaches. We predict the emission of shifted frequency combs and identify spectral features arising from the breakdown of the dipole approximation for the emission. Our results show that each frequency component of HHG can be bunched and squeezed and that each emitted photon is a superposition of all frequencies in the spectrum, i.e., each photon is a comb. Our general approach is applicable to a wide range of nonlinear optical processes, paving the way towards novel quantum phenomena in extreme nonlinear optics.