Miracle-dz/UniFAR-FTUs huggingface dataset:
Optimizing Phosphopeptide Structures That Target 14-3-3ε in Cutaneous Squamous Cell Carcinoma

14-3-3ε is involved in various types of malignancies by increasing cell proliferation, promoting cell invasion or inhibiting apoptosis. In cutaneous squamous cell carcinoma (cSCC), 14-3-3ε is over expressed and mislocalized from the nucleus to the cytoplasm where it interacts with the cell division cycle 25 A (CDC25A) and suppresses apoptosis. Hence inhibition of the 14-3-3ε - CDC25A interaction is an attractive target for promoting apoptosis in cSCC. In this work, we optimized the structure of our previously designed inhibitor of 14-3-3ε – CDC25A interaction, pT, a phosphopeptide fragment corresponding to one of the two binding regions of CDC25A to 14-3-3ε. Starting from pT, we developed peptide analogs that bind 14-3-3ε with nanomolar affinities. Peptide analogs were designed by shortening the pT peptide, and introducing modifications at position 510 of the pT(502-510) analog. Both molecular dynamics (MD) simulations and biophysical methods were used to determine peptides binding to 14-3-3ε. Shortening the pT peptide from 14 to 9 amino acid residues resulted in a peptide (pT(502-510)) that binds 14-3-3ε with a KD value of 45.2 nM. Gly to Phe substitution in position 510 of pT(502-510) led to further improvement in affinity (KD: 22.0 nM) of the peptide for 14-3-3ε. Our results suggest that the designed peptide analogs are potential candidates for inhibiting 14-3-3ε -CDC25A interactions in cSCC cells; thus, inducing their apoptosis.
A compact, ultrahigh-density headstage with high-fidelity hybrid integration for large-scale deep-brain opto-electrophysiology

Recent neuroscientific research seeks to comprehend the sophisticated deep-brain networks of neural circuits consisting of large scale neuronal ensembles across multiple brain regions. An ideal way to unveil the complex connectome might be stimulating individual neurons with high spatial resolution in a broad range of brain, while seamlessly monitoring the correspondent neuronal activities. Optogenetics is known as a key technology to enable such a goal thanks to its high spatial and temporal selectivity in neuromodulation. Existing silicon probe technologies have been able to partially achieve such a goal by recording broad region of brain activities through multiple electrodes per shank, but those cannot complete perfect coverage due to the limited channel counts for the optogenetic stimulation. Here, we present an high-channel-count optogenetic system with simultaneous 256 recoding and 128 optogenetic stimulation sites, exhibiting the highest channel density ever reported, enabled by a flexible polyimide cable-based hybrid-integration of a low-stimulation-artifact micro-LED (µLED) opto-electrode with a low-power and -noise, area-efficient CMOS interfacing integrated-circuit (IC). The presented optogenetic system provides 256-neuron-size electrodes (11 × 15 µm2) with a 40 µm inter-electrode pitch for high spatial oversampling in recording and 128-soma-size µLEDs (8 × 11 µm2) with a 20 µm inter-LED pitch for single-cell resolution in stimulation, resulting in a vertical span of 640 µm and a horizontal span of 2,100 µm with a total 8 shanks. For versatility in optogenetics-based experiments from small rodents to primates with user-preferable settings, the system base that provides programmability of recording and stimulation parameters and rest of signal processing, such as filtering, digitization, and data transmission including serial peripheral interface (SPI) has also been designed within small area of 23.8 × 28.8 mm2 with only 3.5-gram weight, resulting in the highest channel density both in size (0.56 channels/mm2) and weight (109.71 channels/gram) among the state-of-the-art optogenetics-based neuromodulation systems. To verify the system operation in vivo, a compact optogenetics headstage has been also fabricated. Using the prepared optogenetic headstage, 169 isolated neurons have been observed with various stimulation intensities. The results offered in this article indicate that the presented hybrid integrated ultrahigh-density, high-channel-count headstage can be used to realize the massive-scale in-depth brain studies with optogenetics.
Investigation of H9N2 avian influenza immune escape mutant that lacks haemagglutination activity

H9N2 avian influenza viruses pose a global threat to animal and human health. While vaccination is essential for mitigating disease impact, these viruses evolve to evade vaccine immunity through changes in the haemagglutinin (HA) glycoprotein. In this study, we identified immune escape mutation in an H9N2 virus resulting from pressure exerted by homologous chicken antisera. The immune-escape variant acquired an amino acid substitution, replacing glycine (G) with glutamic acid (E) at position 149 in the HA protein. The G149E mutant virus lost the ability to agglutinate chicken erythrocytes, while still maintaining replication comparable to the wild-type virus in chicken embryos and cells. This led to the hypothesis that the G149E substitution, leading to a shift from a neutral to a negative charge polarity at HA position 149, might be crucial for the optimal interaction between the virus and receptors on erythrocytes. Investigation indicated that agglutination could be restored by substituting E to positively charged amino acids histidine (H), arginine (R) or lysine (K). These findings suggest that the H9N2 virus may be likely acquire the G149E mutation under immune pressure in nature. This mutation poses challenges to vaccination and surveillance efforts as it partially evades immune protection and is not easily detectable by conventional haemagglutination assays. This underscores the intricate interplay between antigenic variation and viral traits, emphasising the critical need for ongoing surveillance and research to effectively mitigate the risks associated with avian influenza H9N2 viruses. IMPORTANCE Understanding how avian influenza viruses evolve to persist in nature is crucial for enhancing disease mitigation tools such as vaccines, diagnostics, and risk assessment. In this study, we identified an H9N2 virus antibody escape mutant with G149E mutation in the haemagglutinin that had lost the ability to agglutinate chicken erythrocytes, while retaining infectivity and replication fitness. The lack of haemagglutination activity potentially negatively impacts routine surveillance and commonly used diagnostics such as haemagglutination assay or haemagglutination inhibition assay. Therefore, it is urgent to develop and adopt alternative methods for viral detection. Difficult to detect variants potentially that are not compatible with common surveillance techniques could circulate remain silent while reassort with other influenza viruses, which posing unpredictable risks to animal and human health. This research helps us better understand avian influenza, leading to improved disease control, diagnostics, and risk assessment to protect both animals and humans.
Adolescent environmental enrichment induces social resilience and alters neural gene expression in a selectively bred rodent model with anxious phenotype

Stress is a major influence on mental health status; the ways that individuals respond to or copes with stressors determine whether they are nega9vely affected in the future. Stress responses are established by an interplay between gene9cs, environment, and life experiences. Psychosocial stress is par9cularly impacAul during adolescence, a cri9cal period for the development of mood disorders. In this study we compared two established, selec9vely-bred Sprague Dawley rat lines, the “internalizing” bred Low Responder (bLR) line versus the “externalizing” bred High Responder (bHR) line, to inves9gate how gene9c temperament and adolescent environment impact future responses to social interac9ons and psychosocial stress, and how these determinants of stress response interact. Animals were exposed to social and environmental enrichment in adolescence prior to experiencing social defeat and were then assessed for social interac9on and anxiety-like behavior. Adolescent enrichment caused bLR rats to display less social avoidance, more social interac9on, less submission during defeat, and resilience to the prolonged effects of social stress on cor9costerone, while enrichment caused bHR animals to show greater aggression during defeat and during a neutral social encounter, and decreased anxiety-like behavior. To gain insight into the development of social resilience in the anxious phenotype bLRs, RNA-seq was conducted on the hippocampus and nucleus accumbens, two brain regions that mediate stress regula9on and social behavior. Gene sets previously associated with stress, social behavior, aggression and exploratory ac9vity were enriched with differen9al expression in both regions, with a par9cularly large effect on gene sets that regulate social behaviors. These findings provide further evidence that adolescent enrichment can serve as an inocula9ng experience against future stressors. The ability to induce social resilience in a usually anxious line of animals by manipula9ng their environment has transla9onal implica9ons, as it underscores the feasibility of interven9on strategies targeted at gene9cally vulnerable adolescent popula9ons.
Liver microRNA transcriptome reveals miR-182 as link between type 2 diabetes and fatty liver disease in obesity

Background The development of obesity-associated comorbidities such as type 2 diabetes (T2D) and hepatic steatosis has been linked to selected microRNAs in individual studies; however, an unbiased genome-wide approach to map T2D induced changes in the miRNAs landscape in human liver samples, and a subsequent robust identification and validation of target genes is still missing. Methods Liver biopsies from age- and gender-matched obese individuals with (n=20) or without (n=20) T2D were used for microRNA microarray analysis. The candidate microRNA and target genes were validated in 85 human liver samples, and subsequently mechanistically characterized in hepatic cells as well as by dietary interventions and hepatic overexpression in mice. Results Here we present the human hepatic microRNA transcriptome of type 2 diabetes in liver biopsies and use a novel seed prediction tool to robustly identify microRNA target genes, which were then validated in a unique cohort of 85 human livers. Subsequent mouse studies identified a distinct signature of T2D-associated miRNAs, partly conserved in both species. Of those, human-murine miR-182-5p was the most associated to whole-body glucose homeostasis and hepatic lipid metabolism. Its target gene LRP6 was consistently lower expressed in livers of obese T2D humans and mice as well as under conditions of miR-182-5p overexpression. Weight loss in obese mice decreased hepatic miR-182-5p and restored Lrp6 expression and other miR-182-5p target genes. Hepatic overexpression of miR-182-5p in mice rapidly decreased LRP6 protein levels and increased liver triglycerides and fasting insulin under obesogenic conditions after only seven days. Conclusion By mapping the hepatic miRNA-transcriptome of type 2 diabetic obese subjects, validating conserved miRNAs in diet-induced mice, and establishing a novel miRNA prediction tool, we provide a robust and unique resource that will pave the way for future studies in the field. As proof of concept, we revealed that the repression of LRP6 by miR-182-5p, which promotes lipogenesis and impairs glucose homeostasis, provides a novel mechanistic link between T2D and non-alcoholic fatty liver disease, and demonstrate in vivo that miR-182-5p can serve as a future drug target for the treatment of obesity-driven hepatic steatosis. Graphical Abstract
A Method For Estimating The Cholesterol Affinity Of Integral Membrane Proteins From Experimental Data

The cholesterol affinities of many integral plasma membrane proteins have been estimated by molecular computation. However, these values lack experimental confirmation. We therefore developed a simple mathematical model to extract sterol affinity constants and stoichiometries from published isotherms for the dependence of the activity of such proteins on membrane cholesterol concentration. The binding curves for these proteins are sigmoidal with strongly-lagged thresholds attributable to competition for the cholesterol by bilayer phospholipids. The model provided isotherms that matched the experimental data using published values for the sterol association constants and stoichiometries of the phospholipids. Three oligomeric transporters were found to bind cholesterol without cooperativity with dimensionless association constants of 35 for Kir3.4* and 100 for both Kir2 and a GAT transporter. (The corresponding ρG° values were -8.8, -11.4 and -11.4 KJ/mol, respectively.) These association constants are significantly lower than those for the phospholipids which range from ∼100 to 6,000. The BK channel, the nicotinic acetylcholine receptor and the M192I mutant of Kir3.4* appear to bind multiple cholesterol molecules cooperatively (n = 2 or 4) with subunit affinities of 563, 950 and 700, respectively. The model predicts that the three less avid transporters are approximately half-saturated in their native plasma membranes; hence, sensitive to variations in cholesterol in vivo. The more avid proteins would be nearly saturated in vivo. The method can be applied to any integral protein or other ligand in any bilayer for which there are reasonable estimates of the sterol affinities and stoichiometries of the phospholipids.
The archerfish uses motor adaptation in shooting to correct for changing physical conditions

The archerfish is unique in its ability to hunt by shooting a jet of water from its mouth that hits insects situated above the water’s surface. To aim accurately, the fish needs to overcome physical factors including changes in light refraction at the air-water interface. Nevertheless, archerfish can still hit the target with a high success rate under changing conditions. One possible explanation for this extraordinary ability is that it is learned by trial and error through a motor adaptation process. We tested this possibility by characterizing the ability of the archerfish to adapt to perturbations in the environment to make appropriate adjustments to its shots. We introduced a perturbing airflow above the water tank of archerfish trained to shoot at a target. For each trial shot, we measured the error; i.e., the distance between the center of the target and the center of the water jet produced by the fish. Immediately after the airflow perturbation, there was an increase in shot error. Then, over the course of several trials, the error was reduced and eventually plateaued. After the removal of the perturbation, there was an aftereffect, where the error was in the opposite direction but washed out after several trials. These results indicate that archerfish can adapt to the airflow perturbation. Testing the fish with two opposite airflow directions indicated that adaptation took place within an egocentric frame of reference. These results thus suggest that the archerfish is capable of motor adaptation, as indicated by data showing that the fish produced motor commands that anticipated the perturbation.
First measurement of the displacement rate of the Pacific Plate near the Japan Trench after the 2011 Tohoku‐Oki earthquake using GPS/acoustic technique

The subduction rate of an oceanic plate may accelerate after large earthquakes rupture the interplate coupling between the oceanic and overriding continental plates. To better understand postseismic deformation processes in an incoming oceanic plate, we directly measured the displacement rate of the Pacific Plate near the Japan Trench after the 2011 Tohoku‐Oki earthquake using a GPS/acoustic technique over a period of 2 years (September 2012 to September 2014). The displacement rate was measured to be 18.0 ± 4.5 cm yr−1 (N302.0°E) relative to the North American Plate, which is almost twice as fast as the predicted interseismic plate motion. Because the sum of steady plate motion and viscoelastic response to the Tohoku‐Oki earthquake roughly accounts for the observed displacement rate, we conclude that viscoelastic relaxation is the primary mechanism responsible for postseismic deformation of the Pacific Plate and that significant subduction acceleration did not occur at least not during the observation period.
Adaptation and Invention during the Spread of Agriculture to Southwest China

The spread of an agricultural lifestyle played a crucial role in the development of social complexity and in defining trajectories of human history. This dissertation presents the results of research into how agricultural strategies were modified during the spread of agriculture into Southwest China. By incorporating advances from the fields of plant biology and ecological niche modeling into archaeological research, this dissertation addresses how humans adapted their agricultural strategies or invented appropriate technologies to deal with the challenges presented by the myriad of ecological niches in southwest China. This dissertation uses ecological niche modeling to examine the options and constraints associated with practicing different types of agriculture in the specific ecological niches of southwest China. The predictions made by these models are then tested against archaeobotanical data from a series of sites from across the region. This approach allows one to understand how the spread of agriculture took place in its particular social and economic contexts.
Experiments on waves trapped over the continental slope and shelf in a continuously stratified rotating ocean, and their incidence on a canyon

Continental margins form a waveguide for topographic Rossby waves, which can be trapped to the bottom by continuous stratification and concentrated over the continental slope while propagating along the coast. We present results of laboratory wave simulations designed to keep as many dimensionless numbers (Rossby, Burger, normalized frequency, wave steepness, geometrical, Ekman, and Reynolds) as possible similar to those of coastal-trapped waves, such as are observed in coastal regions around the world. The 13-m diameter rotating tank is salt-stratified and a continental slope joins a shallow shelf region along the outer tank circumference to a deep central region. The velocity field is measured using a correlation-based digital particle image velocimetry technique at several depths. Current ellipses downstream from subinertial forcing indicate along-isobath propagation with energy concentrated at depth and three-dimensional structure in agreement with a numerical wave solution calculated using the experimental geometry, rotation rate, and buoyancy frequency. Contrasting the inviscid wave solution, experimental flow shows an asymmetry with positive time-mean uv correlations (u across isobaths toward deep water, v along isobaths with shallow water to the left), and phase variations perpendicular to isobaths with flow near the shelf break leading that farther inshore and offshore, Both of these attributes have been seen previously in ocean observations and are interpreted as the signature of frictional influences based on stratified slope-Kelvin wave behavior. When incident on a canyon that indents the slope and shelf, a wave propagates in to and out of it along isobaths while remaining concentrated over the sloping topography with only weakly modified amplitude and phase structure. Based on the limited range of parameter space studied, the implication is that alongshore wave propagation will remain largely unmodified by natural corrugations in the slope and shelf and loss of energy by scattering will be weak.
Interannual variations of the Gobi Desert area from 1982-1999

There continues to be controversies among scientists whether humans are contributing to land degradation (desertification) in arid and semi-arid regions of the world. One area of considerable interest is the Gobi desert of central Asia, which is one of the largest deserts on Earth. The Gobi Desert is of particular value for addressing this question because it is divided by two countries that employ vastly different land management practices. Land use in China is high intensity and in Mongolia land use is of low intensity. In this study, climate and satellite remotely sensed data from 1982-1999 were used to investigate interannual variations in the areal extent the Gobi Desert boundary. Our results show substantial year-to-year variations in the size of the Gobi desert which was strongly correlated with annual precipitation (R2 = 0.81, P<0.000). Based on results of logistical analysis of the climatic and remotely sensed data, an actual evapotransporation threshold of 180 mm per year was identified as the factor for discriminating between areas of desert and steppes within the study area. Correlation values between the areal extend of the desert and climate data were highly significant for study areas in both Mongolia and Inner Mongolia, suggesting that at the scale of our study, human activities contributed little to interannual desert boundary fluctuation. Due to data availability constraints, we were only able to examine satellite imagery over an 18- year period which did not include both a wet and dry cycle for this region. Therefore, a more complete understanding of Gobi Desert boundary response to interannual climatic variation will require studies extended over a longer time period.
Moment, energy, stress drop, and source spectra of western United States earthquakes from regional coda envelopes

We present a new method to estimate stable seismic source parameters, such as energy, moment, and Orowan stress drop, using regional coda envelopes from as few as one broadband station. We use the method to compute path- and site-corrected seismic moment-rate spectra for 117 recent western United States earthquakes. Empirical Green's function corrections were applied to our surface- and body-wave coda envelope measurements to generate S-wave source spectra. These source spectra provide stable, single-station estimates of radiated seismic energy Es and seismic moment Mo that for common events are in excellent agreement with network-averaged estimates obtained using local and regional data. Teleseismic moment estimates are compatible with our regional results, but teleseismic energy estimates appear to be nearly an order of magnitude low. We estimated the seismic moment of events ranging between Mw 2.2 and 7.3, and energy estimates for which we had measured at least 70% of the total energy, generally events above Mw 3.3. We use these estimates to examine the behavior of derived parameters such as the Orowan stress drop (Δσ = 2μEs/Mo). While the earthquakes we studied have a small range in Orowan stress drop, generally between 0.1 and 20 MPa, they show a strong tendency for Orowan stress drop to increase with moment, approximately as Mo0.25. We believe this is a source effect and is not due to inadequate bandwidth or attenuation correction, and note that this trend appears to continue for microearthquakes as described in a recent deep borehole study in southern California. Many of the large high stress drop earthquakes show complexity in their moment-rate spectra near the corner frequency and cannot be fit by a simple ω-square model. Instead, above the first corner frequency, the spectral decay ranges between f−1.0 and f−1.5. This leads to larger estimates of radiated energy than predicted with a simple ω-square model and has implications for seismic hazard estimation. Coda envelopes have three main advantages over direct arrivals for estimating seismic moment and energy: (1) Coda amplitudes vary little with geology and source-radiation anisotropy and allow accurate single-station applications; (2) path-corrected coda amplitude measurements can be applied to very large regions, allowing a comparison of source parameters throughout the western United States using a common methodology and stations; (3) because long-period coda can last for hours for large local and regional events, it allows the analysis of seismograms with clipped early arrivals.