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Experimental study on adiabatic pre-cooling systems for air cooled condensers in hot and humid climates
A neuronal code for object representation and memory in the human amygdala and hippocampus
Abstract How the brain encodes, recognizes, and memorizes general visual objects is a fundamental question in neuroscience. Here, we investigated the neural processes underlying visual object perception and memory by recording from 3173 single neurons in the human amygdala and hippocampus across four experiments. We employed both passive-viewing and recognition memory tasks involving a diverse range of naturalistic object stimuli. Our findings reveal a region-based feature code for general objects, where neurons exhibit receptive fields in the high-level visual feature space. This code can be validated by independent new stimuli and replicated across all experiments, including fixation-based analyses with large natural scenes. This region code explains the long-standing visual category selectivity, preferentially enhances memory of encoded stimuli, predicts memory performance, encodes image memorability, and exhibits intricate interplay with memory contexts. Together, region-based feature coding provides an important mechanism for visual object processing in the human brain.
Self-supervision advances morphological profiling by unlocking powerful image representations
Self-optimized contact in air-robust thermoelectric junction towards long-lasting heat harvesting
Health related quality of life and its influencing factors in Chinese patients with ocular tumors
Mitofusin 2 displays fusion-independent roles in proteostasis surveillance
Abstract Mitochondria are essential organelles and their functional state dictates cellular proteostasis. However, little is known about the molecular gatekeepers involved, especially in absence of external stress. Here we identify a role of MFN2 in quality control independent of its function in organellar shape remodeling. MFN2 ablation alters the cellular proteome, marked for example by decreased levels of the import machinery and accumulation of the kinase PINK1. Moreover, MFN2 interacts with the proteasome and cytosolic chaperones, thereby preventing aggregation of newly translated proteins. Similarly to MFN2-KO cells, patient fibroblasts with MFN2-disease variants recapitulate excessive protein aggregation defects. Restoring MFN2 levels re-establishes proteostasis in MFN2-KO cells and rescues fusion defects of MFN1-KO cells. In contrast, MFN1 loss or mitochondrial shape alterations do not alter protein aggregation, consistent with a fusion-independent role of MFN2 in cellular homeostasis. In sum, our findings open new possibilities for therapeutic strategies by modulation of MFN2 levels.
RETRACTED ARTICLE: Saudi calcium bentonite: a novel modifier for enhanced foamed underbalanced drilling performance
Mechanisms of urate transport and uricosuric drugs inhibition in human URAT1
Abstract High urate levels in circulation lead to the accumulation of urate crystals in joints and ultimately inflammation and gout. The reabsorption process of urate in the kidney by the urate transporter URAT1 plays a pivotal role in controlling serum urate levels. Pharmacological inhibition of URAT1 by uricosuric drugs is a valid strategy for gout management. Despite the clinical significance of URAT1, its structural mechanism and dynamics remain incompletely understood. Here, we report the structures of human URAT1 (hURAT1) in complex with substrate urate or inhibitors benzbromarone and verinurad at resolution ranges from 3.0 to 3.3 Å. We observe urate in the central substrate-binding site of hURAT1 in the outward-facing conformation and urate is wrapped in the center of hURAT1 by five phenylalanines and coordinated by two positively charged residues on each side. Uricosuric compounds benzbromarone and verinurad occupy the urate-binding site of hURAT1 in the inward-facing conformation. Structural comparison between different conformations of hURAT1 reveals the rocker-switch-like mechanism for urate transport. Benzbromarone and verinurad exert their inhibitory effect by blocking not only the binding of urate but also the structural isomerization of hURAT1.
Design, synthesis, molecular docking and anticancer activity evaluation of methyl salicylate based thiazoles as PTP1B inhibitors
Sea level since the Last Glacial Maximum from the Atlantic coast of Africa
Trajectory analysis of hepatic stellate cell differentiation reveals metabolic regulation of cell commitment and fibrosis
Single-cell RNA sequencing defines distinct disease subtypes and reveals hypo-responsiveness to interferon in asymptomatic Waldenstrom’s Macroglobulinemia
Author Correction: Medical history predicts phenome-wide disease onset and enables the rapid response to emerging health threats
Macrocycle-based PROTACs selectively degrade cyclophilin A and inhibit HIV-1 and HCV
Abstract Targeting host proteins that are crucial for viral replication offers a promising antiviral strategy. We have designed and characterised antiviral PROteolysis TArgeting Chimeras (PROTACs) targeting the human protein cyclophilin A (CypA), a host cofactor for unrelated viruses including human immunodeficiency virus (HIV) and hepatitis C virus (HCV). The PROTAC warheads are based on fully synthetic macrocycles derived from sanglifehrin A, which are structurally different from the classical Cyp inhibitor, cyclosporine A. Our Cyp-PROTACs decrease CypA levels in cell lines and primary human cells and have high specificity for CypA confirmed by proteomics experiments. Critically, CypA degradation facilitates improved antiviral activity against HIV-1 in primary human CD4+ T cells compared to the non-PROTAC parental inhibitor, at limiting inhibitor concentrations. Similarly, we observe antiviral activity against HCV replicon in a hepatoma cell line. We propose that CypA-targeting PROTACs inhibit viral replication potently and anticipate reduced evolution of viral resistance and broad efficacy against unrelated viruses. Furthermore, they provide powerful tools for probing cyclophilin biology.
A cosmogenic 10Be anomaly during the late Miocene as independent time marker for marine archives
Abstract Cosmogenic nuclide dating relies on the constancy of production and incorporation of radionuclides in geological archives. Anomalous deviations from constancy during the Holocene or Pleistocene are frequently used as global benchmarks to harmonize different data sets. A similar dating anchor on the million year timescale was so far not presented. In this work, we report on a prolonged cosmogenic 10Be anomaly during the late Miocene recorded in several Central and Northern Pacific deep-ocean ferromanganese crusts in the time period 9–11.5 Myr ago peaking at 10.1 Myr. Potential origins of this anomaly are discussed in the light of geological, climatic, solar and astrophysical events. This anomaly has the potential to be an independent time marker for marine archives.