Communications Biology最新文献

The dentate gyrus in the hippocampus makes important contributions to the acquisition of episodic memories by transforming synaptic inputs from the entorhinal cortex into sparse and decorrelated activity patterns of its principal neurons, the granule cells. However, the underlying mechanism remains unclear. Using a combination of electrophysiological and optical recordings, together with optogenetic and pharmacological manipulations, we demonstrate here that the release of noradrenaline plays a key role in this specialization via an enhancement of feedforward inhibition generated by cholecystokinin-expressing interneurons. By imposing coincidence detection with milliseconds temporal resolution onto granule cells, this enhancement of feedforward inhibition makes granule cell activity sparser and their firing patterns decorrelated. Since decorrelation contributes to efficient memory storage during auto-associative learning, these findings reveal a circuit mechanism by which an arousal signal facilitates memory formation in the hippocampus.

Melanocytes are important components of the inner-ear cellular architecture. However, limited morphological research hinders our understanding of inner-ear function. Here, we characterize the morphology of inner-ear melanocytes and cells often misidentified as melanocytes. Immunofluorescence, smart-seq, transmission/field emission scanning electron microscopy, and immunoelectron microscopy are used. Cells previously referred to as "perivascular macrophage-like melanocytes" are not observed in the stria vascularis and are actually macrophages; along with melanocytes, they constitute intermediate cells. Cells with a "black ball" appearance in the vestibule are identified as macrophages. We examine variation in melanocytes or macrophages with age, strain, and cisplatin injury. Kir4.1 expression and the greater noise resistance observed in pigmented mice suggest melanocyte functions. Based on melanin distribution in Pou3f4^y/- mice, we hypothesize that melanocytes migrate from the modiolus along Reissner's membrane area to the stria vascularis, following a base-to-apex gradient. These findings provide novel ultrastructural and immunological insights into inner-ear function.

Single-chain variable fragments (scFvs) antibodies are used in diagnostic and therapeutic biopharmaceuticals. However, its production is limited due to insoluble expression and lack of a universal purification ligand. Here, we report a novel two-in-one protein tag, termed CSQ-tag, utilizing a calsequestrin (CSQ) protein to enable the soluble expression and calcium-dependent purification for scFvs. The CSQ-tag enhanced the solubility of four different therapeutic scFvs with an average solubility of 83.8 ± 4.6% in the BL21(DE3) strain, despite its reducing cytoplasmic environment. Compared to other tags, CSQ-tag showed superior solubility, with 1.8-fold higher solubility than MBP-tag across four scFvs. The solubility enhancement of the CSQ-tag is attributed to two main characteristics: highly acidic sequences with a low isoelectric point of 3.95, and intrinsically disordered protein properties. Furthermore, CSQ-tag can cost-effectively purify therapeutic scFvs with high purity over 95% using the calcium-dependent phase transition properties. Importantly, the anti-VEGF-scFv produced with the CSQ-tag showed a binding affinity of 25.8 pM, similar to that of the existing therapeutic brolucizumab. Therefore, CSQ-tag can significantly improve productivity and simultaneously maintain scFvs' functional integrity, thereby serving as a promising tool for universal expression and purification of therapeutic scFvs.

Neuraminidase inhibitors (NAIs) and cap-dependent endonuclease inhibitors (CENIs) represent two classes of antiviral drugs recommended for early treatment of patients with seasonal influenza A virus (IAV) infections. However, only limited human data, particularly on combination antiviral treatment, are available to inform optimal dosing regimens against novel IAVs, including highly pathogenic avian influenza A(H5N1) virus, associated with severe disease. Clade 2.3.4.4b A(H5N1) viruses have caused outbreaks in avian and mammalian species worldwide, highlighting the need to assess antiviral drug efficacy against these strains. We challenged ferrets with a D1.1 genotype A(H5N1) virus and treated infected animals with the NAI oseltamivir phosphate (OST) and the CENI baloxavir acid (BXA), alone or in combination, with treatment onset commencing pre- or post-symptom onset (24- or 48-hours post-inoculation (p.i.), respectively). When administered pre- or post-illness onset, BXA, but not OST, monotherapy provided significant reduction of clinical signs and significantly decreased infectious viral levels (in both respiratory and extrapulmonary specimens) compared with mock-treated animals. Combination OST/BXA treatment, when administered pre- or post-symptom onset, resulted in significant improvements in both metrics versus OST monotherapy. These data support continued investigation of antiviral treatment modalities that include both NAI and CENI for patients with mild and severe A(H5N1) disease.

Despite the rapid expansion of information on eukaryotic genomes, data on ribosomal DNA (rDNA) loci encoding ribosomal RNAs, crucial for the biogenesis of ribosomes, are absent in almost all cases due to difficulties in assembling the long regions of tandemly repeated DNA units. Taking advantage of the uniquely low rDNA copy number in the aquatic plant Spirodela polyrhiza, we resolved the species' complete 5S rDNA architecture at a nucleotide level. A combination of in situ hybridization, extra-long DNA reads, and conventional DNA sequencing allowed the assembly of near-complete loci sequences of 40,878 bp, specific for one haplotype of chromosome ChrSp6, and of 110,911 bp specific for a haplotype of ChrSp13. The completely resolved 5S rDNA locus of ChrSp6 contains 40 copies of tandemly repeated gene units with an intergenic spacer (NTS) of 400 bp for one haplotype, and more than 60 highly homogenized gene copies for the second haplotype. The ChrSp13 locus contains 5S rDNA clusters with NTSs of 1,056 or 1,069 bp arranged in two sub-clusters. The G/C-rich 5S rDNA arrays in both loci are embedded in A/T-enriched chromosome regions. This work advances our understanding of the basic principles of rDNA organization and evolution of rRNA genes in plants by revealing the molecular architecture and evolutionary dynamics of 5S rDNA loci.

Aurora kinase A/AURKA is a serine/threonine kinase frequently overexpressed in cancer. Recent discoveries pointed to subcellular pools of AURKA, including at mitochondria. There, AURKA induces organelle clearance by mitophagy together with the autophagy mediator LC3, and its receptor PHB2.Here, we show that the natural product capsaicin modifies the AURKA/PHB2 interaction. We synthesize 16 capsaicin analogs, and Förster's Resonance Energy Transfer/Fluorescence Lifetime Imaging Microscopy (FRET/FLIM) in breast cancer cells reveals that compounds 12 and 13 increase the AURKA/PHB2 interaction. Molecular docking shows that they bind to the inhibitory pocket of PHB2 and to the AURKA active site. We demonstrate that compound 13 specifically inhibits mitophagy while leaving AURKA activation unaltered at centrosomes. Our results demonstrate that compound 13 is a PHB ligand acting on the AURKA/PHB2 interaction. Thanks to its specificity, it may lead to the development of anticancer drugs targeting the mitochondrial functions of AURKA.

Obesity increases the risk of male infertility, primarily attributable to reduced testosterone levels. Exosomes, which facilitate intercellular communication during reproduction, may influence this process. However, the relation between exosomal cargo changes and high-fat diet (HFD)-induced testosterone decrease remains unclear. Here, we show that exosomes influence testosterone synthesis and spermatogenesis in HFD mice. Transferring exosomes derived from the serum of HFD mice to mice fed a normal diet decreases testosterone levels and sperm counts. Treatment with inhibitors of exosomes (GW4869) and ferroptosis (Ferrostatin-1) rescue HFD-induced impaired spermatogenesis. Additionally, elevated miR-122-5p levels in serum exosomes from HFD mice is partially attributed to increased hepatic miR-122-5p expression. Exosomal miR-122-5p induces ferroptosis in Leydig cells by inhibiting stearyl-CoA desaturase 2 expression, reducing testosterone synthesis and impairing spermatogenesis. Collectively, these findings highlight the impact of liver-derived exosomal alterations on testosterone production in HFD, revealing a regulatory pathway in the liver-testes axis.

Over the past decade, Immuno-Oncology has largely focused on blocking inhibitory surface receptors like PD-1 to enhance T cell anti-tumor activity. However, intracellular immune checkpoints such as CISH, which function independently of tumor-expressed ligands, offer powerful and previously untapped therapeutic potential. As a downstream regulator of TCR signaling, CISH controls T cell activation, expansion, and neoantigen reactivity. Though historically considered undruggable, recent advances in CRISPR engineering have enabled functional interrogation of these targets. We demonstrate that CISH deletion enhances T cell activation and anti-cancer functions more effectively than other emerging intracellular checkpoints. In CAR-T cells, CISH inactivation significantly increased sensitivity to tumor antigen, enabling robust recognition and killing even at low antigen levels, conditions that often lead to treatment failure with conventional T cell therapies, mirroring antigen escape scenarios seen in solid tumors. Our findings further validate CISH as a potent and druggable intracellular checkpoint capable of boosting anti-tumor T cell responses across diverse cancer types, independent of PD-L1 status. The underlying mechanisms of CISH inhibition may help explain the positive outcomes reported in recent clinical studies of this approach in solid tumor immunotherapy.

As a fundamental cognitive system with limited capacity, working memory (WM) strategically binds various features together to enhance its efficiency. However, the neural mechanisms governing feature binding in WM remain unsettled. Here, we employed functional magnetic resonance imaging combined with graph-based network analysis during a WM task in which participants maintained both color and location information throughout the delay period and subsequently detected and reported changes in color-location bindings versus individual features. Our results revealed a collaborative network that operates through a central workspace encompassing the somatomotor area, insula, and prefrontal cortex, underpinning the effective processing of bindings. Within these regions, we observed increased local efficiency and stronger connections during feature binding. Notably, connections within this workspace significantly correlated with behavioral performance. Among these regions, the somatomotor area, characterized by a shorter intrinsic timescale, responded more rapidly to visual input, carrying rich temporal information with more connections, and potentially served as the starting point during binding processes. These results highlight a dedicated workspace with sufficient and valid internal connections, facilitating successful binding through collaborative regional interactions.

Differences in the ϒ-aminobutyric acid (GABA) system contribute to an excitatory-inhibitory imbalance in autism, particularly affecting sensory processing. However, the brain's broader response to interventions targeting GABA pathways in individuals with autism remains poorly understood. This study tested the hypothesis that GABAergic control of information transfer across large-scale brain functional networks is altered in autism. We conducted a phase-amplitude coupling (PAC) analysis of resting-state EEG signals within and between these networks. Responses were compared after double-blind, randomized oral administration of either a placebo or 15/30 mg of arbaclofen, a GABA_B receptor agonist. Twenty-four non-autistic (9 males; 19-53 years) and 15 autistic participants (9 males; 20-51 years) completed 93 study visits. Autistic participants exhibited significantly higher theta-beta PAC, especially within the limbic network. High-dose arbaclofen shifted PAC metrics in visual and somatomotor networks towards non-autistic levels, but had minimal effects on networks related to higher cognitive functions. Interestingly, altered PAC within and between networks in the limbic system of autistic participants was normalized by low-dose arbaclofen, yet reemerged after high-dose administration. These findings provide compelling evidence for altered GABAergic responsivity in autism, helping explain some of the challenges in prescribing medications for autistic individuals, such as paradoxical reactions and dose sensitivity.