Biochemical Society transactions最新文献

It remains poorly resolved when and how motor cortical output directly influences limb muscle activity through descending projections, which impedes mechanistic understanding of cortical movement control. Here we addressed this in mice performing an ethologically inspired all-limb climbing behavior. We quantified the direct influence of forelimb primary motor cortex (caudal forelimb area, CFA) on muscle activity across the muscle activity states that occur during climbing. We found that CFA instructs muscle activity pattern, mainly by selectively activating certain muscles while exerting much smaller, bidirectional effects on their antagonists. From Neuropixel recordings, we identified linear combinations (components) of motor cortical activity that covary with these effects, finding that these components differ partially from those that covary with muscle activity and differ almost completely from those that covary with kinematics. Collectively, our results reveal an instructive direct motor cortical influence on limb muscles that is selective within a motor behavior and reliant on a distinct neural activity subspace.

Cryo-electron tomography (cryo-ET) has become a key technique for obtaining structures of macromolecular complexes in their native environment, assessing their local organization and describing the molecular sociology of the cell. While microorganisms and adherent mammalian cells are common targets for tomography studies, appropriate sample preparation and data acquisition strategies for larger cellular assemblies such as tissues, organoids or small model organisms have only recently become sufficiently practical to allow for in-depth structural characterization of such samples in situ. These advances include tailored lift-out approaches using focused ion beam (FIB) milling, and improved data acquisition schemes. Consequently, cryo-ET of FIB lamellae from large volume samples can complement ultrastructural analysis with another level of information: molecular anatomy. This review highlights the recent developments towards molecular anatomy studies using cryo-ET, and briefly outlines what can be expected in the near future.

Cell walls can confer amazing properties to plant cells, particularly if they have complex patterns. Complex cell wall patterns in the primary cell wall often lead to complex cell shapes, whereas in the secondary cell wall they lead to advanced material properties that prepare cells for mechanically demanding tasks. Not surprisingly, many of these structures are found in water transporting tissues. In this review, I compare the mechanisms controlling primary and secondary cell wall patterns, with emphasis on water transporting tissues and insights derived from modeling studies. Much of what we know about this is based on complex cell shapes and primary xylem patterns, leading to an emphasis on the Rho-of-plants - cortical microtubule - cellulose microfibril system for secondary cell wall patterning. There is a striking diversity of secondary cell wall patterns with important functional benefits, however, about which we know much less and that may develop in substantially different ways.

Multiple studies have highlighted the crucial role of mitochondrial bioenergetics in understanding the progression of cardiorenal diseases, revealing new potential treatment targets related to mitochondrial metabolism. There are well-established sexual dimorphisms in cardiac and renal physiology, with premenopausal females being generally protected from pathology compared with males. The mechanisms of this protection remain to be fully elucidated, however, they clearly depend, at least in part, on sex hormones. Sex hormones contribute to regulating mitochondrial function, and vice versa, highlighting the existence of a bidirectional relationship pivotal for cellular energy metabolism; however, there are still large gaps in knowledge when the sex differences in mitochondrial bioenergetics in health and disease are concerned. This manuscript provides an overview of the new evidence that has been accumulated regarding the role of sex hormones in renal and cardiac mitochondria-dependent cellular energetics, metabolism, and signaling, mainly focusing on the data obtained within the last 3-5 years. We briefly discuss mitochondrial function and different types of sex hormones for the reader and then focus on novel research underscoring the emerging mitochondrial pathways regulated by sex hormones, which might be of interest for the development of novel therapeutic strategies for cardiorenal conditions.

It is widely regarded that the anti-tumour immune response drives clearance of tumours and leads to prolonged survival in patients. However, tumours are adept at reprogramming the surrounding microenvironment to an immunosuppressive milieu to prevent successful immune directed killing. Adhesion of cells to the extracellular matrix is essential for regulating cellular processes such as survival, proliferation and migration. This adhesion is largely conducted via integrins and their related intracellular signalling networks. Adhesion proteins such as focal adhesion kinase (FAK) are expressed in both tumour cells and cells of the surrounding microenvironment, and are often dysregulated in cancers. Recent work has demonstrated that adhesion proteins are contributing to regulation of the immunosuppressive microenvironment within tumours, and could provide a new avenue to target in combination with immunotherapies. Here, we provide an overview of the effort being made to elucidate the roles adhesion proteins play in modulating anti-tumour responses within a variety of cancer settings. In particular we focus on the multifaceted role of FAK within the tumour immune microenvironment. Finally, we summarise the data in clinical trials, where targeting FAK is being exploited to prime the tumour microenvironment and create potent responses when combined with immunotherapies.

The 2-micron plasmid residing within the host budding yeast Saccharomyces cerevisiae nucleus serves as a model system for understanding the mechanism of segregation and stable maintenance of circular endogenously present extrachromosomal DNA in eukaryotic cells. The plasmid is maintained at a high average copy number (40-60 copies per yeast cell) through generations despite there is no apparent benefit to the host. Notably, the segregation mechanism of 2-micron plasmid shares significant similarities with those of bacterial low-copy-number plasmids and episomal forms of viral genomes in mammalian cells. These similarities include formation of a complex where the plasmid- or viral encoded proteins bind to a plasmid- or viral genome-borne locus, respectively and interaction of the complex with the host proteins. These together form a partitioning system that ensures stable symmetric inheritance of both these genomes from mother to daughter cells. Recent studies with substantial evidence showed that the 2-micron plasmid, like episomes of viruses such as Epstein-Barr virus, relies on tethering itself to the host chromosomes in a non-random fashion for equal segregation. This review delves into the probable chromosome hitchhiking mechanisms of 2-micron plasmid during its segregation, highlighting the roles of specific plasmid-encoded proteins and their interactions with host proteins and the chromosomes. Understanding these mechanisms provides broader insights into the genetic stability and inheritance of extrachromosomal genetic elements across diverse biological systems.

Cells exert forces on each other and their environment, shaping the tissue. The resulting mechanical stresses can be determined experimentally or estimated computationally using stress inference methods. Over the years, mechanical stress inference has become a non-invasive, low-cost computational method for estimating the relative intercellular stresses and intracellular pressures of tissues. This mini-review introduces and compares the static and dynamic modalities of stress inference, considering their advantages and limitations. To date, most software has focused on static inference, which requires only a single microscopy image as input. Although applicable in quasi-equilibrium states, this approach neglects the influence that cell rearrangements might have on the inference. In contrast, dynamic stress inference relies on a time series of microscopy images to estimate stresses and pressures. Here, we discuss both static and dynamic mechanical stress inference in terms of their physical, mathematical, and computational foundations and then outline what we believe are promising avenues for in silico inference of the mechanical states of tissues.

The pathophysiological mechanism involving the proteolytic processing of amyloid precursor protein (APP) and the generation of amyloid plaques is of significant interest in research on Alzheimer's disease (AD). The increasing significance of the downstream AD-related pathophysiological mechanisms has sparked research interest in other products of the APP processing cascades, including the APP intracellular domain (AICD). The potential importance of AICD in various cellular processes in the central nervous system has been established through the identification of its interactors. The interaction between AICD and its physiological binding partners is implicated in cellular events including regulation of transcriptional activity, cytoskeletal dynamics, neuronal growth, APP processing and cellular apoptosis. On the contrary, AICD is also implicated in neurodegeneration, which is a potential outcome of the functional fluctuation of AICD-mediated neuronal processes within the neuronal network. In this review, we summarize the neuronal functions and pathological manifestations of the dynamic AICD interaction network.

Hematopoietic stem cells (HSCs), essential for lifelong blood cell regeneration, are clinically utilized to treat various hematological disorders. These cells originate in the aorta-gonad-mesonephros region, expand in the fetal liver, and mature in the bone marrow. Chemotaxis, involving gradient sensing, polarization, and migration, directs HSCs and is crucial for their homing and mobilization. The molecular regulation of HSC chemotaxis involves chemokines, chemokine receptors, signaling pathways, and cytoskeletal proteins. Recent advances in understanding these regulatory mechanisms have deepened insights into HSC development and hematopoiesis, offering new avenues for therapeutic innovations. Strategies including glucocorticoid receptor activation, modulation of histone acetylation, stimulation of nitric oxide signaling, and interference with m6A RNA modification have shown potential in enhancing CXCR4 expression, thereby improving the chemotactic response and homing capabilities of human HSCs. This review synthesizes current knowledge on the molecular regulation of human HSC chemotaxis and its implications for health and disease.

The adrenal medulla is a key effector of the sympathetic nervous system in the periphery. Its primary function is to translate variations in sympathetic activity into hormone outputs that modify end organ function throughout the body. These hormones include epinephrine, norepinephrine, and a variety of vasoactive peptides. Hormone secretion occurs when neurotransmitters, delivered by sympathetic nerves, bind to, and activate receptors on adrenomedullary chromaffin cells. In this context, two neurotransmitters of particular importance are acetylcholine (ACh) and pituitary adenylate cyclase activating polypeptide (PACAP). PACAP, discovered initially as a secretagogue in the hypothalamus, is now appreciated to provoke a strong secretory response from chromaffin cells in vitro and in situ. However, the cellular mechanisms underlying PACAP-stimulated secretion are still poorly understood. In the sections below, we will summarize what is known about the actions of PACAP in the adrenal medulla, discuss recent advances that pertain to the PACAP signaling pathway, and highlight areas for future investigation.