Open Biology最新文献

Social deficits play a role in numerous psychiatric, neurological and neurodevelopmental disorders. Relating complex behaviour, such as social interaction, to brain activity remains one of the biggest goals and challenges in neuroscience. Availability of standardized tests that assess social preference is however, limited. Here, we present a novel behavioural paradigm that we developed to measure social behaviour, the modified elevated gap interaction test (MEGIT). In this test, animals are placed on one of two elevated platforms separated by a gap, in which they can engage in whisker interaction with either a conspecific or an object. This allows quantification of social preference in real interaction rather than just proximity and forms an ideal setup for social behaviour-related neuronal recordings. We provide a detailed description of the paradigm and its highly reliable, deep-learning based analysis, and show results obtained from wild-type animals as well as mouse models for disorders characterized by either hyposocial (autism spectrum disorder; ASD) or hypersocial (Williams Beuren syndrome; WBS) behaviour. Wild-type animals show a clear social preference. This preference is significantly smaller in an ASD mouse model, whereas it is larger in WBS mice. The results indicate that MEGIT is a sensitive and reliable test for detecting social phenotypes.

Intensive agricultural practices impact the health and nutrition of pollinators like honey bees (Apis mellifera). Rapeseed (Brassica napus L.) is widely cultivated, providing diverse nutrients and phytochemicals, including S-methyl-L-cysteine sulfoxide (SMCSO). While the nutritional impact of rapeseed on bees is known, SMCSO's effects remain unexplored. We examined SMCSO and its related metabolites-3-methylthiolactic acid sulfoxide and N-acetyl-S-methyl-L-cysteine sulfoxide-analysing their seasonal fluctuations, colony variations and distribution in body parts. Our findings showed that these compounds in bee gut vary among colonies, possibly due to the dietary preferences, and are highly concentrated in bodies during the summer. They are distributed differently within bee bodies, with higher concentrations in the abdomens of foragers compared with nurses. Administration of SMCSO in a laboratory setting showed no immediate toxic effects but significantly boosted bees' antioxidant capacity. Long-term administration decreased bee body weight, particularly in the thorax and head, and altered amino acid metabolism. SMCSO is found in the nectar and pollen of rapeseed flowers and highly accumulates in rapeseed honey compared with other types of honey. This study reveals the dual impact of SMCSO on bee health, providing a basis for further ecological and physiological research to enhance bee health and colony sustainability.

Juvenile hormone (JH) is one of the most essential hormones controlling insect metamorphosis and physiology. While it is well known that JH affects many tissues throughout the insect life cycle, the difference in JH responsiveness and the repertoire of JH-inducible genes among different tissues has not been fully investigated. In this study, we monitored JH responsiveness in vivo using transgenic Drosophila melanogaster flies carrying a JH response element-GFP (JHRE-GFP) construct. Our data highlight the high responsiveness of the epithelial cells within the seminal vesicle, a component of the male reproductive tract, to JH. Specifically, we observe an elevation in the JHRE-GFP signal within the seminal vesicle epithelium upon JH analogue administration, while suppression occurs upon knockdown of a gene encoding the intracellular JH receptor, germ cell-expressed. Starting from published transcriptomic and proteomics datasets, we next identified Lactate dehydrogenase as a JH-response gene expressed in the seminal vesicle epithelium, suggesting insect seminal vesicles undergo metabolic regulation by JH. Together, this study sheds new light on the biology of the insect reproductive regulatory system.

Approximately 10-15% of human cancers are telomerase-negative and maintain their telomeres through a recombination-based process known as the alternative lengthening of telomeres (ALT) pathway. Loss of the alpha-thalassemia/mental retardation, X-linked (ATRX) chromatin remodeller is a common event in ALT-positive cancers, but is generally insufficient to drive ALT induction in isolation. We previously demonstrated that ATRX binds to the MRN complex, which is also known to be important in the ALT pathway, but the molecular basis of this interaction remained elusive. Here, we demonstrate that the interaction between ATRX and MRN is dependent on the N-terminal forkhead-associated and BRCA1 C-terminal domains of NBS1, analogous to the previously reported NBS1-MDC1 interaction. A number of conserved 'SDT-like' motifs (serine and threonine residues with aspartic/glutamic acid residues at proximal positions) in the central unstructured region of ATRX were found to be crucial for the ATRX-MRN interaction. Furthermore, treatment with a casein kinase 2 inhibitor prevented the ability of ATRX to bind MRN, suggesting that phosphorylation of these residues by casein kinase 2 is also important for the interaction. Finally, we show that a functional ATRX-MRN interaction is important for the ability of ATRX to prevent induction of ALT hallmarks in the presence of chemotherapeutically induced DNA-protein crosslinks, and might also have implications for individuals with ATR-X syndrome.

Retinal dystrophy, optic nerve oedema, splenomegaly, anhidrosis and migraine headache (ROSAH) syndrome is an autosomal dominant disorder and to date is known to be caused by either the Thr237Met or Tyr254Cys variant in the protein kinase ALPK1. Here, we identify a family in which ROSAH syndrome is caused by a novel variant in which Ser277 is changed to Phe. All six patients examined display ocular inflammation and optic nerve elevation, four have retinal degeneration and four are registered blind. In contrast to wild-type ALPK1, which is activated specifically by bacterial ADP-heptose, ALPK1[Ser277Phe] is also activated by the human metabolites UDP-mannose and ADP-ribose and more strongly than the most frequent ROSAH-causing variant (ALPK1[Thr237Met]) but, unlike ALPK1[Thr237Met], ALPK1[Ser277Phe] is also activated by GDP-mannose. These observations can explain why ALPK1 variants causing ROSAH syndrome display constitutive activity in human cells. The side chains of Ser277 and Tyr254 interact in the crystal structure of ALPK1, but mutational analysis established that it is not the loss of this hydrogen bond between Ser277 and Tyr254 that alters the specificity of the ADP-heptose-binding pocket in the Ser277Phe and Tyr254Cys variants. The characterization of ALPK1 variants that cause ROSAH syndrome suggests ways in which drugs that selectively inhibit these disease-causing variants may be developed.

Proline-rich antimicrobial peptides (PrAMPs) have gained attention due to their antimicrobial properties and low cytotoxicity. B7-005, a small optimized PrAMP, exhibits a broader spectrum of activity than native PrAMPs, due to an antimicrobial mechanism based on inhibiting prokaryotic protein synthesis and destabilizing bacterial membranes. However, the toxicity and the in vivo efficacy of B7-005 remain poorly understood, so in vitro and in vivo microbiology and toxicology experiments were used to assess its suitability as an anti-infective agent. The incidence of resistance towards B7-005 by E. coli was lower than for other PrAMPs and antibiotics; moreover, it maintained antimicrobial activity in the presence of human serum. B7-005 exerted its antimicrobial effect at a much lower concentration than those causing harmful effects on four different cell types, such as membrane permeabilization or non-lytic depolarization of mitochondria. The latter effect may be related to the inhibition of eukaryotic protein synthesis by B7-005 observed in vitro. In a zebrafish embryo model, B7-005 was well tolerated and reduced mortality from pre-existing E. coli bacteraemia. Overall, B7-005 was safe for human cells and effective against systemic infection in vivo, making it a promising lead for developing new antibiotics.

The recently discovered Provora supergroup has primarily been examined to determine their phylogenomic position in the eukaryotic tree. Their morphology is more poorly studied, and here we focus on their cellular organization and how it compares with that of other supergroups. These small eukaryovorous flagellates exhibit several ultrastructural features that are also found in a subset of taxa from a wide variety of deep-branching lineages (Stramenopiles, Alveolata, Hemimastigophora, Malawimonadidae, Discoba and Metamonada), including vesicles beneath the plasmalemma, two opposing vanes on the flagella, a ventral feeding groove and a fibrillar system resembling the excavate type. Additionally, we identified four main microtubular roots (r1-r4) and a singlet root between r1 and r2, which support the strong feeding apparatus resembling 'jaws'. Their unique extrusive organelles (ampulosomes) have a similar organization to Hemimastigophora extrusomes, but most of their cell characteristics most closely resemble features of the TSAR + Haptista grouping. We also describe a new species, Nibbleromonas piranha sp. nov., and highlight features of its feeding behaviour, which can be so aggressive as to result in cannibalism.

Two structurally unrelated small molecule chemotypes, represented by compounds PAV-617 and PAV-951, with antiviral activity in cell culture against Mpox virus (formerly known as monkeypox virus) and human immunodeficiency virus (HIV) respectively, were studied for anti-cancer efficacy. Each exhibited apparent pan-cancer cytotoxicity with reasonable pharmacokinetics. Non-toxicity is demonstrated in a non-cancer cell line and in mice at doses achieving drug exposure at active concentrations. Anti-tumour properties of both chemotypes were validated in mouse xenografts against A549 human lung cancer and, for one of the chemotypes, against HT-29 colorectal cancer. The targets of these compounds are unconventional: each binds to a different transient, energy-dependent multi-protein complex. Treatment with these compounds alters the target multi-protein complexes in a manner that appears to remove a block, crucial for cancer survival and progression, on a homeostatic linkage between uncontrolled proliferation and apoptosis. These compounds provide starting points for development of novel, next-generation, non-toxic, pan-cancer therapeutics.

Hereditary spastic paraplegias (HSPs) are a diverse set of neurological disorders characterized by progressive spasticity and weakness in the lower limbs caused by damage to the axons of the corticospinal tract. More than 88 genetic mutations have been associated with HSP, yet the mechanisms underlying these disorders are not well understood. We replicated the pathophysiology of one form of HSP known as spastic paraplegia 15 (SPG15) in zebrafish. This disorder is caused in humans by mutations in the ZFYVE26 gene, which codes for a protein called SPASTIZIN. We show that, in zebrafish, the significant reduction of Spastizin caused degeneration of large motor neurons. Motor neuron degeneration is associated with axon demyelination in the spinal cord and impaired locomotion in the spastizin mutants. Our findings reveal that the reduction in Spastizin compromises axonal integrity and affects the myelin sheath, ultimately recapitulating the pathophysiology of HSPs.