Bioessays. 2025 Mar 31:e70004. doi: 10.1002/bies.70004. Online ahead of print.

ABSTRACT

Recent studies show the importance of mesoscale changes to plasma membrane (PM) topography during cell shape change. Local folding and flattening of the cell surface is mechanosensitive, changing in response to both microenvironment structural elements and intracellular cytoskeletal activities. These topography changes elicit local mechanical signaling events that act in conjunction with molecular signal transduction pathways to remodel the cell cortex. Experimental manipulations of local PM curvature show its sufficiency for recruiting Arp2/3 actin network induction pathways. Additionally, studies of diverse cell shape changes-ranging from neutrophil migration to early Drosophila embryo cleavage to neural stem cell asymmetric division-show that local generation of PM folding is linked with local Arp2/3 actin network induction, which then remodels the PM topography during dynamic control of cell structure. These examples are reviewed in detail, together with known and potential causes of PM topography changes, downstream effects, and higher-order feedback.

PMID:40159841 | DOI:10.1002/bies.70004

Commun Biol. 2025 Mar 30;8(1):522. doi: 10.1038/s42003-025-07906-2.

ABSTRACT

The Hsp70 chaperone system is capable of disassembling pathological aggregates such as amyloid fibres associated with serious degenerative diseases. Here we examine the role of the J-domain protein co-factor in amyloid disaggregation by the Hsc70 system. We used cryo-EM and tomography to compare the assemblies with wild-type DNAJB1 or inactive mutants. We show that DNAJB1 binds regularly along α-synuclein amyloid fibrils and acts in a 2-step recruitment of Hsc70, releasing DNAJB1 auto-inhibition before activating Hsc70 ATPase. The wild-type DNAJB1:Hsc70:Apg2 complex forms dense arrays of chaperones on the fibrils, with Hsc70 on the outer surface. When the auto-inhibition is removed by mutating DNAJB1 (ΔH5 DNAJB1), Hsc70 is recruited to the fibrils at a similar level, but the ΔH5 DNAJB1:Ηsc70:Apg2 complex is inactive, binds less regularly to the fibrils and lacks the ordered clusters. Therefore, we propose that 2-step activation of DNAJB1 regulates the ordered assembly of Hsc70 on the fibril. The localised, dense packing of chaperones could trigger a cascade of recruitment and activation to give coordinated, sequential binding and disaggregation from an exposed fibril end, as previously observed in AFM videos. This mechanism is likely to be important in maintaining a healthy cellular proteome into old age.

PMID:40159506 | DOI:10.1038/s42003-025-07906-2

Tree Physiol. 2025 Mar 30:tpaf038. doi: 10.1093/treephys/tpaf038. Online ahead of print.

ABSTRACT

Phosphorus (P) deficiency is critical to the renewal barrier of she-oak (Casuarina equisetifolia), an important tree species used for coastal protection. However, the response of she-oak to P deficiency remains unclear. In this study, we compared the phenotypes of two she-oak cultivars, the P deficiency-sensitive 'Chihu219' and the insensitive 'Chihu397', and found that P deficiency significantly increased root growth, P concentration and P absorption efficiency (PAE) in Chihu219, but not in Chihu397. We also analyzed the transcriptome and metabolome of these cultivars under different P conditions and showed that trans-zeatin riboside (tZR) levels were highly suppressed by P deficiency in Chihu219, but not in Chihu397. Furthermore, exogenous tZR suppressed both root P concentration and PAE while promoting phosphorus use efficiency (PUE). We also identified CeIPT5 (isopentenyltransferase 5) as a key regulatory gene of tZR biosynthesis and found that its expression was more highly induced by P deficiency in Chihu219 than in Chihu397. We also showed that overexpression of CeIPT5 in insensitive she-oak lines reduced tZR concentration and increased root P concentration compared to the vector control. Taken together, P deficiency can greatly reduce tZR accumulation in P deficiency-insensitive she-oak at least by activating the tZR accumulation regulatory gene, CeIPT5, thereby promoting root elongation and P concentration. This study not only provides a genetic basis for enhancing PAE in woody plants, but also establishes a theoretical basis for optimizing root structure and improving nutrient utilization efficiency, thereby promoting sustainable forestry development.

PMID:40159239 | DOI:10.1093/treephys/tpaf038

Gut Microbes. 2025 Dec;17(1):2485326. doi: 10.1080/19490976.2025.2485326. Epub 2025 Mar 30.

ABSTRACT

Gastrointestinal symptoms are common during infancy, including infantile colic. Colic can be loosely defined as prolonged and recurrent crying without obvious cause. The cause indeed remains unclear despite much research. Results on infant nutrition are inconclusive, but prior work has linked maternal mental health to infant crying. Recently, several small studies have described associations between gut microbiota and colic. We used a larger cohort to examine the role of the microbiota in infant gastrointestinal health, while also accounting for other biopsychosocial factors. Using fecal 16S rRNA gene amplicon sequencing data from 1,012 infants in the KOALA birth cohort, we examined associations between the 1-month gut microbiota and parent-reported functional gastrointestinal symptoms throughout infancy, including colic, constipation, and cramps. These analyses were adjusted for biopsychosocial factors that were associated with symptoms in a broader analysis involving 2,665 participants. In 257 infants, we also explored associations between breastmilk human milk oligosaccharides (HMOs) and gastrointestinal symptoms. Higher relative abundance of Staphylococcus at one month was associated with less constipation in the first three months of life. Conversely, Ruminococcus gnavus group abundance was associated with more colicky symptoms, particularly between four and seven months. Breastmilk concentrations of the HMOs lacto-N-hexaose (LNH) and lacto-N-neohexaose (LNnH) were associated with less constipation in the first three months. Our results support the conclusion that gut microbiota are relevant in infantile colic and constipation. However more work is needed to elucidate the underlying mechanisms, and explore their interplay with other relevant biopsychosocial factors such as maternal mental health.

PMID:40159147 | DOI:10.1080/19490976.2025.2485326

Antiviral Res. 2025 Mar 28:106154. doi: 10.1016/j.antiviral.2025.106154. Online ahead of print.

ABSTRACT

IPB29 is a lipopeptide-based coronavirus fusion inhibitor with the potent, broad-spectrum antiviral activity, and it has already been advanced to phase III clinical trials for the treatment of SARS-CoV-2 infection. We recently reported its design strategy and initial preclinical characterization; herein, we focused on characterizing its efficacies against newly-emerged Omicron variants, as well as its chronic general toxicity, toxicokinetics, immunogenicity, and reproductive toxicity in animal models. As anticipated, IPB29 demonstrated improved activity in inhibiting JN.1 and KP.2 variants, effectively blocking cell fusion and pseudovirus infections. Nebulized inhalation of IPB29 exhibited high therapeutic efficacy against live BA.5 and EG.5.1 infections in Syrian hamsters. The 26-week toxicity studies revealed that nebulized IPB29 has a favorable safety profile, with well-characterized toxicokinetics in SD rats and Beagle dogs. Notably, short-term nebulization of IPB29 did not elicit anti-drug antibody (ADA) responses in either species. However, IPB29-specific antibodies were detected after long-term administration. Finally, a three-stage reproductive toxicity study in SD rats indicated that IPB29 had no significant toxic effects on fertility, embryo-fetal development, or the development of offspring. In summary, our findings demonstrate that IPB29 is a safe and effective SARS-CoV-2 inhibitor with promising potential for clinical applications.

PMID:40158858 | DOI:10.1016/j.antiviral.2025.106154

Biomed Environ Sci. 2025 Feb 20;38(2):230-247. doi: 10.3967/bes2025.010.

ABSTRACT

The structure of intestinal tissue is complex. In vitro simulation of intestinal structure and function is important for studying intestinal development and diseases. Recently, organoids have been successfully constructed and they have come to play an important role in biomedical research. Organoids are miniaturized three-dimensional (3D) organs, derived from stem cells, which mimic the structure, cell types, and physiological functions of an organ, making them robust models for biomedical research. Intestinal organoids are 3D micro-organs derived from intestinal stem cells or pluripotent stem cells that can successfully simulate the complex structure and function of the intestine, thereby providing a valuable platform for intestinal development and disease research. In this article, we review the latest progress in the construction and application of intestinal organoids.

PMID:40159175 | DOI:10.3967/bes2025.010

Cell Rep. 2025 Mar 28;44(4):115476. doi: 10.1016/j.celrep.2025.115476. Online ahead of print.

ABSTRACT

The clustering of multiple transcription factor binding sites (TFBSs) for the same TF has proved to be a pervasive feature of cis-regulatory elements in the eukaryotic genome. However, the contribution of binding sites within the homotypic clusters of TFBSs (HCTs) to TF binding and target gene expression remains to be understood. Here, we characterize the CHD4 enhancers that harbor unique functional ZNF410 HCTs genome wide. We uncover that ZNF410 controls chromatin accessibility and activity of the CHD4 enhancer regions. We demonstrate that ZNF410 binds to the HCTs in a collaborative fashion, further conferring transcriptional activation. In particular, three ZNF410 motifs (sub-HCTs) located at 3' end of the distal enhancer act as "switch motifs" to control chromatin accessibility and enhancer activity. Mechanistically, the SWI/SNF complex is selectively required to mediate cooperative ZNF410 binding for CHD4 expression. Together, our findings expose a complex functional hierarchy of homotypic clustered motifs, which cooperate to fine-tune target gene expression.

PMID:40158221 | DOI:10.1016/j.celrep.2025.115476

Commun Eng. 2025 Mar 29;4(1):59. doi: 10.1038/s44172-025-00399-1.

NO ABSTRACT

PMID:40158063 | DOI:10.1038/s44172-025-00399-1

Sci Rep. 2025 Mar 29;15(1):10897. doi: 10.1038/s41598-025-95633-3.

ABSTRACT

Lung cancer is the leading cause of cancer-related deaths globally, with radiotherapy as a key treatment modality for inoperable cases. Lactate, once considered a by-product of anaerobic cellular metabolism, is now considered critical for cancer progression. Lactate dehydrogenase B (LDHB) converts lactate to pyruvate and supports mitochondrial metabolism. In this study, a re-analysis of our previous transcriptomic data revealed that LDHB silencing in the NSCLC cell lines A549 and H358 dysregulated 1789 genes, including gene sets associated with cell cycle and DNA repair pathways. LDHB silencing increased H2AX phosphorylation, a surrogate marker of DNA damage, and induced cell cycle arrest at the G1/S or G2/M checkpoint depending on the p53 status. Long-term LDHB silencing sensitized A549 cells to radiotherapy, resulting in increased DNA damage and genomic instability as evidenced by increased H2AX phosphorylation levels and micronuclei accumulation, respectively. The combination of LDHB silencing and radiotherapy increased protein levels of the senescence marker p21, accompanied by increased phosphorylation of Chk2, suggesting persistent DNA damage. Metabolomics analysis revealed that LDHB silencing decreased nucleotide metabolism, particularly purine and pyrimidine biosynthesis, in tumor xenografts. Nucleotide supplementation partially attenuated DNA damage caused by combined LDHB silencing and radiotherapy. These findings suggest that LDHB supports metabolic homeostasis and DNA damage repair in NSCLC, while its silencing enhances the effects of radiotherapy by impairing nucleotide metabolism and promoting persistent DNA damage.

PMID:40158058 | DOI:10.1038/s41598-025-95633-3

Sci Rep. 2025 Mar 29;15(1):10856. doi: 10.1038/s41598-025-95738-9.

ABSTRACT

SF3B1 gene mutations are prevalent in myelodysplastic syndrome (MDS) and define a distinct disease subtype. These mutations are associated with dysregulated genes and pathways, offering potential for novel therapeutic approaches. However, the aberrant mRNA alternative splicing landscape in SF3B1-deficient MDS cells remains underexplored. In this study, we investigated the influence of SF3B1 gene alterations on the pre-mRNA splicing landscape in MDS cells using transcriptomic data from two independent MDS cohorts. we identified over 5000 significant differential alternative splicing events associated with SF3B1 mutation. This work corroborates previous studies, showing significant enrichment of MYC activity and heme metabolism in SF3B1 mutant cells. A key novel finding of this study is the identification of a gene expression signature driven by SF3B1 mutations, centered on protein post-translational modifications. Notably, we discovered aberrant alternative splicing of the tumor suppressor gene UBA7, leading to significantly reduced gene expression. This dysregulation implicates UBA7 as a critical player in MDS pathogenesis. Importantly, the clinical relevance of this finding is underscored by the observation that low UBA7 gene expression was associated with poor overall survival in chronic lymphocytic leukemia (CLL), another hematological malignancy with frequent SF3B1 mutations. Furthermore, a similar association between low UBA7 gene expression and poor survival outcomes was observed across multiple tumor types in the TCGA database, highlighting the broader implications of UBA7 dysregulation in cancer biology. These findings provide new insights into the mechanisms by which SF3B1 mutations reshape the pre-mRNA splicing landscape and drive disease pathogenesis in MDS. Furthermore, they underscore the potential of UBA7 as a biomarker to stratify SF3B1-mutant MDS and CLL patients, offering a refined approach for risk assessment and highlighting opportunities for targeted therapeutic interventions.

PMID:40158006 | DOI:10.1038/s41598-025-95738-9

Nat Commun. 2025 Mar 29;16(1):3065. doi: 10.1038/s41467-025-58259-7.

ABSTRACT

Enzymes are essential catalysts in biological systems. Substrate inhibition, once dismissed, is now observed in 20% of enzymes1 and is attributed to the formation of an unproductive enzyme-substrate complex, with no structural evidence of unproductivity provided to date1-6. This study uncovers the molecular mechanism of substrate inhibition in tobacco glucosyltransferase NbUGT72AY1, which transfers glucose to phenols for plant protection. The peculiarity that β-carotene strongly attenuates the substrate inhibition of NbUGT72AY1, despite being a competitive inhibitor, allows to determine the conformational changes that occur during substrate binding in both active and substrate-inhibited complexes. Crystallography reveals structurally different ternary enzyme-substrate complexes that do not conform to classical mechanisms. An alternative pathway suggests substrates bind randomly, but the reaction occurs only if a specific order is followed (asymmetric cooperativity). This unreported paradigm explains substrate inhibition and reactivation by competitive inhibitors, opening new research avenues in metabolic regulation and industrial applications.

PMID:40157902 | DOI:10.1038/s41467-025-58259-7

Biotechnol Adv. 2025 Mar 27:108568. doi: 10.1016/j.biotechadv.2025.108568. Online ahead of print.

ABSTRACT

Curcumin, a natural compound found in turmeric, has shown promise in treating brain-related diseases and conditions associated with aging. Curcumin has shown multiple anti-inflammatory and brain-protective effects, but its clinical use is limited by challenges like poor absorption, specificity and delivery to the right tissues. A range of contemporary approaches at the intersection with bioengineering and systems biology are being explored to address these challenges. Data from preclinical and human studies highlight various neuroprotective actions of curcumin, including the inhibition of neuroinflammation, modulation of critical cellular signaling pathways, promotion of neurogenesis, and regulation of dopamine levels. However, curcumin's multifaceted effects - such as its impact on microRNAs and senescence markers - suggest novel therapeutic targets in neurodegeneration. Tetrahydrocurcumin, a primary metabolite of curcumin, also shows potential due to its presence in circulation and its anti-inflammatory properties, although further research is needed to elucidate its neuroprotective mechanisms. Recent advancements in delivery systems, particularly brain-targeting nanocarriers like polymersomes, micelles, and liposomes, have shown promise in enhancing curcumin's bioavailability and therapeutic efficacy in animal models. Furthermore, the exploration of drug-laden scaffolds and dermal delivery may extend the pharmacological applications of curcumin. Studies reviewed here indicate that engineered dermal formulations and devices could serve as viable alternatives for neuroprotective treatments and to manage skin or musculoskeletal inflammation. This work highlights the need for carefully designed, long-term studies to better understand how curcumin and its bioactive metabolites work, their safety, and their effectiveness.

PMID:40157560 | DOI:10.1016/j.biotechadv.2025.108568

Gastroenterology. 2025 Mar 27:S0016-5085(25)00540-2. doi: 10.1053/j.gastro.2025.03.018. Online ahead of print.

NO ABSTRACT

PMID:40157433 | DOI:10.1053/j.gastro.2025.03.018

Cell Metab. 2025 Mar 25:S1550-4131(25)00104-4. doi: 10.1016/j.cmet.2025.03.001. Online ahead of print.

ABSTRACT

Aging affects reproductive capabilities in males through physiological and behavioral alterations, including endocrine changes and decreased libido. In this study, we investigated the influence of intermittent fasting (IF) on these aging-related declines, using male C57BL/6J mice. Our findings revealed that IF significantly preserved reproductive success in aged mice, not by improving traditional reproductive metrics such as sperm quality or endocrine functions but by enhancing mating behavior. This behavioral improvement was attributed to IF's ability to counter age-dependent increases in serotonergic inhibition, primarily through the decreased supply of the serotonin precursor tryptophan from the periphery to the brain. Our research underscores the potential of dietary interventions like IF in mitigating age-associated declines in male reproductive health and suggests a novel approach to managing conditions related to reduced sexual desire, highlighting the complex interplay between diet, metabolism, and reproductive behavior.

PMID:40157367 | DOI:10.1016/j.cmet.2025.03.001

Sci Total Environ. 2025 Mar 28;974:179243. doi: 10.1016/j.scitotenv.2025.179243. Online ahead of print.

ABSTRACT

Deforestation is one of the main drivers of environmental degradation around the world. Slash-and-burn is a common practice, performed in tropical forests to create new agricultural lands for local communities. In Madagascar, this practice affects many natural areas that host lemur habitats. Reforestation within nature reserves including fast-growing native species is desirable, for example in this area using native bamboo with the aim of restoring the habitat increased plantation success. In this context, the extensive detection of forest disturbances can effectively support restoration actions, providing an overall framework to address priorities and maximizing ecological benefits. In this work and with respect to a study area located around the Maromizaha New Protected Area (Madagascar), an analysis was conducted based on a time series of NDVI maps from Landsat missions (GSD = 30 m). The period between 1991 and 2022 was investigated to detect the location and moment of forest disturbances with the additional aim of quantifying the level of damage and of the recovery process at every disturbed location. It is worth noting that the Maromizaha New Protected Area currently hosts 12 species of endangered lemurs, highlighting its pivotal role as a critical conservation and restoration priority due to the ecological significance of preserving habitat integrity to sustain these threatened species. Detection was operated at pixel level by analyzing the local temporal profile of Normalized Difference Vegetation Index - NDVI (yearly step). Time of the eventual detected disturbance was found within the profile looking for the first derivative minimum. Significance of NDVI change was evaluated testing the Chebyshev condition and the following parameters mapped: i) year of disturbance; ii) significance of NDVI change; iii) level of damage; (iv) year of vegetation recovery; (v) rate of recovery. Accordingly, the level of the damage and the rate of recovery were used to estimate resistance and resilience indices of lemurs' habitat (inherently forested areas). Finally, temporal trends of both forest loss and recovery were analyzed to investigate potential impacts onto local lemur populations and, more in general, to the entire Reserve.

PMID:40157089 | DOI:10.1016/j.scitotenv.2025.179243

Curr Opin Biotechnol. 2025 Mar 28;93:103297. doi: 10.1016/j.copbio.2025.103297. Online ahead of print.

ABSTRACT

Oleaginous yeast are remarkably versatile organisms, distinguished by their natural capacities to accumulate high levels of neutral lipids and broad substrate range. With recent growing interests in engineering non-model organisms as superior biomanufacturing platforms, oleaginous yeasts have emerged as promising chassis for oleochemicals, terpenoids, organic acids, and other valuable products. Advancement in systems biology along with genetic tool development have significantly expanded our understanding of the metabolism in these species and enabled engineering efforts to produce biofuels and bioproducts from diverse feedstocks. This review examines the latest technical advances in oleaginous yeast research toward sustainable biomanufacturing. We cover recent developments in systems biology-enabled metabolism understanding, genetic tools, feedstock utilization, and strain engineering approaches for the production of various valuable chemicals.

PMID:40157044 | DOI:10.1016/j.copbio.2025.103297

Br J Surg. 2025 Mar 28;112(4):znaf051. doi: 10.1093/bjs/znaf051.

NO ABSTRACT

PMID:40156895 | DOI:10.1093/bjs/znaf051

Nat Rev Genet. 2025 Mar 28. doi: 10.1038/s41576-025-00828-z. Online ahead of print.

ABSTRACT

Transcriptome sequencing revolutionized the analysis of gene expression, providing an unbiased approach to gene detection and quantification that enabled the discovery of novel isoforms, alternative splicing events and fusion transcripts. However, although short-read sequencing technologies have surpassed the limited dynamic range of previous technologies such as microarrays, they have limitations, for example, in resolving full-length transcripts and complex isoforms. Over the past 5 years, long-read sequencing technologies have matured considerably, with improvements in instrumentation and analytical methods, enabling their application to RNA sequencing (RNA-seq). Benchmarking studies are beginning to identify the strengths and limitations of long-read RNA-seq, although there remains a need for comprehensive resources to guide newcomers through the intricacies of this approach. In this Review, we provide a comprehensive overview of the long-read RNA-seq workflow, from library preparation and sequencing challenges to core data processing, downstream analyses and emerging developments. We present an extensive inventory of experimental and analytical methods and discuss current challenges and prospects.

PMID:40155769 | DOI:10.1038/s41576-025-00828-z

Nat Commun. 2025 Mar 28;16(1):3042. doi: 10.1038/s41467-025-58073-1.

ABSTRACT

Mycobacteria harbor a proteasome that was acquired by Actinobacteria through horizontal gene transfer and that supports the persistence of the human pathogen Mycobacterium tuberculosis within host macrophages. The core particle of the proteasome (20S CP) associates with ring-shaped activator complexes to degrade protein substrates. One of these is the bacterial proteasome activator Bpa that stimulates the ATP-independent proteasomal degradation of the heat shock repressor HspR. In this study, we determine the cryogenic electron microscopy 3D reconstruction of the complex between Bpa and its natural substrate HspR at 4.1 Å global resolution. The resulting maps allow us to identify regions of Bpa that interact with HspR. Using structure-guided site-directed mutagenesis and in vitro biochemical assays, we confirm the importance of the identified residues for Bpa-mediated substrate recruitment and subsequent proteasomal degradation. Additionally, we show that the dodecameric Bpa ring associates asymmetrically with the heptameric α-rings of the 20S CP, adopting a conformation resembling a hinged lid, while still engaging all seven docking sites on the proteasome.

PMID:40155375 | DOI:10.1038/s41467-025-58073-1

Cancer Cell. 2025 Mar 20:S1535-6108(25)00108-4. doi: 10.1016/j.ccell.2025.03.007. Online ahead of print.

ABSTRACT

Myeloid cancers such as myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) remain resistant to standard of care (SOC) and targeted therapies. In this study, we demonstrate that responsiveness to therapy is associated with activation of β-catenin-JAG1 in osteoblastic cells of patients treated with all-trans-retinoic acid (ATRA). ATRA suppresses β-catenin activity in patients and leukemic mice. Consequently, it inhibits the growth and survival of MDS/AML cells from patients with active β-catenin-JAG1 signaling and promotes their differentiation. This occurs independently of cytogenetics and mutational profile. ATRA also improves disease outcome in mice with no evidence of relapse and a superior safety profile to SOC. A human anti-JAG1 antibody improves efficacy in leukemic mice and patient-derived MDS/AML cells. β-catenin activation provides an explanation for the differential response to ATRA and a mechanistic biomarker for ATRA repurposing in myeloid malignancies, potentially evading relapse and extending across a broad range of cancers.

PMID:40154481 | DOI:10.1016/j.ccell.2025.03.007