Curr Biol. 2023 Nov 13:S0960-9822(23)01451-3. doi: 10.1016/j.cub.2023.10.050. Online ahead of print.

ABSTRACT

Embryos develop in a surrounding that guides key aspects of their development. For example, the anteroposterior (AP) body axis is always aligned with the geometric long axis of the surrounding eggshell in fruit flies and worms. The mechanisms that ensure convergence of the AP axis with the long axis of the eggshell remain unresolved. We investigate axis convergence in early C. elegans development, where the nascent AP axis, when misaligned, actively re-aligns to converge with the long axis of the egg. We identify two physical mechanisms that underlie axis convergence. First, bulk cytoplasmic flows, driven by actomyosin cortical flows, can directly reposition the AP axis. Second, active forces generated within the pseudocleavage furrow, a transient actomyosin structure similar to a contractile ring, can drive a mechanical re-orientation such that it becomes positioned perpendicular to the long axis of the egg. This in turn ensures AP axis convergence. Numerical simulations, together with experiments that either abolish the pseudocleavage furrow or change the shape of the egg, demonstrate that the pseudocleavage-furrow-dependent mechanism is a major driver of axis convergence. We conclude that active force generation within the actomyosin cortical layer drives axis convergence in the early nematode.

PMID:37979577 | DOI:10.1016/j.cub.2023.10.050

Talanta. 2023 Nov 7;269:125398. doi: 10.1016/j.talanta.2023.125398. Online ahead of print.

ABSTRACT

Due to the ever-increasing challenge of emerging and reemerging infections on global health, the development of POCT tools has been propelled. However, conventional point-of-care testing methods suffer from several limitations, including cumbersome operation, long detection times, and low accuracy, which hamper their widespread application. Compared to traditional disease diagnostic equipment, mobile health platforms offer several advantages, including portability, ease of operation, and automated analysis of detection results through recognition algorithms. Consequently, they hold great promise for the future. Here, we developed a smartphone-based centrifugal mHealth platform implementing daisy-shaped quick response chip for hematocrit measurement. The centrifugal microfluidic chip is combined with a smartphone through a back-clip-on mobile phone adapter whose control circuit is designed with low power consumption to enable the platform to operate without requiring a high-power source that is inconvenient to carry, thereby achieving the goal of portability. Concurrently, we designed a quick response chip featuring a unique hollow daisy structure that is in line with the properties of hematocrit detection. The distinctive configuration of the chip enables adequate centrifugal force to be supplied for hematocrit detection. Additionally, our customized quick response code recognition algorithm is able to recognize this chip, facilitating non-experts in performing hematocrit intelligent recognition with their smartphones.

PMID:37979508 | DOI:10.1016/j.talanta.2023.125398

Biomed Pharmacother. 2023 Nov 16;169:115875. doi: 10.1016/j.biopha.2023.115875. Online ahead of print.

ABSTRACT

Nano-based drug delivery systems are increasingly used for diagnosis, prevention and treatment of several diseases, thanks to several beneficial properties, including the ability to target specific cells or organs, allowing to reduce treatment costs and side effects frequently associated with chemotherapeutic medications, thereby improving treatment compliance of patients. In the field of communicable diseases, especially those caused by intracellular bacteria, the delivery of antibiotics targeting specific cells is of critical importance to maximize their treatment efficacy. Brucella melitensis, an intracellular obligate bacterium surviving and replicating inside macrophages is hard to be eradicated, mainly because of the low ability of antibiotics to enter these phagocityc cells . Although different antibiotics regimens including gentamicin, doxycycline and rifampicin are in fact used against the Brucellosis, no efficient treatment has been attained yet, due to the intracellular life of the respective pathogen. Nano-medicines responding to environmental stimuli allow to maximize drug delivery targeting macropages, thereby boosting treatment efficacy. Several drug delivery nano-technologies, including solid lipid nanoparticles, liposomes, chitosan, niosomes, and their combinations with chitosan sodium alginate can be employed in combination of antibiotics to successfully eradicate Brucellosis infection from patients.

PMID:37979375 | DOI:10.1016/j.biopha.2023.115875

STAR Protoc. 2023 Nov 17;4(4):102682. doi: 10.1016/j.xpro.2023.102682. Online ahead of print.

ABSTRACT

Post-translational modifications (PTMs) serve as key regulatory mechanisms in various cellular processes; altered PTMs can potentially lead to human diseases. We present a protocol for using MIND-S (multi-label interpretable deep-learning approach for PTM prediction-structure version), to study PTMs. This protocol consists of step-by-step guide and includes three key applications of MIND-S: PTM predictions based on protein sequences, important amino acids identification, and elucidation of altered PTM landscape resulting from molecular mutations. For complete details on the use and execution of this protocol, please refer to Yan et al (2023).1.

PMID:37979178 | DOI:10.1016/j.xpro.2023.102682

Mol Biol Evol. 2023 Nov 18:msad246. doi: 10.1093/molbev/msad246. Online ahead of print.

ABSTRACT

Whole genome duplication (WGD) followed by speciation allows us to examine the parallel evolution of ohnolog pairs. In the yeast family Saccharomycetaceae, HRR25 is a rare case of repeated ohnolog maintenance. This gene has reverted to a single copy in S. cerevisiae where it is now essential, but has been maintained as pairs in at least 7 species post WGD. In S. cerevisiae, HRR25 encodes the casein kinase (CK) 1δ/ε and plays a role in a variety of functions through its kinase activity and protein-protein interactions (PPIs). We hypothesized that the maintenance of duplicated HRR25 ohnologs could be a result of repeated subfunctionalization. We tested this hypothesis through a functional complementation assay in S. cerevisiae, testing all pairwise combinations of 25 orthologs (including 7 ohnolog pairs). Contrary to our expectations, we observed no cases of pair-dependent complementation, which would have supported the subfunctionalization hypothesis. Instead, most post-WGD species have one ohnolog that failed to complement, suggesting their nonfunctionalization or neofunctionalization. The ohnologs incapable of complementation have undergone more rapid protein evolution, lost most PPIs that were observed for their functional counterparts and singletons from post and non-WGD species, and have non-conserved cellular localization, consistent with their ongoing loss of function. The analysis in N. castelli shows that the non-complementing ohnolog is expressed at a lower level and has become non-essential. Taken together, our results indicate that HRR25 orthologs are undergoing gradual nonfunctionalization.

PMID:37979156 | DOI:10.1093/molbev/msad246

Carcinogenesis. 2023 Nov 18:bgad085. doi: 10.1093/carcin/bgad085. Online ahead of print.

ABSTRACT

The alcohol metabolite acetaldehyde is a potent human carcinogen linked to esophageal squamous cell carcinoma (ESCC) initiation and development. Aldehyde dehydrogenase 2 (ALDH2) is the primary enzyme that detoxifies acetaldehyde in the mitochondria. Acetaldehyde accumulation causes genotoxic stress in cells expressing the dysfunctional ALDH2E487K dominant negative mutant protein linked to ALDH2*2, the single nucleotide polymorphism highly prevalent amongst East Asians. Heterozygous ALDH2*2 increases the risk for the development of ESCC and other alcohol-related cancers. Despite its prevalence and link to malignant transformation, how ALDH2 dysfunction influences ESCC pathobiology is incompletely understood. Herein, we characterize how ESCC and preneoplastic cells respond to alcohol exposure using cell lines, three dimensional organoids, and xenograft models. We find that alcohol exposure and ALDH2*2 cooperate to increase putative ESCC cancer stem cells with high CD44 expression (CD44H cells) linked to tumor initiation, repopulation, and therapy resistance. Concurrently, ALHD2*2 augmented alcohol-induced reactive oxygen species and DNA damage to promote apoptosis in the non-CD44H cell population. Pharmacological activation of ALDH2 by Alda-1 inhibits this phenotype, suggesting that acetaldehyde is the primary driver of these changes. Additionally, we find that Aldh2 dysfunction affects the response to cisplatin, a chemotherapeutic commonly used for the treatment of ESCC. Aldh2 dysfunction facilitated enrichment of CD44H cells following cisplatin-induced oxidative stress and cell death in murine organoids, highlighting a potential mechanism driving cisplatin resistance. Together, these data provide evidence that ALDH2 dysfunction accelerates ESCC pathogenesis through enrichment of CD44H cells in response to genotoxic stressors such as environmental carcinogens and chemotherapeutic agents.

PMID:37978873 | DOI:10.1093/carcin/bgad085

Biophys J. 2023 Nov 16:S0006-3495(23)00713-0. doi: 10.1016/j.bpj.2023.11.013. Online ahead of print.

ABSTRACT

Studying the role of molecularly distinct lipid species in cell signaling remains challenging due to a scarcity of methods for performing quantitative lipid biochemistry in living cells. We have recently used lipid uncaging to quantify lipid-protein affinities and rates of lipid transbilayer movement and turnover in the diacylglycerol signaling pathway. This approach is based on acquiring live-cell dose-response curves requiring light dose titrations and experimental determination of uncaging photoreaction efficiency. We here aimed to develop a methodological approach that allows to retrieve quantitative kinetic data from uncaging experiments that (i) requires only typically available datasets without the need for specialized additional constraints and (ii) should in principle be applicable to other types of photoactivation experiments. Our new analysis framework allows to identify model parameters such diacylglycerol-protein affinities and transbilayer movement rates, together with initial uncaged diacylglycerol levels, using noisy single cell data for a broad variety of structurally different diacylglycerol species. We find that lipid unsaturation degree and side chain length generally correlate with faster lipid transbilayer movement and turnover and also affect lipid-protein affinities. In summary, our work demonstrates how rate parameters and lipid-protein affinities can be quantified from single cell signaling trajectories with sufficient sensitivity to resolve the subtle kinetic differences caused by the chemical diversity of cellular signaling lipid pools.

PMID:37978803 | DOI:10.1016/j.bpj.2023.11.013

Microbiome. 2023 Nov 18;11(1):257. doi: 10.1186/s40168-023-01701-z.

ABSTRACT

BACKGROUND: The microbiota of multicellular organisms undergoes considerable changes during host ontogeny but the general mechanisms that control community assembly and succession are poorly understood. Here, we use bacterial recolonization experiments in Nematostella vectensis as a model to understand general mechanisms determining bacterial establishment and succession. We compared the dynamic establishment of the microbiome on the germfree host and on inert silicone tubes.

RESULTS: Following the dynamic reconstruction of microbial communities on both substrates, we show that the initial colonization events are strongly influenced by the host but not by the silicone tube, while the subsequent bacteria-bacteria interactions are the main driver of bacterial succession. Interestingly, the recolonization pattern on adult hosts resembles the ontogenetic colonization succession. This process occurs independently of the bacterial composition of the inoculum and can be followed at the level of individual bacteria. To identify potential metabolic traits associated with initial colonization success and potential metabolic interactions among bacteria associated with bacterial succession, we reconstructed the metabolic networks of bacterial colonizers based on their genomes. These analyses revealed that bacterial metabolic capabilities reflect the recolonization pattern, and the degradation of chitin might be a selection factor during early recolonization of the animal. Concurrently, transcriptomic analyses revealed that Nematostella possesses two chitin synthase genes, one of which is upregulated during early recolonization.

CONCLUSIONS: Our results show that early recolonization events are strongly controlled by the host while subsequent colonization depends on metabolic bacteria-bacteria interactions largely independent of host ontogeny. Video Abstract.

PMID:37978412 | DOI:10.1186/s40168-023-01701-z

Nat Nanotechnol. 2023 Nov 17. doi: 10.1038/s41565-023-01568-z. Online ahead of print.

NO ABSTRACT

PMID:37978328 | DOI:10.1038/s41565-023-01568-z

Cancer Treat Res. 2023;186:13-23. doi: 10.1007/978-3-031-30065-3_2.

ABSTRACT

PARP inhibitors now have proven utility in the treatment of homologous recombination (HR) defective cancers. These drugs, and the synthetic lethality effect they exploit, have not only taught us how to approach the treatment of HR defective cancers but have also illuminated how resistance to a synthetic lethal approach can occur, how cancer-associated synthetic lethal effects are perhaps more complex than we imagine, how the better use of biomarkers could improve the success of treatment and even how drug resistance might be targeted. Here, we discuss some of the lessons learnt from the study of PARP inhibitor synthetic lethality and how these lessons might have wider application. Specifically, we discuss the concept of synthetic lethal penetrance, phenocopy effects in cancer such as BRCAness, synthetic lethal resistance, the polygenic and complex nature of synthetic lethal interactions, how evolutionary double binds could be exploited in treatment as well as future horizons for the field.

PMID:37978128 | DOI:10.1007/978-3-031-30065-3_2

Mamm Genome. 2023 Nov 17. doi: 10.1007/s00335-023-10025-0. Online ahead of print.

ABSTRACT

A chronic metabolic illness, type 2 diabetes (T2D) is a polygenic and multifactorial complicated disease. With an estimated 463 million persons aged 20 to 79 having diabetes, the number is expected to rise to 700 million by 2045, creating a significant worldwide health burden. Polygenic variants of diabetes are influenced by environmental variables. T2D is regarded as a silent illness that can advance for years before being diagnosed. Finding genetic markers for T2D and metabolic syndrome in groups with similar environmental exposure is therefore essential to understanding the mechanism of such complex characteristic illnesses. So herein, we demonstrated the exclusive use of the collaborative cross (CC) mouse reference population to identify novel quantitative trait loci (QTL) and, subsequently, suggested genes associated with host glucose tolerance in response to a high-fat diet. In this study, we used 539 mice from 60 different CC lines. The diabetogenic effect in response to high-fat dietary challenge was measured by the three-hour intraperitoneal glucose tolerance test (IPGTT) test after 12 weeks of dietary challenge. Data analysis was performed using a statistical software package IBM SPSS Statistic 23. Afterward, blood glucose concentration at the specific and between different time points during the IPGTT assay and the total area under the curve (AUC0-180) of the glucose clearance was computed and utilized as a marker for the presence and severity of diabetes. The observed AUC0-180 averages for males and females were 51,267.5 and 36,537.5 mg/dL, respectively, representing a 1.4-fold difference in favor of females with lower AUC0-180 indicating adequate glucose clearance. The AUC0-180 mean differences between the sexes within each specific CC line varied widely within the CC population. A total of 46 QTL associated with the different studied phenotypes, designated as T2DSL and its number, for Type 2 Diabetes Specific Locus and its number, were identified during our study, among which 19 QTL were not previously mapped. The genomic interval of the remaining 27 QTL previously reported, were fine mapped in our study. The genomic positions of 40 of the mapped QTL overlapped (clustered) on 11 different peaks or close genomic positions, while the remaining 6 QTL were unique. Further, our study showed a complex pattern of haplotype effects of the founders, with the wild-derived strains (mainly PWK) playing a significant role in the increase of AUC values.

PMID:37978084 | DOI:10.1007/s00335-023-10025-0

Phys Rev Lett. 2023 Nov 3;131(18):188401. doi: 10.1103/PhysRevLett.131.188401.

ABSTRACT

We investigate how randomly oriented cell traction forces lead to fluidization in a vertex model of epithelial tissues. We find that the fluidization occurs at a critical value of the traction force magnitude F_{c}. We show that this transition exhibits critical behavior, similar to the yielding transition of sheared amorphous solids. However, we find that it belongs to a different universality class, even though it satisfies the same scaling relations between critical exponents established in the yielding transition of sheared amorphous solids. Our work provides a fluidization mechanism through active force generation that could be relevant in biological tissues.

PMID:37977637 | DOI:10.1103/PhysRevLett.131.188401

J Chem Inf Model. 2023 Nov 17. doi: 10.1021/acs.jcim.3c00884. Online ahead of print.

ABSTRACT

Computational methods relying on protein structure strongly depend on the structure selected for investigation. Typical sources of protein structures include experimental structures available at the Protein Data Bank (PDB) and high-quality in silico model structures, such as those available at the AlphaFold Protein Structure Database. Either option has significant advantages and drawbacks, and exploring the wealth of available structures to identify the most suitable ones for specific applications can be a daunting task. We provide an open-source software package, PDBminer, with the purpose of making structure identification and selection easier, faster, and less error prone. PDBminer searches the AlphaFold Database and the PDB for available structures of interest and provides an up-to-date, quality-ranked table of structures applicable for further use. PDBminer provides an overview of the available protein structures to one or more input proteins, parallelizing the runs if multiple cores are specified. The output table reports the coverage of the protein structures aligned to the UniProt sequence, overcoming numbering differences in PDB structures and providing information regarding model quality, protein complexes, ligands, and nucleic acid chain binding. The PDBminer2coverage and PDBminer2network tools assist in visualizing the results. PDBminer can be applied to overcome the tedious task of choosing a PDB structure without losing the wealth of additional information available in the PDB. Here, we showcase the main functionalities of the package on the p53 tumor suppressor protein. The package is available at http://github.com/ELELAB/PDBminer.

PMID:37977136 | DOI:10.1021/acs.jcim.3c00884

Epidemics. 2023 Oct 30;45:100724. doi: 10.1016/j.epidem.2023.100724. Online ahead of print.

ABSTRACT

Mathematical modellers model infectious disease dynamics at different scales. Within-host models represent the spread of pathogens inside an individual, whilst between-host models track transmission between individuals. However, pathogen dynamics at one scale affect those at another. This has led to the development of multiscale models that connect within-host and between-host dynamics. In this article, we systematically review the literature on multiscale infectious disease modelling according to PRISMA guidelines, dividing previously published models into five categories governing their methodological approaches (Garira (2017)), explaining their benefits and limitations. We provide a primer on developing multiscale models of infectious diseases.

PMID:37976680 | DOI:10.1016/j.epidem.2023.100724

Anal Chem. 2023 Nov 17. doi: 10.1021/acs.analchem.3c03313. Online ahead of print.

ABSTRACT

We herein describe a novel centrifugal microfluidic system to achieve multiple standard additions, which could minimize the effects of matrix interference and consequently lead to more accurate and reliable measurements of analyte concentrations in complex samples. The system leverages laser-irradiated ferrowax microvalves to automatically control fluid transfer on the disc without the need for external pumps or pressure systems, simplifying the procedures and eliminating the need for manual intervention. The disc incorporates metering chambers with rationally designed varying sizes, which could lead to the formation of six standard addition samples very rapidly in just 2.5 min. The final solutions are designed to contain a target component at gradually increasing concentrations but have an equal final volume containing the same amount of an analyte solution, thereby equalizing the matrix effect that is supposedly caused by the unknown components in the analyte solution. By utilizing this design principle, we were able to successfully quantify a model target component, salivary thiocyanate ions, that could be used as a biomarker for exposure to tobacco smoke. Our centrifugal microfluidic system holds great promise as a powerful analytical tool to achieve fully automated diagnostic microsystems involving a standard addition process.

PMID:37976500 | DOI:10.1021/acs.analchem.3c03313

Elife. 2023 Nov 17;12:e84951. doi: 10.7554/eLife.84951. Online ahead of print.

ABSTRACT

Influential accounts claim that violent video games (VVG) decrease players' emotional empathy by desensitizing them to both virtual and real-life violence. However, scientific evidence for this claim is inconclusive and controversially debated. To assess the causal effect of VVGs on the behavioral and neural correlates of empathy and emotional reactivity to violence, we conducted a prospective experimental study using functional magnetic resonance imaging (fMRI). We recruited eighty-nine male participants without prior VVG experience. Over the course of two weeks, participants played either a highly violent video game, or a non-violent version of the same game. Before and after this period, participants completed an fMRI experiment with paradigms measuring their empathy for pain and emotional reactivity to violent images. Applying a Bayesian analysis approach throughout enabled us to find substantial evidence for the absence of an effect of VVGs on the behavioral and neural correlates of empathy. Moreover, participants in the VVG group were not desensitized to images of real-world violence. These results imply that short and controlled exposure to VVGs does not numb empathy nor the responses to real-world violence. We discuss the implications of our findings regarding the potential and limitations of experimental research on the causal effects of VVGs. While VVGs might not have a discernible effect on the investigated subpopulation within our carefully controlled experimental setting, our results cannot preclude that effects could be found in settings with higher ecological validity, in vulnerable subpopulations, or after more extensive VVG play.

PMID:37975654 | DOI:10.7554/eLife.84951

Cell Cycle. 2023 Nov 16:1-16. doi: 10.1080/15384101.2023.2281816. Online ahead of print.

ABSTRACT

Identifying robust breast cancer subtypes will help to reveal the cancer heterogeneity. However, previous breast cancer subtypes were based on population-level quantitative gene expression, which is affected by batch effects and cannot be applied to individuals. We detected differential gene expression, genomic, and epigenomic alterations to identify driver differential expression at the individual level. The individual driver differential expression reflected the breast cancer patients' heterogeneity and revealed four subtypes. Mesenchymal subtype as the most aggressive subtype harbored deletion and downregulated expression of genes in chromosome 11q23 region. Specifically, silencing of the SDHD gene in 11q23 promoted the invasion and migration of breast cancer cells in vitro by the epithelial-mesenchymal transition. The immunologically hot subtype displayed an immune-hot microenvironment, including high T-cell infiltration and upregulated PD-1 and CTLA4. Luminal and genomic-unstable subtypes showed opposite macrophage polarization, which may be regulated by the ligand-receptor pairs of CD99. The integration of multi-omics data at the individual level provides a powerful framework for elucidating the heterogeneity of breast cancer.

PMID:37974462 | DOI:10.1080/15384101.2023.2281816

Biotechnol Biofuels Bioprod. 2023 Nov 16;16(1):176. doi: 10.1186/s13068-023-02423-y.

NO ABSTRACT

PMID:37974281 | DOI:10.1186/s13068-023-02423-y

BMC Biol. 2023 Nov 16;21(1):261. doi: 10.1186/s12915-023-01764-2.

NO ABSTRACT

PMID:37974169 | DOI:10.1186/s12915-023-01764-2

Nat Commun. 2023 Nov 16;14(1):7436. doi: 10.1038/s41467-023-43237-8.

ABSTRACT

The cranial vault in humans is highly variable, clinically relevant, and heritable, yet its genetic architecture remains poorly understood. Here, we conduct a joint multi-ancestry and admixed multivariate genome-wide association study on 3D cranial vault shape extracted from magnetic resonance images of 6772 children from the ABCD study cohort yielding 30 genome-wide significant loci. Follow-up analyses indicate that these loci overlap with genomic risk loci for sagittal craniosynostosis, show elevated activity cranial neural crest cells, are enriched for processes related to skeletal development, and are shared with the face and brain. We present supporting evidence of regional localization for several of the identified genes based on expression patterns in the cranial vault bones of E15.5 mice. Overall, our study provides a comprehensive overview of the genetics underlying normal-range cranial vault shape and its relevance for understanding modern human craniofacial diversity and the etiology of congenital malformations.

PMID:37973980 | DOI:10.1038/s41467-023-43237-8