Bioprocess Biosyst Eng. 2023 Feb 18. doi: 10.1007/s00449-023-02851-y. Online ahead of print.

ABSTRACT

Hydrogen production from dark fermentation has potential application due to its environmental friendliness, low production cost, and sustainability. However, there is still an obstacle to improving the efficiency of bioH2 production to meet the requirements in practical applications. In this research, copper molybdates are synthesized under different pH conditions as additives to study their different influence processes during anaerobic hydrogen production from cotton straws with the pure cultural system. A series of results indicate that CuMoO4 with appropriate experimental conditions has the highest H2 yield at 191.3 mL/g straws at 37 °C, which is 236% higher than the control group. It can be shown that O. ethanolica 8KG-4 has an obvious accompanying with high stability and low cytotoxicity for this clean energy production system as well as the improvement of metabolic pathway. These results extend new thinking of obtaining higher H2 yield as a biofuel in future production.

PMID:36801972 | DOI:10.1007/s00449-023-02851-y

Cell Death Dis. 2023 Feb 18;14(2):138. doi: 10.1038/s41419-023-05650-1.

ABSTRACT

Alzheimer's disease (AD) is a progressive neurodegenerative disorder leading to dementia. The hippocampus, which is one of the sites where neural stem cells reside and new neurons are born, exhibits the most significant neuronal loss in AD. A decline in adult neurogenesis has been described in several animal models of AD. However, the age at which this defect first appears remains unknown. To determine at which stage, from birth to adulthood, the neurogenic deficits are found in AD, we used the triple transgenic mouse model of AD (3xTg). We show that defects in neurogenesis are present as early as postnatal stages, well before the onset of any neuropathology or behavioral deficits. We also show that 3xTg mice have significantly fewer neural stem/progenitor cells, with reduced proliferation and decreased numbers of newborn neurons at postnatal stages, consistent with reduced volumes of hippocampal structures. To determine whether there are early changes in the molecular signatures of neural stem/progenitor cells, we perform bulk RNA-seq on cells sorted directly from the hippocampus. We show significant changes in the gene expression profiles at one month of age, including genes of the Notch and Wnt pathways. These findings reveal impairments in neurogenesis very early in the 3xTg AD model, which provides new opportunities for early diagnosis and therapeutic interventions to prevent neurodegeneration in AD.

PMID:36801910 | DOI:10.1038/s41419-023-05650-1

Sci Immunol. 2023 Feb 24;8(80):eadd1823. doi: 10.1126/sciimmunol.add1823. Epub 2023 Feb 17.

ABSTRACT

Both B cell receptor (BCR) and CD40 signaling are rewired in germinal center (GC) B cells (GCBCs) to synergistically induce c-MYC and phosphorylated S6 ribosomal protein (p-S6), markers of positive selection. How interleukin-21 (IL-21), a key T follicular helper (TFH)-derived cytokine, affects GCBCs is unclear. Like BCR and CD40 signals, IL-21 receptor (IL-21R) plus CD40 signals also synergize to induce c-MYC and p-S6 in GCBCs. However, IL-21R plus CD40 stimulation differentially affects GCBC fate compared with BCR plus CD40 ligation-engaging unique molecular mechanisms-as revealed by bulk RNA sequencing (RNA-seq), single-cell RNA-seq, and flow cytometry of GCBCs in vitro and in vivo. Whereas both signal pairs induced BLIMP1 in some GCBCs, only the IL-21R/CD40 combination induced IRF4hi/CD138+ cells, indicative of plasma cell differentiation, along with CCR6+/CD38+ memory B cell precursors. These findings reveal a second positive selection pathway in GCBCs, document rewired IL-21R signaling in GCBCs, and link specific TFH- and Ag-derived signals to GCBC differentiation.

PMID:36800413 | DOI:10.1126/sciimmunol.add1823

PLoS One. 2023 Feb 17;18(2):e0281903. doi: 10.1371/journal.pone.0281903. eCollection 2023.

ABSTRACT

Here in this study we adopted genome-wide association studies (GWAS) to investigate the genetic components of the personality constructs in the Chinese Personality Assessment Inventory 2 (CPAI-2) in Taiwanese Hakka populations, who are likely the descendants of a recent admixture between a group of Chinese immigrants with high emigration intention and a group of the Taiwanese aboriginal population generally without it. A total of 279 qualified participants were examined and genotyped by an Illumina array with 547,644 SNPs to perform the GWAS. Although our sample size is small and that unavoidably limits our statistical power (Type 2 error but not Type 1 error), we still found three genomic regions showing strong association with Enterprise, Diversity, and Logical vs. Affective Orientation, respectively. Multiple genes around the identified regions were reported to be nervous system related, which suggests that genetic variants underlying the certain personalities should indeed exist in the nearby areas. It is likely that the recent immigration and admixture history of the Taiwanese Hakka people created strong linkage disequilibrium between the emigration intention-related genetic variants and their neighboring genetic markers, so that we could identify them despite with only limited statistical power.

PMID:36800362 | DOI:10.1371/journal.pone.0281903

PLoS One. 2023 Feb 17;18(2):e0279669. doi: 10.1371/journal.pone.0279669. eCollection 2023.

ABSTRACT

Discrimination of brain cancer versus non-cancer patients using serum-based attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy diagnostics was first developed by Hands et al with a reported sensitivity of 92.8% and specificity of 91.5%. Cameron et al. then went on to stratifying between specific brain tumour types: glioblastoma multiforme (GBM) vs. primary cerebral lymphoma with a sensitivity of 90.1% and specificity of 86.3%. Expanding on these studies, 30 GBM, 30 lymphoma and 30 non-cancer patients were selected to investigate the influence on test performance by focusing on specific molecular weight regions of the patient serum. Membrane filters with molecular weight cut offs of 100 kDa, 50 kDa, 30 kDa, 10 kDa and 3 kDa were purchased in order to remove the most abundant high molecular weight components. Three groups were classified using both partial least squares-discriminate analysis (PLS-DA) and random forest (RF) machine learning algorithms; GBM versus non-cancer, lymphoma versus non-cancer and GBM versus lymphoma. For all groups, once the serum was filtered the sensitivity, specificity and overall balanced accuracies decreased. This illustrates that the high molecular weight components are required for discrimination between cancer and non-cancer as well as between tumour types. From a clinical application point of view, this is preferable as less sample preparation is required.

PMID:36800340 | DOI:10.1371/journal.pone.0279669

Elife. 2023 Feb 17;12:e81850. doi: 10.7554/eLife.81850. Online ahead of print.

ABSTRACT

Allostery is fundamental to many biological processes. Due to the distant regulation nature, how allosteric mutations, modifications and effector binding impact protein function is difficult to forecast. In protein engineering, remote mutations cannot be rationally designed without large-scale experimental screening. Allosteric drugs have raised much attention due to their high specificity and possibility of overcoming existing drug-resistant mutations. However, optimization of allosteric compounds remains challenging. Here, we developed a novel computational method KeyAlloSite to predict allosteric site and to identify key allosteric residues (allo-residues) based on the evolutionary coupling model. We found that protein allosteric sites are strongly coupled to orthosteric site compared to non-functional sites. We further inferred key allo-residues by pairwise comparing the difference of evolutionary coupling scores of each residue in the allosteric pocket with the functional site. Our predicted key allo-residues are in accordance with previous experimental studies for typical allosteric proteins like BCR-ABL1, Tar and PDZ3, as well as key cancer mutations. We also showed that KeyAlloSite can be used to predict key allosteric residues distant from the catalytic site that are important for enzyme catalysis. Our study demonstrates that weak coevolutionary couplings contain important information of protein allosteric regulation function. KeyAlloSite can be applied in studying the evolution of protein allosteric regulation, designing and optimizing allosteric drugs, performing functional protein design and enzyme engineering.

PMID:36799896 | DOI:10.7554/eLife.81850

Elife. 2023 Feb 17;12:e84379. doi: 10.7554/eLife.84379. Online ahead of print.

ABSTRACT

Cycling of co-substrates, whereby a metabolite is converted among alternate forms via different reactions, is ubiquitous in metabolism. Several cycled co-substrates are well known as energy and electron carriers (e.g. ATP and NAD(P)H), but there are also other metabolites that act as cycled co-substrates in different parts of central metabolism. Here, we develop a mathematical framework to analyse the effect of co-substrate cycling on metabolic flux. In the cases of a single reaction and linear pathways, we find that co-substrate cycling imposes an additional flux limit on a reaction, distinct to the limit imposed by the kinetics of the primary enzyme catalysing that reaction. Using analytical methods, we show that this additional limit is a function of the total pool size and turnover rate of the cycled co-substrate. Expanding from this insight and using simulations, we show that regulation of these two parameters can allow regulation of flux dynamics in branched and coupled pathways. To support these theoretical insights, we analysed existing flux measurements and enzyme levels from the central carbon metabolism and identified several reactions that could be limited by the dynamics of co-substrate cycling. We discuss how the limitations imposed by co-substrate cycling provide experimentally testable hypotheses on specific metabolic phenotypes. We conclude that measuring and controlling co-substrate dynamics is crucial for understanding and engineering metabolic fluxes in cells.

PMID:36799616 | DOI:10.7554/eLife.84379

Plant J. 2023 Feb 17. doi: 10.1111/tpj.16157. Online ahead of print.

ABSTRACT

Plants are the most sophisticated biofactories and sources of food and biofuels present in nature. Engineering the plant metabolism can increase the production of desired compounds and improve the nutritional or commercial value of the plant species. However, this can be challenging because of the complexity of the regulation of multiple genes and the involvement of different protein interactions. To improve metabolic engineering (ME) capabilities, different tools and strategies for rerouting the metabolic pathways have been developed, including genome editing and transcriptional regulation approaches. In addition, cutting-edge technologies have provided new methods for understanding uncharacterized biosynthetic pathways, protein degradation mechanisms, protein-protein interactions, or allosteric feedback, enabling the design of novel ME approaches.

PMID:36799285 | DOI:10.1111/tpj.16157

Adv Biomed Res. 2022 Dec 26;11:122. doi: 10.4103/abr.abr_97_21. eCollection 2022.

ABSTRACT

BACKGROUND: In this study, the effects of methadone and naloxone on the expression of toll-like receptor 4 (TLR4) gene have been evaluated in human non-small cell lung carcinoma A549 cell line migration using in-silico and in vitro techniques.

MATERIALS AND METHODS: Lung cancer A549 cell cultures were stimulated for 24 h with methadone (5, 10, and 20 μM) and naloxone (20 and 40 μM) concentrations. The level of TLR4 expression was determined by the quantitative real-time polymerase chain reaction. Migration of the A549 cells was investigated after a 4-h incubation period with methadone using the Boyden Chamber assay.

RESULTS: Migration rate of the A549 cells treated with 5 (P < 0.05) and 20 (P < 0.01) μM methadone was, respectively, increased and decreased with 20 μM naloxone (P < 0.05). Furthermore, the TLR4 expression was enhanced with 5 (P < 0.05) and 20 (P < 0.01) μM methadone and decreased with 20 (P < 0.05) and 40 μM naloxone (P < 0.01). In addition, in silico docking analysis revealed docking of methadone to MD-2 and TLR4.

CONCLUSION: According to the present DATA, methadone affects the TLR4 expression. It may however cause adverse consequences by increasing the TLR4 expression. Therefore, the useful analgesic properties of methadone should be separated from the unwanted TLR4-mediated side effects.

PMID:36798925 | PMC:PMC9926039 | DOI:10.4103/abr.abr_97_21

iScience. 2023 Jan 18;26(2):106007. doi: 10.1016/j.isci.2023.106007. eCollection 2023 Feb 17.

ABSTRACT

Bacteriophages, viruses specific to bacteria, coexist with their bacterial hosts with limited diversity fluctuations in the guts of healthy individuals where they replicate mostly via lysogenic replication. This favors 'piggy-back-the-winner' over 'kill-the-winner' dynamics which are driven by lytic bacteriophage replication. Revisiting the deep-viral sequencing data of a healthy individual sampled over 2.4 years, we explore how these dynamics occur. Prophages found in assembled bacterial metagenomes were also found extra-cellularly, as induced phage particles (iPPs), likely derived from prophage activation. These iPPs were diverse and continually present in low abundance, relative to the highly abundant but less diverse lytic phage population. The continuous detection of low levels of iPPs suggests that spontaneous induction regularly occurs in this healthy individual, possibly allowing prophages to maintain their ability to replicate and avoiding degradation and loss from the gut microbiota.

PMID:36798434 | PMC:PMC9926308 | DOI:10.1016/j.isci.2023.106007

iScience. 2023 Jan 19;26(2):106021. doi: 10.1016/j.isci.2023.106021. eCollection 2023 Feb 17.

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis due to the difficulty of its diagnosis. Because human satellite II (HSATII) RNA, a satellite repeat RNA, is highly and specifically expressed in human PDAC, the serum HSATII RNA level may be a biomarker of PDAC. To measure the serum HSATII RNA level with high sensitivity and reproducibility, we previously developed a convenient method, tandem repeat amplification by nuclease protection (TRAP) combined with droplet digital PCR (ddPCR). Here, we refined the original method by simultaneously measuring the serum miR-21-5p level to enhance the detection of PDAC. The resulting PDAC-Index, constructed using serum HSATII RNA and miR-21-5p levels, discriminated patients with PDAC with high accuracy. We verified the clinical usefulness of the PDAC-Index as a supportive test in difficult-to-diagnose cases. The PDAC-Index has satisfactory diagnostic performance and may routinely be applied for detecting PDAC.

PMID:36798431 | PMC:PMC9926314 | DOI:10.1016/j.isci.2023.106021

Res Sq. 2023 Feb 10:rs.3.rs-2367727. doi: 10.21203/rs.3.rs-2367727/v1. Preprint.

ABSTRACT

Spaceflight poses a unique set of challenges to humans and the hostile spaceflight environment can induce a wide range of increased health risks, including dermatological issues. The biology driving the frequency of skin issues in astronauts is currently not well understood. To address this issue, we used a systems biology approach utilizing NASA’s Open Science Data Repository (OSDR) on spaceflown murine transcriptomic datasets focused on the skin, biomedical profiles from fifty NASA astronauts, and confirmation via transcriptomic data from JAXA astronauts, the NASA Twins Study, and the first civilian commercial mission, Inspiration4. Key biological changes related to skin health, DNA damage & repair, and mitochondrial dysregulation were determined to be involved with skin health risks during spaceflight. Additionally, a machine learning model was utilized to determine key genes driving spaceflight response in the skin. These results can be used for determining potential countermeasures to mitigate spaceflight damage to the skin.

PMID:36798347 | PMC:PMC9934743 | DOI:10.21203/rs.3.rs-2367727/v1

Phys Rev E. 2023 Jan;107(1-1):014118. doi: 10.1103/PhysRevE.107.014118.

ABSTRACT

Chemically active systems such as living cells are maintained out of thermal equilibrium due to chemical events which generate heat and lead to active fluctuations. A key question is to understand on which time and length scales active fluctuations dominate thermal fluctuations. Here, we formulate a stochastic field theory with Poisson white noise to describe the heat fluctuations which are generated by stochastic chemical events and lead to active temperature fluctuations. We find that on large length- and timescales, active fluctuations always dominate thermal fluctuations. However, at intermediate length- and timescales, multiple crossovers exist which highlight the different characteristics of active and thermal fluctuations. Our work provides a framework to characterize fluctuations in active systems and reveals that local equilibrium holds at certain length- and timescales.

PMID:36797936 | DOI:10.1103/PhysRevE.107.014118

Curr Stem Cell Res Ther. 2023 Feb 16. doi: 10.2174/1574888X18666230216085615. Online ahead of print.

ABSTRACT

BACKGROUND: Bone tissue engineering, as a relatively new approach, has focused on combining biodegradable scaffolds, cells, and biologically active molecules for the recovery of different damaged tissues, such as bone defects. Polyurethane (PU), as a synthetic polymer, benefits from a porous structure which impersonates bone's natural environment. However, PU lacks osteoinduction activities. Cobalt nanoparticles (CoNPs) stimulate angiogenesis and biomineralization, which greatly favors osteogenesis.

METHODS: Here, we designed a novel scaffold based on PU and combined it with CoNPs for bone regeneration applications. The composition and structure of PU-CoNPs nanocomposite were characterized using Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and differential scanning calorimetry (DSC). MTT and AO data showed biocompatibility and enhanced viability and proliferation of fibroblasts on PU-CoNPs scaffold. Ascorbic acid-2-phosphate, β-glycerophosphate, and dexamethasone-induced osteogenesis for 14 days.

RESULTS: The alkaline phosphatase test asserts the increased mineralization of hADSCs cultured on PU-CoNPs compared to pure PU scaffold. Further, the results disclosed an elevated osteogenic differentiation at the level of genes and proteins using immunocytochemical analysis (ICC) and quantitative real-time PCR (qPCR).

CONCLUSION: These findings provide an evidence that PU-CoNPs nanocomposite might be a promising candidate for bone repair applications.

PMID:36797606 | DOI:10.2174/1574888X18666230216085615

Nat Immunol. 2023 Feb 16. doi: 10.1038/s41590-023-01436-x. Online ahead of print.

ABSTRACT

Blocking pyrimidine de novo synthesis by inhibiting dihydroorotate dehydrogenase is used to treat autoimmunity and prevent expansion of rapidly dividing cell populations including activated T cells. Here we show memory T cell precursors are resistant to pyrimidine starvation. Although the treatment effectively blocked effector T cells, the number, function and transcriptional profile of memory T cells and their precursors were unaffected. This effect occurred in a narrow time window in the early T cell expansion phase when developing effector, but not memory precursor, T cells are vulnerable to pyrimidine starvation. This vulnerability stems from a higher proliferative rate of early effector T cells as well as lower pyrimidine synthesis capacity when compared with memory precursors. This differential sensitivity is a drug-targetable checkpoint that efficiently diminishes effector T cells without affecting the memory compartment. This cell fate checkpoint might therefore lead to new methods to safely manipulate effector T cell responses.

PMID:36797499 | DOI:10.1038/s41590-023-01436-x

Nat Microbiol. 2023 Feb 16. doi: 10.1038/s41564-023-01334-w. Online ahead of print.

NO ABSTRACT

PMID:36797488 | DOI:10.1038/s41564-023-01334-w

Commun Biol. 2023 Feb 16;6(1):183. doi: 10.1038/s42003-023-04541-7.

ABSTRACT

Many parasites interfere with the behaviour of their hosts. In social animals, such as ants, parasitic interference can cause changes on the level of the individual and also on the level of the society. The ant-parasitic fungus Rickia wasmannii influences the behaviour of Myrmica ants by expanding the host's nestmate recognition template, thereby increasing the chance of the colony accepting infected non-nestmates. Infected ants consistently show an increase of the alkane tricosane (n-C23) in their cuticular hydrocarbon profiles. Although experimental application of single compounds often elicits aggression towards manipulated ants, we hypothesized that the increase of n-C23 might underlie the facilitated acceptance of infected non-nestmates. To test this, we mimicked fungal infection in M. scabrinodis by applying synthetic n-C23 to fresh ant corpses and observed the reaction of infected and uninfected workers to control and manipulated corpses. Infected ants appeared to be more peaceful towards infected but not uninfected non-nestmates. Adding n-C23 to uninfected corpses resulted in reduced aggression in uninfected ants. This supports the hypothesis that n-C23 acts as a 'pacifying' signal. Our study indicates that parasitic interference with the nestmate discrimination of host ants might eventually change colony structure by increasing genetic heterogeneity in infected colonies.

PMID:36797462 | DOI:10.1038/s42003-023-04541-7

Nat Methods. 2023 Feb 16. doi: 10.1038/s41592-023-01773-7. Online ahead of print.

ABSTRACT

Spatial omics technologies generate wealthy but highly complex datasets. Here we present Spatial Omics DataBase (SODB), a web-based platform providing both rich data resources and a suite of interactive data analytical modules. SODB currently maintains >2,400 experiments from >25 spatial omics technologies, which are freely accessible as a unified data format compatible with various computational packages. SODB also provides multiple interactive data analytical modules, especially a unique module, Spatial Omics View (SOView). We conduct comprehensive statistical analyses and illustrate the utility of both basic and advanced analytical modules using multiple spatial omics datasets. We demonstrate SOView utility with brain spatial transcriptomics data and recover known anatomical structures. We further delineate functional tissue domains with associated marker genes that were obscured when analyzed using previous methods. We finally show how SODB may efficiently facilitate computational method development. The SODB website is https://gene.ai.tencent.com/SpatialOmics/ . The command-line package is available at https://pysodb.readthedocs.io/en/latest/ .

PMID:36797409 | DOI:10.1038/s41592-023-01773-7

Nat Chem Biol. 2023 Feb 16. doi: 10.1038/s41589-022-01243-9. Online ahead of print.

NO ABSTRACT

PMID:36797405 | DOI:10.1038/s41589-022-01243-9

Nat Chem Biol. 2023 Feb 16. doi: 10.1038/s41589-022-01241-x. Online ahead of print.

NO ABSTRACT

PMID:36797402 | DOI:10.1038/s41589-022-01241-x