Physiological Response of Penicillium chrysogenum to Mimicked Local and Global Perturbations of Substrate and Dissolved Oxygen Gradients at Industrial-Scale.

Industrial-scale microbial fermentation processes often face limitations in mixing and mass transfer, leading to the formation of environmental gradients within the bioreactor. These gradients expose microbes to heterogeneous conditions over time and space. In this study, we evaluated the effects of combined substrate and dissolved oxygen (DO) gradients on the metabolic response of Penicillium chrysogenum at an industrial scale.

Novel gut-restricted bivalent agonists targeting mucosal 5-HT4R: Design, synthesis, and biological evaluation.

Chronic idiopathic constipation (CIC) is a prevalent gastrointestinal disorder with limited therapeutic options that balance efficacy and safety. Current therapies, such as the 5-HT receptor (5-HTR) agonist prucalopride, demonstrate efficacy but are often associated with systemic side effects, highlighting the need for gut-restricted alternatives. Herein, we report for the first time the rational design and synthesis of gut-restricted bivalent agonists targeting mucosal 5-HTR by integrating pharmacophores of prucalopride and tenapanor.

Enhancement of abdominal Low-Dose CT image quality utilizing Clear View reconstruction technique at Mzuzu Central Hospital, Malawi.

Objective: This study aimed to investigate the impact of Clear View dual-domain iterative reconstruction (IR) technology on the quality of low-dose abdominal CT images and to determine the optimal weight ratio to optimize image quality.

Methods: We studied 40 patients (28 males, 12 females, aged 19-69) undergoing low-dose abdominal CT scans (CTDI = 5.32 ± 0.

Metabolomic Analysis Reveals the Diversity of Defense Metabolites in Nine Cereal Crops.

Cereal crops are important staple foods, and their defense metabolites hold significant research importance. In this study, we employed LC-MS-based untargeted and widely-targeted metabolomics to profile the leaf metabolome of nine cereal species, including rice, wheat, maize, barley, sorghum, common oat, foxtail millet, broomcorn millet, and adlay. A total of 9869 features were detected, among them, 1131 were annotated, encompassing 18 classes such as flavonoids, lipids, and alkaloids.

A scientometric visualization analysis of the gut microbiota and gestational diabetes mellitus.

Background: The prevalence of gestational diabetes mellitus (GDM), a condition that is widespread globally, is increasing. The relationship between the gut microbiota and GDM has been a subject of research for nearly two decades, yet there has been no bibliometric analysis of this correlation. This study aimed to use bibliometrics to explore the relationship between the gut microbiota and GDM, highlighting emerging trends and current research hotspots in this field.

A first-in-class selective inhibitor of ERK1/2 and ERK5 overcomes drug resistance with a single-molecule strategy.

Despite significant advancements in kinase-targeted therapy, the emergence of acquired drug resistance to targets such as KRAS and MEK remains a challenge. Extracellular-regulated kinase 1/2 (ERK1/2), positioned at the terminus of this pathway, is highly conserved and less susceptible to mutations, thereby garnering attention as a crucial therapeutical target. However, attempts to use monotherapies that target ERK1/2 have achieved only limited clinical success, mainly due to the issues of limited efficacy and the emergence of drug resistance.

cGAS-STING targeting offers novel therapeutic opportunities in neurological diseases.

Cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) (cGAMP) synthase (cGAS) is a cytosolic DNA sensor that produces the secondary messenger cGAMP. cGAMP activates the endoplasmic reticulum-associated adaptor stimulator of interferon genes (STING) and activates the innate immune system to produce a type I interferon response. Besides sensing microbial DNA, cGAS can also be activated by self-DNA or endogenous DNA, including that derived from genotoxic extranuclear chromatin and mitochondrially released DNA, indicating that cGAS-STING is an important mechanism in sterile inflammatory responses, autoimmunity, and cellular senescence.

D-morphinan analogs with favorable pharmacokinetic profiles as dual-acting antidepressants.

Dextromethorphan (DM) is a dual inhibitor of NMDAR and SERT (IC: IC = 31), but lacks therapeutic clinical value for the treatment of depression due to its low exposure in the human body. In this study, a series of d-morphinan derivatives were designed, synthesized and evaluated both in vitro and in vivo to identify dual inhibitors with improved metabolic stability. Structure-activity relationship studies revealed that a methyl group at the morphinan N-17 position is essential for maintaining SERT activity.

Silicon Nutrition Improves Lodging Resistance of Rice Under Dry Cultivation.

Silicon (Si) has been proven to enhance the stress resistance of rice, but its effect on the lodging resistance of rice under dry cultivation (DCR) is still unclear. The purpose of this experiment is to clarify the appropriate amount of silicon fertilizer for DCR to resist lodging and to elucidate how it coordinates lodging resistance and yield. This experiment used the 'Suigeng 18' cultivar as the material and set six silicon fertilizers (SiO) with dosages of 0, 15, 30, 45, 60, and 75 kg·ha (Si0, Si1, Si2, Si3, Si4, Si5).

Mitophagy in Neurodegenerative Diseases: Mechanisms of Action and the Advances of Drug Discovery.

Neurodegenerative diseases (NDDs), such as Parkinson's disease (PD) and Alzheimer's disease (AD), are devastating brain diseases and are incurable at the moment. Increasing evidence indicates that NDDs are associated with mitochondrial dysfunction. Mitophagy removes defective or redundant mitochondria to maintain cell homeostasis, whereas deficient mitophagy accelerates the accumulation of damaged mitochondria to mediate the pathologies of NDDs.

Locally administered liposomal drug depot enhances rheumatoid arthritis treatment by inhibiting inflammation and promoting cartilage repair.

Rheumatoid arthritis (RA) is a chronic autoimmune condition characterized by synovial hyperplasia, where inflammatory macrophages within the joint synovium produce multiple inflammatory cytokines, leading to cartilage damage. The development of therapeutic strategies that combine anti-inflammatory effects and cartilage repair mechanisms holds great promise for effective RA treatment. To address the limitations associated with the off-target effects of intravenous administration and the risk of synovial cavity infection with repeated local injections, we have innovatively developed a liposomal drug depot through hyaluronic acid (HA)-modified liposomes encapsulating dexamethasone sodium phosphate (DSP)-loaded nanogels, termed HA-Lipo@G/D.

The Clinical Value of the MAR+ Metal Artifact Reduction Algorithm for Postoperative Assessment of Lumbar Internal Fixation.

Background: With the widespread use of lumbar pedicle screws for internal fixation, the morphology of the screws and the surrounding tissues should be evaluated. The metal artifact reduction (MAR) technique can reduce the artifacts caused by pedicle screws, improve the quality of computed tomography (CT) images after pedicle fixation, and provide more imaging information to the clinic.

Purpose: To explore whether the MAR+ method, a projection-based algorithm for correcting metal artifacts through multiple iterative operations, can reduce metal artifacts and have an impact on the structure of the surrounding metal.

Fasting enhances the efficacy of Sorafenib in breast cancer via mitophagy mediated ROS-driven p53 pathway.

The multi-kinase inhibitor sorafenib has shown potential to inhibit tumor cell growth and intra-tumoral angiogenesis by targeting several kinases, including VEGFR2 and RAF. Abnormal activation of the Ras/Raf/MAPK/ERK kinase cascade and the VEGF pathway is a common feature in breast cancer. However, the efficacy of sorafenib in breast cancer treatment remains limited.

Regulation of enzymatic lipid peroxidation in osteoblasts protects against postmenopausal osteoporosis.

Oxidative stress plays a critical role in postmenopausal osteoporosis, yet its impact on osteoblasts remains underexplored, limiting therapeutic advances. Our study identifies phospholipid peroxidation in osteoblasts as a key feature of postmenopausal osteoporosis. Estrogen regulates the transcription of glutathione peroxidase 4 (GPX4), an enzyme crucial for reducing phospholipid peroxides in osteoblasts.

Efficient Photocatalytic Water Purification Through Novel Janus-Nanomicelles with Long-Lived Charge Separation Properties.

Although the design of photocatalysts incorporating donor-acceptor units has garnered significant attention for its potential to enhance the efficiency of the photocatalysis process, the primary bottleneck lies in the challenge of generating long-lived charge separation states during exciton separation. Therefore, a novel Janus-nanomicelles photocatalyst is developed using carbazole (Cz) as the donor unit, perylene-3,4,9,10-tetracarboxydiimide (PDI) with long-excited state as the acceptor unit and polyethylene glycol (PEG) as the hydrophilic segment through ROMP polymerization. After optimizing the ratio, Cz-PDI-PEG rapidly adsorbs bisphenol A (BPA) within 10 s through π-π interaction, hydrogen-bonding interaction, and hydrophobic interaction between BPA and hydrophobic blocks when exposed to aqueous humor and efficiently photodegrades BPA (50 ppm) within 120 min for water purification purposes due to its long-lived charge separation state and achieving the highest reported efficiency so far.

Concentration-Bias-Free Discrimination of Single Nucleotide Variants Using Isothermal Nucleic Acid Amplification and Mismatch-Guided DNA Assembly.

Isothermal nucleic acid amplification techniques are promising alternatives to polymerase chain reaction (PCR) for amplifying and detecting nucleic acids under resource-limited conditions. While many isothermal amplification strategies, such as recombinase polymerase amplification (RPA), offer comparable sensitivity to PCR, they often lack the specificity and robustness for discriminating single nucleotide variants (SNVs), mainly due to the uncontrolled production of massive amplicons. Herein, we introduce a mismatch-guided DNA assembly (MGDA) approach capable of discriminating SNVs in the presence of high concentrations of wild-type (WT) interferences.

ONC213: a novel strategy to resensitize resistant AML cells to venetoclax through induction of mitochondrial stress.

Background: Venetoclax + azacitidine is a frontline treatment for older adult acute myeloid leukemia (AML) patients and a salvage therapy for relapsed/refractory patients who have been treated with intensive chemotherapy. While this is an important treatment option, many patients fail to achieve complete remission and of those that do, majority relapse. Leukemia stem cells (LSCs) are believed to be responsible for AML relapse and can be targeted through oxidative phosphorylation reduction.

Development of Citric-Acid-Modified Cellulose Monolith for Enriching Glycopeptides.

Prior to mass spectrometry (MS) analysis, pretreatment of low-abundance glycopeptides is vital for identifying protein glycosylation. In this study, we fabricated an environmentally friendly citric-acid-modified cellulose monolith (CCM) characterized by a coral-like porous structure and high-density hydrophilic groups using a thermally induced phase separation (TIPS) method. The CCM production leverages biomass resources, specifically cellulose and citric acid, utilizing TIPS to synthesize continuous porous materials through a straightforward heating and cooling process of polymer solutions.

A rapid chemical reprogramming system to generate human pluripotent stem cells.

Chemical reprogramming enables the generation of human pluripotent stem (hCiPS) cells from somatic cells using small molecules, providing a promising strategy for regenerative medicine. However, the current method is time consuming, and some cell lines from different donors are resistant to chemical induction, limiting the utility of this approach. Here, we developed a fast reprogramming system capable of generating hCiPS cells in as few as 10 days.

Distinct microbes, metabolites, and the host genome define the multi-omics profiles in right-sided and left-sided colon cancer.

Background: Studies have reported clinical heterogeneity between right-sided colon cancer (RCC) and left-sided colon cancer (LCC). However, none of these studies used multi-omics analysis combining genetic regulation, microbiota, and metabolites to explain the site-specific difference.

Methods: Here, 494 participants from a 16S rRNA gene sequencing cohort (50 RCC, 114 LCC, and 100 healthy controls) and a multi-omics cohort (63 RCC, 79 LCC, and 88 healthy controls) were analyzed.

The influence of vaginal microbiota on the pregnancy outcome of artificial insemination with husband's sperm based on microscope images combined with PCR fluorescence method.

The vaginal microbiota plays an important role in reproductive health, especially in the process of artificial insemination. The imbalance of microbiota may affect pregnancy outcomes. Therefore, this study aims to explore the composition of vaginal microbiota and its impact on artificial insemination pregnancy outcomes, combined with microscopic images and PCR fluorescence methods, in order to provide scientific basis for improving the pregnancy outcomes of husband sperm artificial insemination.

Near-Infrared Organic Small-Molecule Photosensitizer With O Self-Supply for Cancer Photodynamic-Photothermal Synergistic Therapy.

Tumor hypoxia and heat resistance as well as the light penetration deficiency severely compromise the phototherapeutic efficacy, developing phototherapeutic agents to overcome these issues has been sought-after goal. Herein, a diradical-featured organic small-molecule semiconductor, namely TTD-CN, has been designed to show low exciton binding energy of 42 meV by unique dimeric π-π aggregation, promoting near-infrared (NIR) absorption beyond 808 nm and effective photo-induced charge separation. More interestingly, its redox potentials are tactfully manipulated for water splitting to produce O and reduction of O to generate O .

Photoinduced Radical Relay Reaction of 2-Methylthiolated Phenylacetylenes/Alkynones Initiated by Electron Donor-Acceptor Complexes.

A method was found to construct sulfur-containing five- and six-membered heterocyclic alkyl sulfonyl compounds by using visible light and free radicals activated and/or generated by EDA complexes/homolytic cleavage as initiators to stimulate the relay reaction of alkynes/alkynones. This method puts forward a new strategy to initiate alkyl sulfonation of alkynes/alkynones with only a catalytic amount of the initiator. This strategy of generating the initiator by EDA complex activation/homolytic cleavage provides a new idea for the following substances that must be excited.