Roles of Menin in T cell differentiation and function: Current knowledge and perspectives.

The commitment to specific T lymphocytes (T cell) lineages is governed by distinct transcription factors, whose expression is modulated through epigenetic mechanisms. Unravelling these epigenetic mechanisms that regulate T cell differentiation and function holds significant importance for understanding T cells. Menin, a multifunctional scaffolding protein, is implicated in various cellular processes, such as cell proliferation, cell cycle control, DNA repair and transcriptional regulation, primarily through epigenetic mechanisms. Existing research indicates Menin's impact on T cell differentiation and function, while a comprehensive and systematic review is currently lacking to consolidate these findings. In the current review, we have highlighted recent studies on the role of Menin in T cell differentiation and function, focusing mainly on its impact on the memory Th2 maintenance, Th17 differentiation and maintenance, CD4+ T cell senescence, and effector CD8+ T cell survival. Considering Menin's crucial function in maintaining effector T cell function, the potential of inhibiting Menin activity in mitigating inflammatory diseases associated with excessive T cell activation has also been emphasised.

In situ surface turbidity sensor based on localized light scattering from tilted fiber Bragg gratings.

We propose a compact fiber-optic sensor for in situ and continuous turbidity monitoring, based on surface optical scattering of polarized evanescent waves from targeted particles. The sensor is composed of a tilted fiber Bragg grating (TFBG) packaged inside a microfluidic capillary. The transmission spectrum of the TFBG provides a fine comb of narrow cladding resonances that are highly sensitive to the turbidity due to the localized light scattering of polarized evanescent waves from the microparticles near the fiber surface (as opposed to traditional bulk/volumetric turbidity measurement). We also propose a transmission spectral area interrogation method and quantify the repeatable correlation between the surface turbidity and the optical spectral area response. We show that the maximum sensitive turbidity response is achieved when the wavelength of the sensing cladding resonance matches the size of surrounding solid particles.

Effects of Various Nectar and Pollen Plants on the Survival, Reproduction, and Predation of Neoseiulus bicaudus.

Neoseiulus bicaudus is a predatory mite species that could potentially be used for the biological control of spider mites and thrips. Floral resources can provide excellent habitats and abundant nutrients for natural enemies. The objective of this experiment was to evaluate the effects of eight floral resources on the longevity, fecundity, and predation ability of N. bicaudus. Among the considered plants, Cnidium monnieri led to the highest longevity (24 days) and fecundity (13.8 eggs) of N. bicaudus, while Tagetes erecta resulted in the lowest longevity (7 days) and fecundity (0.1 eggs) observed in the predatory mites. By comparing the effects of three nectar and pollen plants on the predation of predatory mites, it was observed that N. bicaudus still exhibited a type II functional response to Tetranychus turkestani. In the presence of pollen, the predation efficacy (a/Th) of N. bicaudus exhibited a lower value, compared to that in the absence of pollen (Control: a/Th = 24.00). When pollen was supplied, the maximum consumption (1/Th) of predatory mites was higher than in its absence (Control: 1/Th = 9.90 d-1), with the highest value obtained in the presence of B. officinalis pollen (B. officinalis: 1/Th = 17.86 d-1). The influence coefficient of predation of N. bicaudus on T. turkestani in the presence of pollen was compared in the presence of three nectar and pollen plants: Cnidium monnieri, Centaurea cyanus, and Borago officinalis. At low prey densities, the influence coefficient of C. cyanus exceeded that of B. officinalis, and the overall influence coefficient values were negative (i.e., the presence of pollen reduced predatory mite feeding on T. turkestani). They exhibited similar values at high prey densities, and all of the influence coefficient values were close to 0 (i.e., the presence of pollen had no effect on predatory mite feeding on T. turkestani). The findings revealed that diverse plant species exert differential impacts on N. bicaudus, with some influencing its lifespan and others affecting its reproductive capabilities. Furthermore, the presence of nectar and pollen plants had a significant impact on predatory mite feeding on T. turkestani at low prey densities; however, this effect diminished as the prey density increased. Therefore, we recommend planting C. monnieri, C. cyanus, and B. officinalis in the field to ensure an ample population of predatory mites. The obtained results hold significant implications for the utilization of nectar and pollen plants in eco-friendly pest management strategies within agricultural contexts.

Ultrasensitive and Multiple Biomarker Discrimination for Alzheimer's Disease via Plasmonic & Microfluidic Sensing Technologies.

As the population ages, the worldwide prevalence of Alzheimer's disease (AD) as the most common dementia in the elderly is increasing dramatically. However, a long-term challenge is to achieve rapid and accurate early diagnosis of AD by detecting hallmarks such as amyloid beta (Aß42). Here, a multi-channel microfluidic-based plasmonic fiber-optic biosensing platform is established for simultaneous detection and differentiation of multiple AD biomarkers. The platform is based on a gold-coated, highly-tilted fiber Bragg grating (TFBG) and a custom-developed microfluidics. TFBG excites a high-density, narrow-cladding-mode spectral comb that overlaps with the broad absorption of surface plasmons for high-precision interrogation, enabling ultrasensitive monitoring of analytes. In situ detection and in-parallel discrimination of different forms of Aß42 in cerebrospinal fluid (CSF) are successfully demonstrated with a detection of limit in the range of ≈30-170 pg mL-1, which is one order of magnitude below the clinical cut-off level in AD onset, providing high detection sensitivity for early diagnosis of AD. The integration of the TFBG sensor with multi-channel microfluidics enables simultaneous detection of multiple biomarkers using sub-µL sample volumes, as well as combining initial binding rate and real-time response time to differentiate between multiple biomarkers in terms of binding kinetics. With the advantages of multi-parameter, low consumption, and highly sensitive detection, the sensor represents an urgently needed potentials for large-scale diagnosis of diseases at early stage.

Everolimus combined with PD-1 blockade inhibits progression of triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer. Due to rapid progression and a lack of targetable receptors, TNBC is exceptionally difficult to treat. Available treatment options are nonspecific cytotoxic agents, which have had modest success; thus, there is a need for novel therapies for TNBC. The mammalian/mechanistic target of rapamycin (mTOR) signaling pathway is aberrantly activated in TNBC, and this pathway has been shown to promote cancer cell survival and chemoresistance. As such, mTOR inhibition has been considered a potential therapeutic strategy for TNBC. The mTOR inhibitor everolimus (EVE) has been approved for the treatment of estrogen positive breast cancer; however, its efficacy in TNBC is still undetermined. In this study, we evaluated the effects of EVE monotherapy and the mechanism of EVE resistance in the 4T1 model of TNBC. Whereas EVE monotherapy inhibited mTOR signaling activity, it did not attenuate tumor progression. Additionally, tumors from EVE-treated mice had abnormal vasculature characterized by disorganized architecture and hyperpermeability. We also found that treatment with EVE increased PD-L1 expression in intratumoral vascular endothelial cells, and this increase in endothelial cell-associated PD-L1 corresponded to reduced CD8 + T cell tumor infiltration. Importantly, combination treatment with anti-PD-1 antibody and EVE normalized the tumor vasculature, rescued CD8 + T cell tumor infiltration, and reduced tumor growth. Taken together, our findings improve our current understanding of mechanisms underlying mTOR inhibition resistance in TNBC and identify a novel combination treatment strategy in the treatment of mTOR resistant tumors.

Evaluating Human Natural Killer Cells Antibody-dependent Cellular Cytotoxicity (ADCC) Using Plate-bound Anti-CD16 Antibodies.

Natural killer (NK) cells are large granular lymphocytes that keep in check the health of neighboring cells through a large array of intrinsically expressed germline-coded receptors. Most importantly, CD16 is a low affinity Fc receptor for IgG that mediates the antibody-dependent cellular cytotoxicity (ADCC) of NK cells, bridging the innate and adaptive immunities. There has been a significant interest in genetically engineering NK cells to enhance its ADCC, with the ultimate goal to produce off-the-shelf NK cell therapy products that can be combined with target-specific monoclonal antibodies to improve clinical outcomes. Previous protocols of ADCC assays use complex cell-based antigen-antibody models, which are both costly and time-consuming. This current protocol is devoid of target cells and uses plate-bound immobilized anti-CD16 antibodies as the trigger. It greatly shortens the experimental time, while faithfully evaluating NK cells ADCC. Graphic abstract: Workflow of stimulating NK cells via CD16 by plate-bound anti-CD16 mAb.

FcRγ Gene Editing Reprograms Conventional NK Cells to Display Key Features of Adaptive Human NK Cells.

Adaptive human natural killer (NK) cells display significantly enhanced responsiveness to a broad-range of antibody-bound targets through the engagement of CD16 compared to conventional NK cells, yet direct reactivity against tumor targets is generally reduced. Adaptive NK cells also display a distinct phenotype and differential expression of numerous genes, including reduced expression of signaling adapter FcRγ and transcription factor PLZF. However, it is unclear whether differential expression of specific genes is responsible for the characteristics of adaptive NK cells. Using CRISPR-Cas9, we show deletion of FcRγ in conventional NK cells led to enhanced CD16 responsiveness, abolished cell surface expression of natural cytotoxicity receptors, NKp46 and NKp30, and dramatically reduced responsiveness to K562 and Raji tumor cells. However, deletion of PLZF had no notable effects. These results suggest multiple roles for FcRγ and identify its deficiency as an important factor responsible for the functional and phenotypic characteristics exhibited by adaptive NK cells.

Performing meta-analysis with incomplete statistical information in clinical trials.

BACKGROUND: Results from clinical trials are usually summarized in the form of sampling distributions. When full information (mean, SEM) about these distributions is given, performing meta-analysis is straightforward. However, when some of the sampling distributions only have mean values, a challenging issue is to decide how to use such distributions in meta-analysis. Currently, the most common approaches are either ignoring such trials or for each trial with a missing SEM, finding a similar trial and taking its SEM value as the missing SEM. Both approaches have drawbacks. As an alternative, this paper develops and tests two new methods, the first being the prognostic method and the second being the interval method, to estimate any missing SEMs from a set of sampling distributions with full information. A merging method is also proposed to handle clinical trials with partial information to simulate meta-analysis. METHODS: Both of our methods use the assumption that the samples for which the sampling distributions will be merged are randomly selected from the same population. In the prognostic method, we predict the missing SEMs from the given SEMs. In the interval method, we define intervals that we believe will contain the missing SEMs and then we use these intervals in the merging process. RESULTS: Two sets of clinical trials are used to verify our methods. One family of trials is on comparing different drugs for reduction of low density lipprotein cholesterol (LDL) for Type-2 diabetes, and the other is about the effectiveness of drugs for lowering intraocular pressure (IOP). Both methods are shown to be useful for approximating the conventional meta-analysis including trials with incomplete information. For example, the meta-analysis result of Latanoprost versus Timolol on IOP reduction for six months provided in 1 was 5.05 +/- 1.15 (Mean +/- SEM) with full information. If the last trial in this study is assumed to be with partial information, the traditional analysis method for dealing with incomplete information that ignores this trial would give 6.49 +/- 1.36 while our prognostic method gives 5.02 +/- 1.15, and our interval method provides two intervals as Mean in [4.25, 5.63] and SEM in [1.01, 1.24]. CONCLUSION: Both the prognostic and the interval methods are useful alternatives for dealing with missing data in meta-analysis. We recommend clinicians to use the prognostic method to predict the missing SEMs in order to perform meta-analysis and the interval method for obtaining a more cautious result.

The characterization, renoprotection and antioxidation of enzymatic and acidic exopolysaccharides from Hypsizigus marmoreus.

The present work was designed to investigate the characterization, as well as the antioxidation and renoprotection in streptozocin (STZ)-induced diabetic mice, of exopolysaccharides (EPS) and the enzymatic-EPS (EEPS) and acidic-EPS (AEPS) hydrolysates, which were separated from the fermentation liquor of Hypsizigus marmoreus. Animal results demonstrated that EPS, EEPS and AEPS had potential antioxidant and renoprotective effects, especially EEPS. Additionally, they were the most effective, reflecting increases in superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), total antioxidant capacity (T-AOC), and albumin (ALB) of 168.33%, 124.8%, 268.17% 179.49%, and 68.71%, respectively, and decreases in the contents of malondialdehyde (MDA), lipid peroxide (LPO) and levels of serum urea nitrogen (BUN) and creatinine (CRE) by 70.58%, 58.43%, 23.97% and 29.60%, respectively, at a dose of 800 mg/kg compared to those of model mice. Three polysaccharides ameliorated the histopathological alterations which were observed in the kidney of diabetic mice. Furthermore, the characterization of polysaccharides had been expressed. These findings indicated that the EEPS from H. marmoreus possesses more effective renoprotection and antioxidation effects and provided insight into its potential clinical values on preventing diabetes.

Purification, in vitro antioxidant and in vivo anti-aging activities of soluble polysaccharides by enzyme-assisted extraction from Agaricus bisporus.

In present study, the soluble polysaccharides by enzyme-assisted extraction from Agaricus bisporus (EnAPS) and its purified fractions of EnAPS-1, -2 and -3 were successfully obtained, and the antioxidant activities and anti-aging effects were investigated. The in vitro antioxidant assay demonstrated that EnAPS-2 had superior scavenging activities on DPPH and hydroxyl radicals, chelating activities of Fe2+ and reducing power. The in vivo animal experiments showed that both EnAPS and its purifies fractions had potential anti-aging effects against the d-galctose-induced aging diseases on liver, kidney, brain and skin, possibly by increasing the antioxidant enzymes, reducing the lipid peroxidation, improving the organ functions and remitting the lipid metabolism. The conclusions demonstrated that the polysaccharides by A. bisporus might be suitable for applying functional foods and natural drugs in preventing and delaying the aging and its complications.

Characterization, antioxidation, anti-inflammation and renoprotection effects of selenized mycelia polysaccharides from Oudemansiella radicata.

The present work investigated the characteristics, antioxidative, anti-inflammative and renoprotective effects of mycelia selenized polysaccharides (MSPS) from Oudemansiella radicata on lipopolysaccharide (LPS)-induced kidney damaged mice. The results demonstrated that both MSPS and mycelia polysaccharides (MPS) showed potential renoprotective effects reflecting by decreasing the serum levels of CRE, BUN and UA, increasing the nephritic enzyme activities of SOD, GSH-Px, CAT and T-AOC, reducing the activities of MPO, as well as down-regulating the contents of MDA and LPO, respectively. And the MSPS showed superior effects. Furthermore, the selenium contents and physical properties of polysaccharides were investigated by FAAS, GC, HPGPC, FT-IR, NMR and AFM analysis, and the results indicated that MSPS was a homogeneous heteropolysaccharide with an average molecular weight of 3.12×104Da. These results may provide theoretical basis in applying natural and functional foods for the prevention and alleviation of kidney damages and its complications.

Hepatoprotective effects of Auricularia cornea var. Li. polysaccharides against the alcoholic liver diseases through different metabolic pathways.

The present work was designed to evaluate the antioxidation and hepatoprotective effects of Auricularia cornea var. Li. polysaccharides (APS) and enzymatic-extractable APS (EAPS) on the acute alcohol-induced alcoholic liver diseases (ALD). The in vitro antioxidant activities demonstrated that both APS and EAPS had strong reducing power and potential effects on scavenging reactive oxygen species. The in vivo mice experiments showed that the pretreatment with APS or EAPS showed potential hepatoprotective effects on the ALD possibly by increasing the antioxidant activities, reducing the lipid peroxidation, improving the alcohol metabolism, inhibiting the expression levels of inflammatory mediators and preventing the alcohol-induced histopathological alterations. In addition, the fourier-transform infrared (FT-IR), 1H and 13C nuclear magnetic resonance spectroscopy (NMR) and gas chromatography (GC) had been analyzed to obtained the primarily characteristics. The results indicated that abundant xylose and glucose contents probably had potential effects on possessing the bioactivities. The findings suggested that the A. cornea var. Li. might be considered as promising natural resource on exploring clinical drugs for the prevention and treatment with ALD and its complications.

Antioxidant and Hepatoprotective Activities of Polysaccharides from Spent Mushroom Substrates (Laetiporus sulphureus) in Acute Alcohol-Induced Mice.

In order to contribute to the exploitation and utilization of spent mushroom substrates (SMS) of Laetiporus sulphureus, hot-water-extractable polysaccharides (H-SMPS) and enzymatic-extractable polysaccharides (E-SMPS) were successfully isolated from SMS of L. sulphureus. Both H-SMPS and E-SMPS were found to have high reducing power and potential scavenging activities against hydroxyl, DPPH, and superoxide anion radicals. In vivo assays showed that the administration of H-SMPS and E-SMPS has potential hepatoprotective effects against alcohol-induced alcoholic liver disease (ALD), possibly brought about by improving liver function, increasing antioxidant status, and reducing lipid peroxidation. Furthermore, monosaccharide composition analysis showed that fucose may play a vital role in guaranteeing stronger hepatoprotection. These results may provide references for the exploitation of the SMS of L. sulphureus as a source of H-SMPS and E-SMPS, which in turn can be used as functional foods or natural drugs for the prevention of ALD and other liver diseases.

A cytoplasmic peptidoglycan amidase homologue controls mycobacterial cell wall synthesis.

Regulation of cell wall assembly is essential for bacterial survival and contributes to pathogenesis and antibiotic tolerance in Mycobacterium tuberculosis (Mtb). However, little is known about how the cell wall is regulated in stress. We found that CwlM, a protein homologous to peptidoglycan amidases, coordinates peptidoglycan synthesis with nutrient availability. Surprisingly, CwlM is sequestered from peptidoglycan (PG) by localization in the cytoplasm, and its enzymatic function is not essential. Rather, CwlM is phosphorylated and associates with MurA, the first enzyme in PG precursor synthesis. Phosphorylated CwlM activates MurA ~30 fold. CwlM is dephosphorylated in starvation, resulting in lower MurA activity, decreased cell wall metabolism, and increased tolerance to multiple antibiotics. A phylogenetic analysis of cwlM implies that localization in the cytoplasm drove the evolution of this factor. We describe a system that controls cell wall metabolism in response to starvation, and show that this regulation contributes to antibiotic tolerance.

A ligand predication tool based on modeling and reasoning with imprecise probabilistic knowledge.

Ligand prediction has been driven by a fundamental desire to understand more about how biomolecules recognize their ligands and by the commercial imperative to develop new drugs. Most of the current available software systems are very complex and time-consuming to use. Therefore, developing simple and efficient tools to perform initial screening of interesting compounds is an appealing idea. In this paper, we introduce our tool for very rapid screening for likely ligands (either substrates or inhibitors) based on reasoning with imprecise probabilistic knowledge elicited from past experiments. Probabilistic knowledge is input to the system via a user-friendly interface showing a base compound structure. A prediction of whether a particular compound is a substrate is queried against the acquired probabilistic knowledge base and a probability is returned as an indication of the prediction. This tool will be particularly useful in situations where a number of similar compounds have been screened experimentally, but information is not available for all possible members of that group of compounds. We use two case studies to demonstrate how to use the tool.