Molecular insights into P2X signalling cascades in acute kidney injury.

Acute kidney injury (AKI) is a critical health issue with high mortality and morbidity rates in hospitalized individuals. The complex pathophysiology and underlying health conditions further complicate AKI management. Growing evidence suggests the pivotal role of ion channels in AKI progression, through promoting tubular cell death and altering immune cell functions. Among these channels, P2X purinergic receptors emerge as key players in AKI pathophysiology. P2X receptors gated by adenosine triphosphate (ATP), exhibit increased extracellular levels of ATP during AKI episodes. More importantly, certain P2X receptor subtypes upon activation exacerbate the situation by promoting the release of extracellular ATP. While therapeutic investigations have primarily focused on P2X4 and P2X7 subtypes in the context of AKI, while understanding about other subtypes still remains limited. Whilst some P2X antagonists show promising results against different types of kidney diseases, their role in managing AKI remains unexplored. Henceforth, understanding the intricate interplay between P2X receptors and AKI is crucial for developing targeted interventions. This review elucidates the functional alterations of all P2X receptors during normal kidney function and AKI, offering insights into their involvement in AKI. Notably, we have highlighted the current knowledge of P2X receptor antagonists and the possibilities to use them against AKI in the future. Furthermore, the review delves into the pathways influenced by activated P2X receptors during AKI, presenting potential targets for future therapeutic interventions against this critical condition.

Immunosuppressants against acute kidney injury: what to prefer or to avoid?

BACKGROUND: Acute kidney injury (AKI) is a critical global health issue associated with high mortality rates, particularly in patients undergoing renal transplants and major surgeries. These individuals often receive immunosuppressants to dampen immune responses, but the impact of these drugs on AKI remains unclear. OBJECTIVE: This review aims to provide a detailed understanding of the effects of different classes of immunosuppressants against AKI, elucidating their role in either exacerbating or mitigating the occurrence or progression of AKI. METHODS: Several preclinical and clinical reports were analyzed to evaluate the impact of various immunosuppressants on AKI. Relevant preclinical and clinical studies were reviewed through different databases such as Scopus, PubMed, Google Scholar, and ScienceDirect, and official websites like https://clinicaltrials.gov to understand the mechanisms underlying the effects of immunosuppressants on kidney function. RESULTS AND DISCUSSION: Specific immunosuppressants have been linked to the progression of AKI, while others demonstrate renoprotective effects. However, there is no consensus on the preferred or avoided immunosuppressants for AKI patients. This review outlines the classes of immunosuppressants commonly used and their impact on AKI, providing guidance for physicians in selecting appropriate drugs to prevent or ameliorate AKI. CONCLUSION: Understanding the effects of immunosuppressants on AKI is crucial for optimizing patient care. This review highlights the need for further research to determine the most suitable immunosuppressants for AKI patients, considering both their efficacy and potential side effects.

The Alzheimer's gene SORL1 is a regulator of endosomal traffic and recycling in human neurons.

BACKGROUND: Loss of the Sortilin-related receptor 1 (SORL1) gene seems to act as a causal event for Alzheimer's disease (AD). Recent studies have established that loss of SORL1, as well as mutations in autosomal dominant AD genes APP and PSEN1/2, pathogenically converge by swelling early endosomes, AD's cytopathological hallmark. Acting together with the retromer trafficking complex, SORL1 has been shown to regulate the recycling of the amyloid precursor protein (APP) out of the endosome, contributing to endosomal swelling and to APP misprocessing. We hypothesized that SORL1 plays a broader role in neuronal endosomal recycling and used human induced pluripotent stem cell-derived neurons (hiPSC-Ns) to test this hypothesis. We examined endosomal recycling of three transmembrane proteins linked to AD pathophysiology: APP, the BDNF receptor Tropomyosin-related kinase B (TRKB), and the glutamate receptor subunit AMPA1 (GLUA1). METHODS: We used isogenic hiPSCs engineered to have SORL1 depleted or to have enhanced SORL1 expression. We differentiated neurons from these cell lines and mapped the trafficking of APP, TRKB and GLUA1 within the endosomal network using confocal microscopy. We also performed cell surface recycling and lysosomal degradation assays to assess the functionality of the endosomal network in both SORL1-depleted and -overexpressing neurons. The functional impact of GLUA1 recycling was determined by measuring synaptic activity. Finally, we analyzed alterations in gene expression in SORL1-depleted neurons using RNA sequencing. RESULTS: We find that as with APP, endosomal trafficking of GLUA1 and TRKB is impaired by loss of SORL1. We show that trafficking of all three cargoes to late endosomes and lysosomes is affected by manipulating SORL1 expression. We also show that depletion of SORL1 significantly impacts the endosomal recycling pathway for APP and GLUA1 at the level of the recycling endosome and trafficking to the cell surface. This has a functional effect on neuronal activity as shown by multi-electrode array (MEA). Conversely, increased SORL1 expression enhances endosomal recycling for APP and GLUA1. Our unbiased transcriptomic data further support SORL1's role in endosomal recycling. We observe altered expression networks that regulate cell surface trafficking and neurotrophic signaling in SORL1-depleted neurons. CONCLUSION: Collectively, and together with other recent observations, these findings suggest that one role for SORL1 is to contribute to endosomal degradation and recycling pathways in neurons, a conclusion that has both pathogenic and therapeutic implications for Alzheimer's disease.

The role of Alzheimer's disease risk genes in endolysosomal pathways.

There is ample pathological and biological evidence for endo-lysosomal dysfunction in Alzheimer's disease (AD) and emerging genetic studies repeatedly implicate endo-lysosomal genes as associated with increased AD risk. The endo-lysosomal network (ELN) is essential for all cell types of the central nervous system (CNS), yet each unique cell type utilizes cellular trafficking differently (see Fig. 1). Challenges ahead involve defining the role of AD associated genes in the functionality of the endo-lysosomal network (ELN) and understanding how this impacts the cellular dysfunction that occurs in AD. This is critical to the development of new therapeutics that will impact, and potentially reverse, early disease phenotypes. Here we review some early evidence of ELN dysfunction in AD pathogenesis and discuss the role of selected AD-associated risk genes in this pathway. In particular, we review genes that have been replicated in multiple genome-wide association studies(Andrews et al., 2020; Jansen et al., 2019; Kunkle et al., 2019; Lambert et al., 2013; Marioni et al., 2018) and reviewed in(Andrews et al., 2020) that have defined roles in the endo-lysosomal network. These genes include SORL1, an AD risk gene harboring both rare and common variants associated with AD risk and a role in trafficking cargo, including APP, through the ELN; BIN1, a regulator of clathrin-mediated endocytosis whose expression correlates with Tau pathology; CD2AP, an AD risk gene with roles in endosome morphology and recycling; PICALM, a clathrin-binding protein that mediates trafficking between the trans-Golgi network and endosomes; and Ephrin Receptors, a family of receptor tyrosine kinases with AD associations and interactions with other AD risk genes. Finally, we will discuss how human cellular models can elucidate cell-type specific differences in ELN dysfunction in AD and aid in therapeutic development.

Activin A-derived human embryonic stem cells show increased competence to differentiate into primordial germ cell-like cells.

Protocols for specifying human primordial germ cell-like cells (hPGCLCs) from human embryonic stem cells (hESCs) remain hindered by differences between hESC lines, their derivation methods, and maintenance culture conditions. This poses significant challenges for establishing reproducible in vitro models of human gametogenesis. Here, we investigated the influence of activin A (ActA) during derivation and maintenance on the propensity of hESCs to differentiate into PGCLCs. We show that continuous ActA supplementation during hESC derivation (from blastocyst until the formation of the post-inner cell mass intermediate [PICMI]) and supplementation (from the first passage of the PICMI onwards) is beneficial to differentiate hESCs to PGCLCs subsequently. Moreover, comparing isogenic primed and naïve states prior to differentiation, we showed that conversion of hESCs to the 4i-state improves differentiation to (TNAP [tissue nonspecific alkaline phosphatase]+/PDPN [podoplanin]+) PGCLCs. Those PGCLCs expressed several germ cell markers, including TFAP2C (transcription factor AP-2 gamma), SOX17 (SRY-box transcription factor 17), and NANOS3 (nanos C2HC-type zinc finger 3), and markers associated with germ cell migration, CXCR4 (C-X-C motif chemokine receptor 4), LAMA4 (laminin subunit alpha 4), ITGA6 (integrin subunit alpha 6), and CDH4 (cadherin 4), suggesting that the large numbers of PGCLCs obtained may be suitable to differentiate further into more mature germ cells. Finally, hESCs derived in the presence of ActA showed higher competence to differentiate to hPGCLC, in particular if transiently converted to the 4i-state. Our work provides insights into the differences in differentiation propensity of hESCs and delivers an optimized protocol to support efficient human germ cell derivation.

Chaotic cavity design of a UV-C disinfection chamber for uniform radiation distribution.

UV-C radiation has been used extensively for disinfection wherein the dosage of radiation varies with the microorganism concerned. The efficacy of disinfection largely relies on the radiation reaching uniformly across the chamber without simultaneously leaving out dark regions within the chamber. The regular geometries of the chambers, such as with circular or rectangular cross sections, invariably lead to hot spots accompanied by regions that remain dark, thereby severely limiting the germicidal effects of the UV-C radiation. We propose and demonstrate the use of a chaotic Bunimovich stadium design chamber that ensures uniform UV-C exposure without any accompanying "dark spots." The design incorporates the shape parameters of a chaotic Bunimovich stadium, wherein ray-tracing simulations confirm the space-filling nature of the photon trajectories, typical of chaotic dynamics. This leads to uniform radiation distribution across the whole volume. Experimental results are presented for a biosafety cabinet that can be used for UV-C disinfection wherein the UV-C light intensity distribution is more evenly distributed than the conventional regular (cuboidal) geometry. Adaptation of this simple design consideration is paramount for air disinfection, wherein dark regions in conventional air ducts can severely compromise the efficacy of the disinfection.

Computational identification of micro-structural variations and their proteogenomic consequences in cancer.

Motivation: Rapid advancement in high throughput genome and transcriptome sequencing (HTS) and mass spectrometry (MS) technologies has enabled the acquisition of the genomic, transcriptomic and proteomic data from the same tissue sample. We introduce a computational framework, ProTIE, to integratively analyze all three types of omics data for a complete molecular profile of a tissue sample. Our framework features MiStrVar, a novel algorithmic method to identify micro structural variants (microSVs) on genomic HTS data. Coupled with deFuse, a popular gene fusion detection method we developed earlier, MiStrVar can accurately profile structurally aberrant transcripts in tumors. Given the breakpoints obtained by MiStrVar and deFuse, our framework can then identify all relevant peptides that span the breakpoint junctions and match them with unique proteomic signatures. Observing structural aberrations in all three types of omics data validates their presence in the tumor samples. Results: We have applied our framework to all The Cancer Genome Atlas (TCGA) breast cancer Whole Genome Sequencing (WGS) and/or RNA-Seq datasets, spanning all four major subtypes, for which proteomics data from Clinical Proteomic Tumor Analysis Consortium (CPTAC) have been released. A recent study on this dataset focusing on SNVs has reported many that lead to novel peptides. Complementing and significantly broadening this study, we detected 244 novel peptides from 432 candidate genomic or transcriptomic sequence aberrations. Many of the fusions and microSVs we discovered have not been reported in the literature. Interestingly, the vast majority of these translated aberrations, fusions in particular, were private, demonstrating the extensive inter-genomic heterogeneity present in breast cancer. Many of these aberrations also have matching out-of-frame downstream peptides, potentially indicating novel protein sequence and structure. Availability and implementation: MiStrVar is available for download at https://bitbucket.org/compbio/mistrvar, and ProTIE is available at https://bitbucket.org/compbio/protie. Contact: cenksahi@indiana.edu. Supplementary information: Supplementary data are available at Bioinformatics online.

Microbial processing of fruit and vegetable wastes into potential biocommodities: a review.

The review focuses on some of the high value-end biocommodities, such as fermented beverages, single-cell proteins, single-cell oils, biocolors, flavors, fragrances, polysaccharides, biopesticides, plant growth regulators, bioethanol, biogas and biohydrogen, developed from the microbial processing of fruit and vegetable wastes. Microbial detoxification of fruit and vegetable processing effluents is briefly described. The advances in genetic engineering of microorganisms for enhanced yield of the above-mentioned biocommodities are elucidated with selected examples. The bottleneck in commercialization, integrated approach for improved production, techno-economical feasibility and real-life uses of some of these biocommodities, as well as research gaps and future directions are discussed.

Genotypic variation of photosynthetic gas exchange and stomatal traits in some traditional rice (Oryza sativa L.) landraces from Koraput, India for crop improvement.

Variations in photosynthetic gas exchange, stomatal traits and photosystem (PS) II activity were investigated in three popular rice (Oryza sativa L.) landraces namely Kalajeera, Machakanta and Haladichudi from Koraput, India and compared with high yielding modern varieties (IR 64 and IR 42) to judge the possibility of using them in crop improvement programmes. The leaf CO2 photosynthetic rate (PN), stomatal conductance (gs), water use efficiency and carboxylation efficiency were significantly higher in traditional landraces as compared to the high yielding variety. In contrast, the transpiration rate, internal CO2 concentration, special analysis device (SPAD) index and chlorophyll were higher in high yielding varieties. In addition, the traditional landraces showed better stomatal traits such as stomatal density (SD), stomatal size (SS) and stomatal index. Further, multiple correlations between different gas-exchange characteristics and other physiological traits revealed that the PN was not dependent on the leaf pigment content or PS II activity. However, it was dependent on stomatal traits like gs, SD and SS. Taken together, the traditional landraces such as Kalajeera, Machakanta and Haladichudi had superior PN and stomatal efficiency compared to the high yielding variety under prevailing environmental condition. Further research is required to elucidate the genetic diversity of these popular landraces compared to high-yielding ones in relation to photosynthesis efficiency for future crop improvement programmes.

Physiological characterization and allelic diversity of selected drought tolerant traditional rice (Oryza sativa L.) landraces of Koraput, India.

Water-deficit stress tolerance in rice is important for maintaining stable yield, especially under rain-fed ecosystem. After a thorough drought-tolerance screening of more than 130 rice genotypes from various regions of Koraput in our previous study, six rice landraces were selected for drought tolerance capacity. These six rice landraces were further used for detailed physiological and molecular assessment under control and simulated drought stress conditions. After imposing various levels of drought stress, leaf photosynthetic rate (PN), photochemical efficiency of photosystem II (Fv/Fm), SPAD chlorophyll index, membrane stability index and relative water content were found comparable with the drought-tolerant check variety (N22). Compared to the drought-susceptible variety IR64, significant positive attributes and varietal differences were observed for all the above physiological parameters in drought-tolerant landraces. Genetic diversity among the studied rice landraces was assessed using 19 previously reported drought tolerance trait linked SSR markers. A total of 50 alleles with an average of 2.6 per locus were detected at the loci of the 19 markers across studied rice genotypes. The Nei's genetic diversity (He) and the polymorphism information content (PIC) ranged from 0.0 to 0.767 and 0.0 to 0.718, respectively. Seven SSR loci, such as RM324, RM19367, RM72, RM246, RM3549, RM566 and RM515, showed the highest PIC values and are thus, useful in assessing the genetic diversity of studied rice lines for drought tolerance. Based on the result, two rice landraces (Pandkagura and Mugudi) showed the highest similarity index with tolerant check variety. However, three rice landraces (Kalajeera, Machhakanta and Haldichudi) are more diverse and showed highest genetic distance with N22. These landraces can be considered as the potential genetic resources for drought breeding program.

Diverse Functions of Retinoic Acid in Brain Vascular Development.

UNLABELLED: As neural structures grow in size and increase metabolic demand, the CNS vasculature undergoes extensive growth, remodeling, and maturation. Signals from neural tissue act on endothelial cells to stimulate blood vessel ingression, vessel patterning, and acquisition of mature brain vascular traits, most notably the blood-brain barrier. Using mouse genetic and in vitro approaches, we identified retinoic acid (RA) as an important regulator of brain vascular development via non-cell-autonomous and cell-autonomous regulation of endothelial WNT signaling. Our analysis of globally RA-deficient embryos (Rdh10 mutants) points to an important, non-cell-autonomous function for RA in the development of the vasculature in the neocortex. We demonstrate that Rdh10 mutants have severe defects in cerebrovascular development and that this phenotype correlates with near absence of endothelial WNT signaling, specifically in the cerebrovasculature, and substantially elevated expression of WNT inhibitors in the neocortex. We show that RA can suppress the expression of WNT inhibitors in neocortical progenitors. Analysis of vasculature in non-neocortical brain regions suggested that RA may have a separate, cell-autonomous function in brain endothelial cells to inhibit WNT signaling. Using both gain and loss of RA signaling approaches, we show that RA signaling in brain endothelial cells can inhibit WNT-ß-catenin transcriptional activity and that this is required to moderate the expression of WNT target Sox17. From this, a model emerges in which RA acts upstream of the WNT pathway via non-cell-autonomous and cell-autonomous mechanisms to ensure the formation of an adequate and stable brain vascular plexus. SIGNIFICANCE STATEMENT: Work presented here provides novel insight into important yet little understood aspects of brain vascular development, implicating for the first time a factor upstream of endothelial WNT signaling. We show that RA is permissive for cerebrovascular growth via suppression of WNT inhibitor expression in the neocortex. RA also functions cell-autonomously in brain endothelial cells to modulate WNT signaling and its downstream target, Sox17. The significance of this is although endothelial WNT signaling is required for neurovascular development, too much endothelial WNT signaling, as well as overexpression of its target Sox17, are detrimental. Therefore, RA may act as a "brake" on endothelial WNT signaling and Sox17 to ensure normal brain vascular development.

Cerebrovascular defects in Foxc1 mutants correlate with aberrant WNT and VEGF-A pathways downstream of retinoic acid from the meninges.

Growth and maturation of the cerebrovasculature is a vital event in neocortical development however mechanisms that control cerebrovascular development remain poorly understood. Mutations in or deletions that include the FOXC1 gene are associated with congenital cerebrovascular anomalies and increased stroke risk in patients. Foxc1 mutant mice display severe cerebrovascular hemorrhage at late gestational ages. While these data demonstrate Foxc1 is required for cerebrovascular development, its broad expression in the brain vasculature combined with Foxc1 mutant's complex developmental defects have made it difficult to pinpoint its function(s). Using global and conditional Foxc1 mutants, we find 1) significant cerebrovascular growth defects precede cerebral hemorrhage and 2) expression of Foxc1 in neural crest-derived meninges and brain pericytes, though not endothelial cells, is required for normal cerebrovascular development. We provide evidence that reduced levels of meninges-derived retinoic acid (RA), caused by defects in meninges formation in Foxc1 mutants, is a major contributing factor to the cerebrovascular growth defects in Foxc1 mutants. We provide data that suggests that meninges-derived RA ensures adequate growth of the neocortical vasculature via regulating expression of WNT pathway proteins and neural progenitor derived-VEGF-A. Our findings offer the first evidence for a role of the meninges in brain vascular development and provide new insight into potential causes of cerebrovascular defects in patients with FOXC1 mutations.

Effects of different treatments of fly ash and mining soil on growth and antioxidant protection of Indian wild rice.

The aim of the present study was investigation of the effects of fly ash and mining soil on growth and antioxidant protection of two cultivars of Indian wild rice (Oryza nivara and Oryza rufipogon) for possible phytoremediation and restoration of metal-contaminated site. In this study, Indian wild rice showed significant changes in germination, growth, and biochemical parameters after exposure to different ratio of fly ash and mining soil with garden soil. There was significant reduction of germination, fresh weight, dry weight, leaf chlorophyll content, leaf area, Special Analysis Device Chlorophyll (SPAD) Index, proteins, and activities of antioxidant enzymes in both cultivars of the wild rice grown in 100% fly ash and mining soil compared to the plants grown in 100% garden soil. Results from this study showed that in both cultivars of wild rice, all growth and antioxidant parameters increased when grown in 50% fly ash and mining soil. Taken together, Indian wild rice has the capacity to tolerate 50% of fly ash and mining soil, and can be considered as a good candidate for possible phytoremediation of contaminated soils.

Microbial-processing of fruit and vegetable wastes for production of vital enzymes and organic acids: Biotechnology and scopes.

Wastes generated from fruits and vegetables are organic in nature and contribute a major share in soil and water pollution. Also, green house gas emission caused by fruit and vegetable wastes (FVWs) is a matter of serious environmental concern. This review addresses the developments over the last one decade on microbial processing technologies for production of enzymes and organic acids from FVWs. The advances in genetic engineering for improvement of microbial strains in order to enhance the production of the value added bio-products as well as the concept of zero-waste economy have been briefly discussed.

The lectin receptor kinase-VI.2 is required for priming and positively regulates Arabidopsis pattern-triggered immunity.

Plant cells can be sensitized toward a subsequent pathogen attack by avirulent pathogens or by chemicals such as ß-aminobutyric acid (BABA). This process is called priming. Using a reverse genetic approach in Arabidopsis thaliana, we demonstrate that the BABA-responsive L-type lectin receptor kinase-VI.2 (LecRK-VI.2) contributes to disease resistance against the hemibiotrophic Pseudomonas syringae and the necrotrophic Pectobacterium carotovorum bacteria. Accordingly, LecRK-VI.2 mRNA levels increased after bacterial inoculation or treatments with microbe-associated molecular patterns (MAMPs). We also show that LecRK-VI.2 is required for full activation of pattern-triggered immunity (PTI); notably, lecrk-VI.2-1 mutants show reduced upregulation of PTI marker genes, impaired callose deposition, and defective stomatal closure. Overexpression studies combined with genome-wide microarray analyses indicate that LecRK-VI.2 positively regulates the PTI response. LecRK-VI.2 is demonstrated to act upstream of mitogen-activated protein kinase signaling, but independently of reactive oxygen production and Botrytis-induced kinase1 phosphorylation. In addition, complex formation between the MAMP receptor flagellin sensing2 and its signaling partner brassinosteroid insensitive1-associated kinase1 is observed in flg22-treated lecrk-VI.2-1 mutants. LecRK-VI.2 is also required for full BABA-induced resistance and priming of PTI. Our work identifies LecRK-VI.2 as a novel mediator of the Arabidopsis PTI response and provides insight into molecular mechanisms governing priming.

Larvae of Colorado potato beetle (Leptinotarsa decemlineata Say) resistant to double-stranded RNA (dsRNA) remain susceptible to small-molecule pesticides.

BACKGROUND: Implementation of resistance management tools is crucial for the continued efficacy of insect control technologies. An important aspect of insect resistance management (IRM) is the combined or sequential use of different modes-of-action to reduce selection pressure and delay evolution of resistance. This is especially important for insect pests with established ability to develop resistance to insecticides, such as the Colorado potato beetle (Leptinotarsa decemlineata, CPB). A new class of insecticides, based on double-stranded RNA (dsRNA) activating the gene silencing RNA-interference (RNAi) pathway, are currently under review for regulatory approval and commercial use in the USA against CPB. However, there is no information available on the potential for cross-resistance between RNAi insecticides and other classes of insecticides used against CPB. Herein, we aim to fill this knowledge gap by capitalizing on the availability of a CPB strain highly resistant to dsRNAs and test its susceptibility to diverse small-molecule insecticide classes compared to reference dsRNA-susceptible CPB strains. RESULTS: Differences in activity were observed among the four insecticides tested, with abamectin demonstrating highest activity against all three strains of CPB. However, no differences were observed among the dsRNA-resistant and susceptible CPB strains for any of the tested compounds. Overall, these results demonstrate lack of cross-resistance to commonly used chemical insecticides in the dsRNA-resistant strain of CPB. CONCLUSION: These data support the use of these different insecticide classes along with RNAi-based insecticides as part of an effective insect resistance management framework aimed at delaying resistance in CPB. © 2023 Society of Chemical Industry.

Differential effects of SORL1 deficiency on the endo-lysosomal network in human neurons and microglia.

The endosomal gene SORL1 is a strong Alzheimer's disease (AD) risk gene that harbours loss-of-function variants causative for developing AD. The SORL1 protein SORL1/SORLA is an endosomal receptor that interacts with the multi-protein sorting complex retromer to traffic various cargo through the endo-lysosomal network (ELN). Impairments in endo-lysosomal trafficking are an early cellular symptom in AD and a novel therapeutic target. However, the cell types of the central nervous system are diverse and use the ELN differently. If this pathway is to be effectively therapeutically targeted, understanding how key molecules in the ELN function in various cell types and how manipulating them affects cell-type specific responses relative to AD is essential. Here, we discuss an example where deficiency of SORL1 expression in a human model leads to stress on early endosomes and recycling endosomes in neurons, but preferentially leads to stress on lysosomes in microglia. The differences observed in these organelles could relate to the unique roles of these cells in the brain as neurons are professional secretory cells and microglia are professional phagocytic cells. Experiments to untangle these differences are fundamental to advancing the understanding of cell biology in AD and elucidating important pathways for therapeutic development. Human-induced pluripotent stem cell models are a valuable platform for such experiments. This article is part of a discussion meeting issue 'Understanding the endo-lysosomal network in neurodegeneration'.

Primary sclerosing encapsulating peritonitis.

Sclerosing encapsulating peritonitis also known as cocoon abdomen is a rare chronic inflammatory condition of the peritoneum in which the bowel loops are encircled by a membrane (cocoon formation) within the peritoneal cavity leading to intestinal obstruction. It can be primary (idiopathic) or secondary (chemotherapy, beta-blockers, peritoneal dialysis, shunts, tuberculosis, systemic lupus erythematosus, etc.). The symptomatology report includes recurrent episodes of abdominal pain and vomiting. We present here a case of a 32-year-old male who presented with complaints of being unable to pass stools, vomiting (3-4 times), and abdomen pain for 4 days. This case is considered worth mentioning due to its rarity, lack of identification of secondary causes, and diminutive mention of histopathological aspect.

Characterization of covalent inhibitors that disrupt the interaction between the tandem SH2 domains of SYK and FCER1G phospho-ITAM.

RNA sequencing and genetic data support spleen tyrosine kinase (SYK) and high affinity immunoglobulin epsilon receptor subunit gamma (FCER1G) as putative targets to be modulated for Alzheimer's disease (AD) therapy. FCER1G is a component of Fc receptor complexes that contain an immunoreceptor tyrosine-based activation motif (ITAM). SYK interacts with the Fc receptor by binding to doubly phosphorylated ITAM (p-ITAM) via its two tandem SH2 domains (SYK-tSH2). Interaction of the FCER1G p-ITAM with SYK-tSH2 enables SYK activation via phosphorylation. Since SYK activation is reported to exacerbate AD pathology, we hypothesized that disruption of this interaction would be beneficial for AD patients. Herein, we developed biochemical and biophysical assays to enable the discovery of small molecules that perturb the interaction between the FCER1G p-ITAM and SYK-tSH2. We identified two distinct chemotypes using a high-throughput screen (HTS) and orthogonally assessed their binding. Both chemotypes covalently modify SYK-tSH2 and inhibit its interaction with FCER1G p-ITAM, however, these compounds lack selectivity and this limits their utility as chemical tools.

Poly(alkylene oxide) copolymers for nucleic acid delivery.

The advancement of gene-based therapeutics to the clinic is limited by the ability to deliver physiologically relevant doses of nucleic acids to target tissues safely and effectively. Over the last couple of decades, researchers have successfully employed polymer and lipid based nanoassemblies to deliver nucleic acids for the treatment of a variety of diseases. Results of phase I/II clinical studies to evaluate the efficacy and biosafety of these gene delivery vehicles have been encouraging, which has promoted the design of more efficient and biocompatible systems. Research has focused on designing carriers to achieve biocompatibility, stability in the circulatory system, biodistribution to target the disease site, and intracellular delivery, all of which enhance the resulting therapeutic effect. The family of poly(alkylene oxide) (PAO) polymers includes random, block, and branched structures, among which the ABA type triblocks copolymers of ethylene oxide (EO) and propylene oxide (PO) (commercially known as Pluronic) have received the greatest consideration. In this Account, we highlight examples of polycation-PAO conjugates, liposome-PAO formulations, and PAO micelles for nucleic acid delivery. Among the various polymer design considerations, which include molecular weight of polymer, molecular weight of blocks, and length of blocks, the overall hydrophobic-lipophilic balance (HLB) is a critical parameter in defining the behavior of the polymer conjugates for gene delivery. We discuss the effects of varying this parameter in the context of improving gene delivery processes, such as serum stability and association with cell membranes. Other innovative macromolecular modifications discussed in this category include our work to enhance the serum stability and efficiency of lipoplexes using PAO graft copolymers, the development of a PAO gel-based carrier for sustained and stimuli responsive delivery, and the development of biodegradable PAO-based amphiphilic block copolymers.