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Diabetes patients are at a high risk of developing complications related to angiopathy and disruption of the signal transduction system. The liver is one of the multiple organs damaged during diabetes. Few studies have evaluated the morphological effects of adhesion factors in diabetic liver. The influence of diurnal variation has been observed in the expression and functioning of adhesion molecules to maintain tissue homeostasis associated with nutrient uptake. The present study demonstrated that the rhythm-influenced functioning of tight junction was impaired in the liver of ob/ob mice. The tight junctions of hepatocytes were loosened during the dark period in normal mice compared to those in ob/ob mice, where the hepatocyte gaps remained open throughout the day. The time-dependent expression of zonula occludens 1 (ZO1) in the liver plays a vital role in the functioning of the tight junction. The time-dependent expression of ZO1 was nullified and its expression was attenuated in the liver of ob/ob mice. ZO1 expression was inhibited at the mRNA and protein levels. The expression rhythm of ZO1 was found to be regulated by heat shock factor (HSF)1/2, the expression of which was reduced in the liver of ob/ob mice. The DNA-binding ability of HSF1/2 was decreased in the liver of ob/ob mice compared to that in normal mice. These findings suggest the involvement of impaired expression and functioning of adhesion factors in diabetic liver complications.

Objective: After injury, humans and other mammals heal by forming fibrotic scar tissue with diminished function, and this healing process involves the dynamic interplay between resident cells withi...

Abstract. Folate and vitamin B12(V-B12) deficiencies are associated with metabolic diseases that may impair memory function. We hypothesized that folate and V-B12 may differently alter mild cognitive impairment, glucose metabolism, and inflammation by modulating the gut microbiome in rats with Alzheimer’s disease (AD)-like dementia. The hypothesis was examined in hippocampal amyloid-β infused rats, and its mechanism was explored. Rats that received an amyloid-β(25–35) infusion into the CA1 region of the hippocampus were fed either control(2.5 mg folate plus 25 μg V-B12/kg diet; AD-CON, n = 10), no folate(0 folate plus 25 μg V-B12/kg diet; AD-FA, n = 10), no V-B12(2.5 mg folate plus 0 μg V-B12/kg diet; AD-V-B12, n = 10), or no folate plus no V-B12(0 mg folate plus 0 μg V-B12/kg diet; AD-FAB12, n = 10) in high-fat diets for 8 weeks. AD-FA and AD-VB12 exacerbated bone mineral loss in the lumbar spine and femur whereas AD-FA lowered lean body mass in the hip compared to AD-CON(P

Chemokines are small proteins that are critical for immune function, being primarily responsible for the activation and chemotaxis of leukocytes. As such, many viruses, as well as parasitic arthropods, have evolved systems to counteract chemokine function in order to maintain virulence, such as binding chemokines, mimicking chemokines, or producing analogs of transmembrane chemokine receptors that strongly bind their targets. The focus of this review is the large group of chemokine binding proteins (CBP) with an emphasis on those produced by mammalian viruses. Because many chemokines mediate inflammation, these CBP could possibly be used pharmaceutically as anti-inflammatory agents. In this review, we summarize the structural properties of a diverse set of CBP and describe in detail the chemokine binding properties of the poxvirus-encoded CBP called vCCI (viral CC Chemokine Inhibitor). Finally, we describe the current and emerging capabilities of combining computational simulation, structural analysis, and biochemical/biophysical experimentation to understand, and possibly re-engineer, protein-protein interactions.

KIF17, which belongs to the kinesin-2 protein family, plays an indispensable role in mammalian spermiogenesis. However, the role of KIF17 in fish spermatid remodeling during spermiogenesis remains poorly understood. Therefore, we aimed to study the role of KIF17 in spermatid remodeling during Larimichthys crocea (L. crocea) spermiogenesis. The kif17 cDNA sequence, 3247 bp in length, was cloned from L. crocea testis, which consisted of a 347 bp 5ʹ-untranslated region (UTR), 413 bp 3ʹ -UTR, and 2487 bp open reading frame. Bioinformatic analyses revealed that KIF17 obtained from L. crocea (Lc-KIF17) exhibited a high sequence identity compared with those from other teleosts and possessed the structural features of other kinesin-2 proteins. Based on structural similarity, we speculate that the role of Lc-KIF17 may be similar to that of KIF17 in other animals. Lc-kif17 mRNA was diffusely expressed in L. crocea tissues and was highly expressed in the testis, especially at stage IV testicular development. Immunofluorescence analysis revealed that Lc-KIF17 signals colocalized with β-tubulin signals and migrated from the perinuclear cytoplasm to the side of the nucleus where the tail forms during spermiogenesis. These findings revealed that KIF17 may be involved in L. crocea spermiogenesis. In particular, KIF17 may participate in spermatid remodeling by interacting with perinuclear microtubules during L. crocea spermiogenesis. Collectively, this study contributes to an improved understanding of the mechanism underlying L. crocea spermiogenesis and provides a basis for further research on L. crocea reproduction and development.

SIGNIFICANCE The presence of a large number of thioredoxin superfamily members suggests a complex mechanism of redox-based regulation in mammalian cells. However, whether these members are functionally redundant or play separate and distinct roles in each cellular compartment remains to be elucidated. Recent advances: In the mammalian endoplasmic reticulum (ER), approximately 20 thioredoxin-like proteins have been identified. Most ER oxidoreductases are soluble proteins located in the luminal compartment, while a small family of five thioredoxin-related transmembrane proteins (TMX) also reside in the ER membrane and play crucial roles with specialized functions. CRITICAL ISSUES In addition to the predicted function of ER protein quality control, several independent studies have suggested the diverse roles of TMX family proteins in the regulation of cellular processes, including calcium homeostasis, bioenergetics, and thiol-disulfide exchange in the extracellular space. Moreover, recent studies have provided evidence of their involvement in the pathogenesis of various diseases. FUTURE DIRECTIONS Extensive research is required to unravel the physiological roles of TMX family proteins. Given that membrane-associated proteins are prime targets for drug discovery in a variety of human diseases, expanding our knowledge on the mechanistic details of TMX action on the cell membrane will provide molecular basis for developing novel diagnostic and therapeutic approaches as a potent molecular target in a clinical setting.

SIGNIFICANCE: Adaptor proteins control the spatiotemporal dynamics of cellular signaling. Dysregulation of adaptor protein function can cause aberrant cell signaling and promote cancer. The arrestin family of adaptor proteins are known to regulate signaling by the superfamily of G protein-coupled receptors (GPCRs). The GPCRs are highly druggable and implicated in cancer progression. However, the molecular mechanisms responsible for arrestin dysregulation and the impact on GPCR function in cancer have yet to be fully elucidated. RECENT ADVANCES: A new family of mammalian arrestins, termed the α-arrestins, was recently discovered. The α-arrestin, arrestin domain-containing protein 3 (ARRDC3), in particular, has been identified as a tumor suppressor and is reported to control cellular signaling of GPCRs in cancer. CRITICAL ISSUES: Compared with the extensively studied mammalian β-arrestins, there is limited information regarding the regulatory mechanisms that control α-arrestin activation and function. Here, we discuss the molecular mechanisms that regulate ARRDC3, which include post-translational modifications such as phosphorylation and ubiquitination. We also provide evidence that ARRDC3 can interact with a wide array of proteins that control diverse biological functions. FUTURE DIRECTIONS: ARRDC3 interacts with numerous proteins and is likely to display diverse functions in cancer, metabolic disease, and other syndromes. Thus, understanding the regulatory mechanisms of ARRDC3 activity in various cellular contexts is critically important. Recent studies suggest that α-arrestins may be regulated through post-translational modification, which is known to impact adaptor protein function. However, additional studies are needed to determine how these regulatory mechanisms affect ARRDC3 tumor suppressor function. Antioxid. Redox Signal. 36, 1066–1079.

Excessive inflammatory response caused by infiltration of a large number of neutrophils is one of the important features of acute lung injury(ALI)/acute respiratory distress syndrome (ARDS). Lipoxin A4 (LXA4) is an important endogenous mediator in the process of inflammation resolution, which has a strong role in promoting inflammation resolution. In this study, we examined the impact of LXA4 on the pulmonary inflmmatory response and the neutrophil function in a rat model of ARDS. Our results indicated that Exogenous administration of LXA4 could reduce the degree of lung injury in ARDS rats and inhibit the release of pro-inflammatory factors TNF- α and IL-1β in lung tissue homogenate. However, LXA4 has no lung protective effect on ARDS rats with neutrophil depletion in rats, nor can it inhibit the levels of pro-inflammatory factors TNF-α and IL-1β in lung tissue homogenate. LXA4 can inhibit the production of reactive oxygen species (ROS) and NETs in peripheral blood neutrophils of ARDS rats. At the same time, LXA4 can promote the phagocytosis of neutrophils in ARDS rats in vitro, and can also promote the apoptosis of neutrophils in ARDS rats and reduce neutrophil NETosis. In addition, the effect of LXA4 on the function of peripheral blood neutrophils in ARDS rats is mediated by its receptor ALX. LXA4 can inhibit the release of NE and MPO from neutrophils, thereby inhibiting the production of NETs, and the effect of LXA4 can be comparable to NEi and MPO inhibitors. In summary, these findings indicate that LXA4 has a protective effect on LPS-induced ARDS rats by affecting the function of neutrophils.Summary sentenceLXA4 has protective effect on LPS induced ARDS rats by affecting the function of neutrophils.

Modulation of neutrophil recruitment and function is crucial for targeting inflammatory cells to sites of infection to combat invading pathogens while, at the same time, limiting host tissue injury or autoimmunity. The underlying mechanisms regulating recruitment of neutrophils, 1 of the most abundant inflammatory cells, have gained increasing interest over the years. The previously described classical recruitment cascade of leukocytes has been extended to include capturing, rolling, adhesion, crawling, and transmigration, as well as a reverse-transmigration step that is crucial for balancing immune defense and control of remote organ endothelial leakage. Current developments in the field emphasize the importance of cellular interplay, tissue environmental cues, circadian rhythmicity, detection of neutrophil phenotypes, differential chemokine sensing, and contribution of distinct signaling components to receptor activation and integrin conformations. The use of therapeutics modulating neutrophil activation responses, as well as mutations causing dysfunctional neutrophil receptors and impaired signaling cascades, have been defined in translational animal models. Human correlates of such mutations result in increased susceptibility to infections or organ damage. This review focuses on current advances in the understanding of the regulation of neutrophil recruitment and functionality and translational implications of current discoveries in the field with a focus on acute inflammation and sepsis.

Transgenic mouse models have facilitated research of human diseases and validation of therapeutic approaches. Inclusion of optical reporter genes (fluorescent or bioluminescent genes) in the targeting vectors used to develop such models makes in vivo imaging of cellular and molecular events possible, from the microscale to the macroscale. In particular, transgenic mouse models expressing optical reporter genes allowed accurately distinguishing immune cell types from trafficking in vivo using intravital microscopy or whole-body optical imaging. Besides lineage tracing and trafficking of different subsets of immune cells, the ability to monitor the function of immune cells is of pivotal importance for investigating the effects of immunotherapies against cancer. Here, we introduce the reader to state-of-the-art approaches to develop transgenics, optical imaging techniques, and several notable examples of transgenic mouse models developed for immunology research by critically highlighting the models that allow the following of immune cell function.

Asparagines in proteins deamidate spontaneously, which changes the chemical structure of a protein and often affects its function. Current prediction algorithms for asparagine deamidation require a structure as an input or are too slow to be applied at a proteomic scale. We present NGOME-Lite, a new version of our sequence-based predictor for spontaneous asparagine deamidation that is faster by over two orders of magnitude at a similar degree of accuracy. The algorithm takes into account intrinsic sequence propensities and slowing down of deamidation by local structure. NGOME-Lite can run in a proteomic analysis mode that provides the half-time of the intact form of each protein, predicted by taking into account sequence propensities and structural protection or sequence propensities only, and a structure protection factor. The detailed analysis mode also provides graphical output for all Asn residues in the query sequence. We applied NGOME-Lite to over 257,000 sequences in 38 proteomes and found that different taxa differ in their predicted deamidation dynamics. Spontaneous protein deamidation is faster in Eukarya than in Bacteria because of a higher degree of structural protection in the latter. Predicted protein deamidation half-lifes correlate with protein turnover in human, mouse, rat, C. elegans and budding yeast but not in two plants and two bacteria. NGOME-Lite is implemented in a docker container available at https://ngome.proteinphysiologylab.org.

Replacement of pancreatic beta-cells is one of the most promising treatment options for treatment of type 1 diabetes (T1D), even though, toxic immunosuppressive drugs are required. In this study, we aim to deliver allogeneic beta-cell therapies without antirejection drugs using a bioengineered hybrid device that contains microencapsulated beta-cells inside 3D polycaprolactone (PCL) scaffolds printed using melt electrospin writing (MEW). Mouse beta-cell (MIN6) pseudoislets and QS mouse islets are encapsulated in alginate microcapsules, without affecting viability and insulin secretion. Microencapsulated MIN6 cells are then seeded within 3D MEW scaffolds, and these hybrid devices implanted subcutaneously in streptozotocin-treated diabetic NOD/SCID and BALB/c mice. Similar to NOD/SCID mice, blood glucose levels (BGL) are lowered from 30.1 to 4.8 mM in 25-41 days in BALB/c. In contrast, microencapsulated islets placed in prevascularized MEW scaffold 3 weeks after implantation in BALB/c mice normalize BGL (Impact statementThe retrievable 3D printed PCL scaffold we have produced promotes vascularization when implanted subcutaneously and allows seeded microencapsulated insulin-producing cells to normalize blood glucose of diabetic mice for at least 2 months, without the need for antirejection drugs to be administered. The scaffold is scalable for possible human use, but will require modification to ensure that normalization of blood glucose levels can be maintained long term.

β-Arrestin-1 and -2 (also known as arrestin-2 and -3, respectively) are ubiquitously expressed cytoplasmic proteins that dampen signaling through G protein-coupled receptors. However, β-arrestins can also act as signaling molecules in their own right. To investigate the potential metabolic roles of the two β-arrestins in modulating glucose and energy homeostasis, recent studies analyzed mutant mice that lacked or overexpressed β-arrestin-1 and/or -2 in distinct, metabolically important cell types. Metabolic analysis of these mutant mice clearly demonstrated that both β-arrestins play key roles in regulating the function of most of these cell types, resulting in striking changes in whole-body glucose and/or energy homeostasis. These studies also revealed that β-arrestin-1 and -2, though structurally closely related, clearly differ in their metabolic roles under physiological and pathophysiological conditions. These new findings should guide the development of novel drugs for the treatment of various metabolic disorders, including type 2 diabetes and obesity. Expected final online publication date for the Annual Review of Physiology, Volume 84 is February 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Objectives Intervertebral disc (IVD) degeneration is an important disease with no efficient biological therapy identified. Autophagy, a wildly known therapeutic target for human disease, has been demonstrated to be activated under hypoxia, with underlying mechanism remains elusive. Thus, this study aims to specify the role of autophagy in IVD degeneration, the regulating mechanism of hypoxia-inducing autophagy, and the therapeutic value of autophagy for IVD degeneration. Methods RNA-seq was used to screen the primary pathway affected in NP cells under hypoxia, the specific link between hypoxia and autophagy were investigated using ChIP-seq and dual luciferase reporter assay. Conditional ATG7 knockout mice (ATG7-/-) were constructed for assessing the effect of autophagy on IVD degeneration, and puncture induced mice model of IVD degeneration were used for intradiscal injection to evaluate the therapeutic value of autophagy. Results We demonstrated that hypoxia induces autophagy by transcriptional activation of autophagic gene LC3B and ATG7, which is controlled by PERK signaling. Then, we observed that inhibiting autophagy or PERK signaling leads to impaired NP cell viability and function, furthermore, using ATG7 knockout (ATG7-/-) mice, we identified the protective role of autophagy in IVD. Furthermore, we found that intradiscal injection of PERK signaling agonist, CCT020312, significantly restores the degeneration level of needle punctured mice IVD. Conclusion We showed that the activation of PERK signaling upon hypoxia serves as a vital mechanism to induce autophagy and identified the therapeutic value of PERK signaling agonist for IVD degeneration treatment.

Bracoviruses (BVs) and ichnoviruses (IVs) evolved from different endogenized viruses but through convergence have been coopted by parasitoids in the families Braconidae and Ichneumonidae for similar functions in parasitizing hosts. Experimentally studying the role of endogenized viral genes in virion morphogenesis remains a key challenge in the study of BVs and IVs. Here we summarize how multiomics, electron microscopy, and RNA interference (RNAi) methods have provided new insights about BV and IV gene function.

Embryonic dorsal-ventral (DV) patterning by Bone Morphogenetic Proteins (BMPs) is a conserved feature of Bilateria, based on graded BMP activity set up by diffusible BMP ligands and Chordin/Sog antagonists. In the fly Drosophila melanogaster BMP function is secondary to patterning by the Toll pathway, suggesting a more restricted role for BMPs in insects. With widespread genome sequencing technologies allied to functional analysis in a growing number of species, recent work has shown that BMP's role in DV patterning relative to Toll varies among insect orders. Further, the role of BMP antagonists to set up BMP gradients is also greatly diversified. Here we review the recent findings concerning the role of BMP in the DV patterning of insects and address the potential aspects that may have co-evolved with BMPs to attain this functional divergence.

Bacterial endosymbionts induce dramatic phenotypes in their arthropod hosts, including cytoplasmic incompatibility, feminization, parthenogenesis, male killing, parasitoid defense, and pathogen blocking. The molecular mechanisms underlying these effects remain largely unknown, but recent evidence suggests that protein toxins secreted by the endosymbionts play a role. Here, we describe the diversity and function of endosymbiont proteins with homology to known bacterial toxins. We focus on maternally transmitted endosymbionts belonging to the Wolbachia, Rickettsia, Arsenophomis, Hamiltonella, Spiroplasma, and Cardinium genera, because of their ability to induce the above phenotypes. We identify at least 16 distinct toxin families with diverse enzymatic activities, including AMPylases, nucleases, proteases, and glycosyltransferases. Notably, several annotated toxins contain domains with homology to eukaryotic proteins, suggesting that arthropod endosymbionts mimic host biochemistry to manipulate host physiology, similar to bacterial pathogens.

Beetles are hosts to a remarkable diversity of bacterial symbionts. In this article, we review the role of these partnerships in promoting beetle fitness following a surge of recent studies characterizing symbiont localization and function across the Coleoptera. Symbiont contributions range from the supplementation of essential nutrients and digestive or detoxifying enzymes to the production of bioactive compounds providing defense against natural enemies. Insights on this functional diversity highlight how symbiosis can expand the host's ecological niche, but also constrain its evolutionary potential by promoting specialization. As bacterial localization can differ within and between beetle clades, we discuss how it corresponds to the microbe's beneficial role and outline the molecular and behavioral mechanisms underlying symbiont translocation and transmission by its holometabolous host. In reviewing this literature, we emphasize how the study of symbiosis can inform our understanding of the phenotypic innovations behind the evolutionary success of beetles. Expected final online publication date for the Annual Review of Entomology, Volume 67 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

The spermatozoon is a highly differentiated and polarized cell, with two main structures: the head, containing a haploid nucleus and the acrosomal exocytotic granule, and the flagellum, which generates energy and propels the cell; both structures are connected by the neck. The sperm's main aim is to participate in fertilization, thus activating development. Despite this common bauplan and function, there is an enormous diversity in structure and performance of sperm cells. For example, mammalian spermatozoa may exhibit several head patterns and overall sperm lengths ranging from ∼30 to 350 µm. Mechanisms of transport in the female tract, preparation for fertilization, and recognition of and interaction with the oocyte also show considerable variation. There has been much interest in understanding the origin of this diversity, both in evolutionary terms and in relation to mechanisms underlying sperm differentiation in the testis. Here, relationships between sperm bauplan and function are examined at two levels: first, by analyzing the selective forces that drive changes in sperm structure and physiology to understand the adaptive values of this variation and impact on male reproductive success and second, by examining cellular and molecular mechanisms of sperm formation in the testis that may explain how differentiation can give rise to such a wide array of sperm forms and functions., This work was supported by the National Institutes of Health (Grant R03 HD-101762), the Spanish Ministry of Science and Innovation (Grants CGL2016-80577-P and PID2019-108649GB-I00), and Consejo Superior de Investigaciones Científicas (Grant 2019AEP165).

Influenza NS1 is a promising anti-influenza target, considering its conserved and druggable structure, and key function in influenza replication and pathogenesis. Notwithstanding, target identification and validation, strengthened by experimental data, are lacking. Here, we further explored our previously designed structure-based antiviral rationale directed to highly conserved druggable NS1 regions across a broad spectrum of influenza A viruses. We aimed to identify NS1-mutated viruses exhibiting a reduced growth phenotype and/or an altered cell apoptosis profile. We found that NS1 mutations Y171A, K175A (consensus druggable pocket 1), W102A (consensus druggable pocket 3), Q121A and G184P (multiple consensus druggable pockets) - located at hot spots amenable for pharmacological modulation - significantly impaired A(H1N1)pdm09 virus replication, in vitro. This is the first time that NS1-K175A, -W102A, and -Q121A mutations are characterized. Our map-and-mutate strategy provides the basis to establish the NS1 as a promising target using a rationale with a higher resilience to resistance development. Highlights: Structure-based anti-influenza strategies that facilitate the rapid identification and validation of robust targets are lacking; We have previously identified and characterized 3 NS1 conserved druggable pockets - amenable to pharmacological modulation; NS1 mutations Y171A, K175A (CDP1), W102A (CDP3), Q121A and G184P (Multi-CDPs) impaired A(H1N1)pdm09 virus replication, in vitro; The new NS1 hot spots: NS1–K175, -W102, and -Q121 were characterized for the first time, using the A(H1N1)pdm09 virus; This map-and-mutate antiviral rationale can be promptly applied to other proteins of (re)emergent viruses. This work was funded by the FCT – Fundação para a Ciência e a Tecnologia, I.P. (project number POCI-01 0145-FEDER-032572 | PTDC/QUI-OUT/32572/2017 and PTDC/SAU-INF/30729/2017); and sup ported by the PhD grant PD/BD/128402/2017 from FCT PhD Pro gramme in Medicines and Pharmaceutical Innovation (i3DU) to JTL Ph. D. candidate. info:eu-repo/semantics/publishedVersion

While it is well recognized that exercise represents a radical preventive and therapeutic measure for lifestyle-related diseases, it is clear that contemporary lifestyles abound with situations where exercise may be found difficult to implement on a continuous basis. Indeed, this has led to global expectations for elucidation of the exercise-activated skeletal muscle signaling pathways as well as for development of exercise mimics that effectively activate such pathways. It is shown that exercise activates the transcriptional coactivator PGC-1α via AMPK/SIRT1 in muscle, thereby not only enhancing mitochondrial function and muscle endurance but upregulating energy metabolism. Further, adipocyte-derived adiponectin is also shown to activate AMPK/SIRT1/PGC-1α via its receptor AdipoR1 in skeletal muscles. Thus, adiponectin/AdipoR1 signaling is thought to constitute exercise-mimicking signaling. Indeed, it has become clear that AMPK, SIRT1 and AdipoR activators act as exercise mimetics. With the crystal structures of AdipoR elucidated and humanized AdipoR mice generated toward optimization of candidate AdipoR-activators for human use, expectations are mounting for the clinical application in the near future of AdipoR activators as exercise mimetics in humans. This review provides an overview of molecules activated by exercise and compounds activating these molecules, with a focus on the therapeutic potential of AdipoR activators as exercise mimetics.

International audience; Macrophages comprise a heterogeneous immune cell population and display niche-specific phenotypes and functions in almost all organs. Testicular macrophages (TMs) perform essential immune and non-immune functions in the mammalian male gonads. Here, we discuss the most recent findings on TM ontogeny, heterogeneity, and function under steady state and inflammatory conditions. We also highlight new discoveries regarding the functions of macrophages during bacterial and viral infections of the testes and how macrophages may indirectly help the establishment of a reservoir through virus seeding. Understanding TM function and macrophage-related mechanisms of disease might assist in developing new opportunities for intervention in male infertility. © 2021 Elsevier Ltd

Aminoacyl tRNA synthetases (ARSs) are a group of proteins, acting as transporters to transfer and attach the appropriate amino acids onto their cognate tRNAs for translation. So far, 18 out of 20 cytoplasmic ARSs are reported to be connected to different neuropathy disorders with multi-organ defects that are often accompanied with developmental delays. Thus, it is important to understand functions and impacts of ARSs at the whole organism level. Here, we systematically analyzed the spatiotemporal expression of 14 ars and 2 aimp genes during development in zebrafish that have not be previously reported. Not only in the brain, their dynamic expression patterns in several tissues such as in the muscles, liver and intestine suggest diverse roles in a wide range of development processes in addition to neuronal function, which is consistent with potential involvement in multiple syndrome diseases associated with ARS mutations. In particular, hinted by its robust expression pattern in the brain, we confirmed that aimp1 is required for the formation of cerebrovasculature by a loss-of-function approach. Overall, our systematic profiling data provides a useful basis for studying roles of ARSs during development and understanding their potential functions in the etiology of related diseases.

Graphical abstract, Highlights • Parasites possess a reduced complement of Caenorhabditis elegans neuropeptide-like protein (NLP)-encoding genes. • Parasite NLP profiles are broadly conserved between nematode clades. • Five NLP-encoding genes are completely conserved in the nine parasitic nematodes examined. • Fourteen novel nematode NLP encoding genes are identified. • Several highly conserved NLPs are bioactive., Nematode parasite infections cause disease in humans and animals and threaten global food security by reducing productivity in livestock and crop farming. The escalation of anthelmintic resistance in economically important nematode parasites underscores the need for the identification of novel drug targets in these worms. Nematode neuropeptide signalling is an attractive system for chemotherapeutic exploitation, with neuropeptide G-protein coupled receptors (NP-GPCRs) representing the lead targets. In order to successfully validate NP-GPCRs for parasite control it is necessary to characterise their function and importance to nematode biology. This can be aided through identification of receptor activating ligand(s) via deorphanisation. Such efforts require the identification of all neuropeptide ligands within parasites. Here we mined the genomes of nine therapeutically relevant pathogenic nematodes to characterise the neuropeptide-like protein complements and demonstrate that: (i) parasitic nematodes possess a reduced complement of neuropeptide-like protein-encoding genes relative to Caenorhabditis elegans; (ii) parasite neuropeptide-like protein profiles are broadly conserved between nematode clades; (iii) five Ce-nlps are completely conserved across the nematode species examined; (iv) the extent and position of neuropeptide-like protein-motif conservation is variable; (v) novel RPamide-encoding genes are present in parasitic nematodes; (vi) novel Allatostatin-C-like peptide encoding genes are present in both C. elegans and parasitic nematodes; (vii) novel neuropeptide-like protein families are absent in C. elegans; and (viii) highly conserved nematode neuropeptide-like proteins are bioactive. These data highlight the complexity of nematode neuropeptide-like proteins and reveal the need for nomenclature revision in this diverse neuropeptide family. The identification of neuropeptide-like protein ligands, and characterisation of those with functional relevance, advance our understanding of neuropeptide signalling to support exploitation of the neuropeptidergic system as an anthelmintic target.

RNA binding proteins (RBPs) regulate nearly all post-transcriptional processes within cells. To fully understand RBP function, it is essential to identify their in vivo targets. Standard techniques for profiling RBP targets, such as crosslinking immunoprecipitation (CLIP) and its variants, are limited or suboptimal in some situations, e.g. when compatible antibodies are not available and when dealing with small cell populations such as neuronal subtypes and primary stem cells. This review summarizes and compares several genetic approaches recently designed to identify RBP targets in such circumstances. TRIBE (targets of RNA binding proteins identified by editing), RNA tagging, and STAMP (surveying targets by APOBEC-mediated profiling) are new genetic tools useful for the study of post-transcriptional regulation and RBP identification. We describe the underlying RNA base editing technology, recent applications, and therapeutic implications.

In the past several decades, the establishment of in vitro models of pluripotency has ushered in a golden era for developmental and stem cell biology. Research in this arena has led to profound insights into the regulatory features that shape early embryonic development. Nevertheless, an integrative theory of the epigenetic principles that govern the pluripotent nucleus remains elusive. Here, we summarize the epigenetic characteristics that define the pluripotent state. We cover what is currently known about the epigenome of pluripotent stem cells and reflect on the use of embryonic stem cells as an experimental system. In addition, we highlight insights from super-resolution microscopy, which have advanced our understanding of the form and function of chromatin, particularly its role in establishing the characteristically "open chromatin" of pluripotent nuclei. Further, we discuss the rapid improvements in 3C-based methods, which have given us a means to investigate the 3D spatial organization of the pluripotent genome. This has aided the adaptation of prior notions of a "pluripotent molecular circuitry" into a more holistic model, where hotspots of co-interacting domains correspond with the accumulation of pluripotency-associated factors. Finally, we relate these earlier hypotheses to an emerging model of phase separation, which posits that a biophysical mechanism may presuppose the formation of a pluripotent-state-defining transcriptional program.

Cells respond to extracellular agents by activation of intracellular signaling pathways. Viruses can be regarded as such agents, leading to a firework of signaling inside the cell, primarily induced by pathogen-associated molecular patterns (PAMPs) that provoke safeguard mechanisms to defend from the invader. In the constant arms race between pathogen and cellular defense, viruses not only have evolved mechanisms to suppress or misuse supposedly antiviral signaling processes for their own benefit but also actively induce signaling to promote replication. This creates viral dependencies that may be exploited for novel strategies of antiviral intervention. Here, we will summarize the current knowledge of activation and function of influenza virus-induced signaling pathways with a focus on nuclear factor (NF)-κB signaling, mitogen-activated protein kinase cascades, and the phosphatidylinositol-3-kinase pathway. We will discuss the opportunities and drawbacks of targeting these signaling pathways for antiviral intervention.

The polycomb repressive complex 2 (PRC2) can methylate at lysine 27 of histone H3 at the trimethylation level (H3K27me3). This leads to gene silencing and is known to be dysregulated in many cancers. PRC2 is made up of three core subunits: EZH2, SUZ12, and EED. EED is essential for the regulation of PRC2 function by binding to H3K27me3. Targeting the allosteric site within EED offers new strategies to disrupt the PRC2 activity. In this minireview, we summarize some of the recent developments in small molecules that target EED and its interaction with other core proteins in the PRC2 complex.

With proteomic analysis, we identified 379 egg surface proteins from an endoparasitoid, Cotesia chilonis. Proteins containing conserved enzymatic domains constitute a large proportion of egg surface components. Some proteins, such as superoxidase dismutase, homolog of C. rubecula 32-kDa protein and immunoevasive protein-2A, are classical parasitism factors that have known functions in host immunity regulation. Melanization assays revealed that a novel egg surface protein, C. chilonis egg surface serpin domain-containing protein had the same function as a C. chilonis venom serpin, as both suppressed host melanization in a dose-dependent manner. C. chilonis egg surface serpin domain-containing protein is mainly transcribed in C. chilonis oocytes with follicular cells, and it is located on both the anterior and posterior sides of the mature egg surface. Additionally, we used LC-MS/MS to identify 586 binding proteins sourced from C. suppressalis plasma located on the eggshell surface of C. chilonis, which included some immunity-related proteins. These results not only indicate that C. chilonis uses its egg surface proteins to reduce the immune response of its host, but also imply that endoparasitoid egg surface proteins might be a new parasitism factor involved in host immune regulation. This article is protected by copyright. All rights reserved.

China has the largest pork consumption worldwide. However, the high incidence of piglet fetal mummification (3%–5%) is an important factor that causes the slow improvement of pig reproductive capacity, and the genetic mechanism is still unclear. This study aimed to identify candidate genes associated with piglet fetal mummification. RNA-seq technology was used to compare transcriptome profiling of blood from healthy and mummified piglets at different stages of pregnancy (35, 56, 77, and 98 days). A total of 137–420 differentially expressed genes (DEGs) were detected at each stage. Seven DEGs were significantly differentially expressed at various stages. IL-9R, TLR8, ABLIM3, FSH-α, ASCC1, PRKCZ, and GCK may play important roles in the course of piglet fetal mummification. The differential genes we identified between the groups were mainly enriched in immune and inflammation regulation, while others were mainly enriched in reproduction. Considering the function of candidate genes, IL-9R and TLR8 were suggested as the most promising candidate genes involved in mummified piglet traits. We speculate that during pregnancy, it may be the combined effects of the above-mentioned inflammation, immune response, and reproduction-related signaling pathways that affect the occurrence of mummified piglets and further affect pig reproduction.

Spinal cord injury (SCI) is a disastrous central nervous system (CNS) disorder, which was intimately associated with oxidative stress. Studies have confirmed that Iridoids Effective Fraction of Valeriana jatamansi Jones (IEFV) can scavenge reactive oxygen species. This study aimed to confirm the efficacy of IEFV in ameliorating SCI.For establish the SCI model, the Sprague-Dawley rats underwent a T10 laminectomy with transient violent oppression by aneurysm clip. Then, the rats received IEFV intragastrically for 8 consecutive weeks to evaluate the protective effect of IEFV on motor function, oxidative stress, inflammation and neurotrophic factors in SCI rats.Basso, Beattie and Bresnahan scores, hematoxylin and eosin (HE) staining and transmission electron microscopy experiments found IEFV protected motor function and alleviated neuron damage. Meanwhile, IEFV treatment decreased the release of malondialdehyde, interleukin-6 (IL-6), cyclooxygenase-2 and tumor necrosis factor-α. Moreover, IEFV treatment elevated the expression levels of brain-derived neurotrophic factor and nerve growth factor of SCI rats. Finally, administration of IEFV significantly inhibited the expression of p-p65 and toll-like receptor 4 (TLR4).This study suggests that IEFV could attenuate the oxidative stress and inflammatory response of the spinal cord after SCI, which was associated with inhibition of the TLR4/nuclear factor-kappaB signaling pathway.

Mitochondria are considered to be the powerhouse of the cell. Normal functioning of the mitochondria is not only essential for cellular energy production but also for several immunomodulatory processes. Macrophages operate in metabolic niches and rely on rapid adaptation to specific metabolic conditions such as hypoxia, nutrient limitations, or reactive oxygen species to neutralize pathogens. In this regard, the fast reprogramming of mitochondrial metabolism is indispensable to provide the cells with the necessary energy and intermediates to efficiently mount the inflammatory response. Moreover, mitochondria act as a physical scaffold for several proteins involved in immune signaling cascades and their dysfunction is immediately associated with a dampened immune response. In this review, we put special focus on mitochondrial function in macrophages and highlight how mitochondrial metabolism is involved in macrophage activation.

Cadmium (Cd) represents a unique hazard because of the long biological half-life in humans (20–30 years). This metal accumulates in organs causing a continuum of responses, with organ disease/failure as extreme outcome. Some of the cellular and molecular alterations in target tissues can be related to immune-modulating potential of Cd. This metal may cause adverse responses in which components of the immune system function as both mediators and effectors of Cd tissue toxicity, which, in combination with Cd-induced alterations in homeostatic reparative activities may contribute to tissue dysfunction. In this work, current knowledge concerning inflammatory/autoimmune disease manifestations found to be related with cadmium exposure are summarized. Along with epidemiological evidence, animal and in vitro data are presented, with focus on cellular and molecular immune mechanisms potentially relevant for the disease susceptibility, disease promotion, or facilitating development of pre-existing pathologies.

Connexin-50 (Cx50) is among the most frequently mutated genes associated with congenital cataracts. While most of these disease-linked variants cause loss-of-function due to misfolding or aberrant trafficking, others directly alter channel properties. The mechanistic bases for such functional defects are mostly unknown. We investigated the functional and structural properties of a cataract-linked mutant, Cx50T39R (T39R), in the Xenopus oocyte system. T39R exhibited greatly enhanced hemichannel currents with altered voltage-gating properties compared to Cx50 and induced cell death. Co-expression of mutant T39R with wild-type Cx50 (to mimic the heterozygous state) resulted in hemichannel currents whose properties were indistinguishable from those induced by T39R alone, suggesting that the mutant had a dominant effect. Co-expression with Cx46 also produced channels with altered voltage-gating properties, particularly at negative potentials. All-atom molecular dynamics simulations indicate that the R39 substitution can form multiple electrostatic salt-bridge interactions between neighboring subunits that could stabilize the open-state conformation of the N-terminal domain, while also neutralizing the voltage-sensing residue D3 as well as residue E42 which participates in loop-gating. Together, these results suggest T39R acts as a dominant gain-of-function mutation that produces leaky hemichannels that may cause cytotoxicity in the lens and lead to development of cataracts.Statement of significanceWe investigated the functional and structural properties of a cataract-linked mutant, Cx50T39R (T39R), in the Xenopus oocyte system and showed that T39R exhibited greatly enhanced hemichannel currents with altered voltage-gating properties compared to Cx50 and induced cell death. Consistent with our experimental findings, all-atom equilibrium state molecular dynamics (MD) simulations of T39R show that R39 stabilized the open-state configuration of the N-terminal (NT) domain from an adjacent subunit. These results suggest that T39R causes disease by preventing the hemichannels from closing when present in the plasma membrane in the undocked state and provide an atomistic rationalization for the Cx50 disease-linked phenotype. They also expand our understanding of how connexin hemichannel channel gating is controlled.

The Notch signaling pathway is conserved among mammalian species and controls proliferation, differentiation, and cell death in many organs throughout the body including the reproductive tract. Notch signaling plays critical roles in the development and function of both the male and female reproductive systems. Specifically, within the female reproductive tract, Notch signaling is hormone regulated and mediates key reproductive events important for ovarian and uterine function. In this review, we highlight the tissues that express Notch receptors, ligands, and downstream effectors and distinguish how these molecules regulate reproductive function in male and female mice, non-human primates, and humans. Finally, we describe some of the aberrations in Notch signaling in female reproductive pathologies and identify opportunities for future investigation.

The function of the skin as a barrier against a dry environment evolved in a common ancestor of terrestrial vertebrates such as mammals and birds. However, it is unknown which elements of the genetic program of skin barrier formation are evolutionarily ancient and conserved. In this study, we determined the transcriptomes of chicken keratinocytes (KCs) grown in monolayer culture and in an organotypic model of avian skin. The differentiation-associated changes in global gene expression were compared with previously published transcriptome changes of human KCs cultured under equivalent conditions. We found that specific keratins and genes of the epidermal differentiation complex were upregulated during the differentiation of both chicken and human KCs. Likewise, the transcriptional upregulation of genes that control the synthesis and transport of lipids, anti-inflammatory cytokines of the IL-1 family, protease inhibitors, and other regulators of tissue homeostasis was conserved in the KCs of both species. However, some avian KC differentiation-associated transcripts lack homologs in mammals and vice versa, indicating a genetic basis for taxon-specific skin features. The results of this study reveal an evolutionarily ancient program in which dynamic gene transcription controls the metabolism and transport of lipids as well as other core processes during terrestrial skin barrier formation.

Tumor angiogenesis is a critical target for cancer treatment and its inhibition has become a common anticancer approach following chemotherapy. However, due to the simultaneous activation of different compensatory molecular mechanisms that enhance tumor angiogenesis, clinically authorized anti-angiogenic medicines are ineffective. Additionally, medications used to treat cancer have an effect on normal body cells; nonetheless, more research is needed to create new cancer therapeutic techniques. With advances in molecular biology, it is now possible to use gene-editing technology to alter the genome and study the functional changes resulting from genetic manipulation. With the development of CRISPR/Cas9 technology, it has become a very powerful tool for altering the genomes of many organisms. It was determined that CRISPR/Cas9, which first appeared in bacteria as a part of an adaptive immune system, could be used, in modified forms, to alter genomes and function. In conclusion, CRISPR/Cas9 could be a major step forward to cancer management by providing patients with an effective method for dealing with cancers by dissecting the carcinogenesis pathways, identifying new biologic targets, and perhaps arming cancer cells with drugs. Hence, this review will discuss the current applications of CRISPR/Cas9 technology in tumor angiogenesis research for the purpose of cancer treatment.

Calcium ion (Ca(2+)) signaling is one of the most frequently employed mechanisms of signal transduction by eukaryotic cells, and starts with either Ca(2+) release from intracellular stores or Ca(2+) entry through the plasma membrane. In intracellular protist parasites Ca(2+) signaling initiates a sequence of events that may facilitate their invasion of host cells, respond to environmental changes within the host, or regulate the function of their intracellular organelles. In this review we examine recent findings in Ca(2+) signaling in two groups of intracellular protist parasites that have been studied in more detail, the apicomplexan and the trypanosomatid parasites.

Copper and iron proteins play a wide range of functions in living organisms. Metal assembly into metalloproteins is a complex process, where mismetalation is detrimental and energy-consuming to cells. Under metal deficiency, metal distribution is expected to reach a metalation ranking, prioritizing essential versus dispensable metalloproteins, while avoiding interferences with other metals and protecting metal-sensitive processes. In this review, we propose that posttranscriptional Modulators of Metalloprotein messenger RNA (ModMeR) are good candidates in metal prioritization under metal-limited conditions. ModMeR target high quota or redundant metalloproteins and, by adjusting their synthesis, ModMeR act as internal metal distribution valves. Unappropriate metalation of ModMeR targets could compete with metal delivery to essential metalloproteins and interfere with metal-sensitive processes, such as chloroplastic photosynthesis and mitochondrial respiration. Regulation of ModMeR targets could increase or decrease the metal flow through interconnected pathways in cellular metal distribution, helping to adequate differential metal requirements. Here, we describe and compare ModMeR that function in response to copper and iron deficiencies. Specifically, we describe copper-microRNAs from Arabidopsis thaliana and diverse iron ModMeR from yeast, mammals and bacteria, under copper and iron deficiencies, as well as the influence of oxidative stress. Putative functions derived from their role as ModMeR are also discussed., This work was supported by grants BIO2017-87828-C2-1-P and PID2020-116940RB-I00 funded by MCIN/AEI/10.13039/501100011033 and, in the case of BIO2017-87828-C2-1-P, by ERDF A way of making Europe.

Subcellular restriction of gene expression is crucial to the functioning of a wide variety of cell types. The cellular machinery driving spatially restricted gene expression has been studied for many years, but recent advances have highlighted novel mechanisms by which cells can generate subcellular microenvironments with specialized gene expression profiles. Particularly intriguing are recent findings that phase separation plays a role in certain RNA localization pathways. The burgeoning field of phase separation has revolutionized how we view cellular compartmentalization, revealing that, in addition to membrane-bound organelles, phase-separated cytoplasmic microenvironments — termed biomolecular condensates — are compositionally and functionally distinct from the surrounding cytoplasm, without the need for a lipid membrane. The coupling of phase separation and RNA localization allows for precise subcellular targeting, robust translational repression and dynamic recruitment of accessory proteins. Despite the growing interest in the intersection between RNA localization and phase separation, it remains to be seen how exactly components of the localization machinery, particularly motor proteins, are able to associate with these biomolecular condensates. Further studies of the formation, function, and transport of biomolecular condensates promise to provide a new mechanistic understanding of how cells restrict gene expression at a subcellular level.

Tunneling nanotubes (TNTs) are F-actin-based, membrane-enclosed tubular connections between animal cells that transport a variety of cellular cargo. Over the last 15 years since their discovery, TNTs have come to be recognized as key players in normal cell communication and organism development, and are also exploited for the spread of various microbial pathogens and major diseases like cancer and neurodegenerative disorders. TNTs have also been proposed as modalities for disseminating therapeutic drugs between cells. Despite the rapidly expanding and wide-ranging relevance of these structures in both health and disease, there is a glaring dearth of molecular mechanistic knowledge regarding the formation and function of these important but enigmatic structures. A series of fundamental steps are essential for the formation of functional nanotubes. The spatiotemporally controlled and directed modulation of cortical actin dynamics would be required to ensure outward F-actin polymerization. Local plasma membrane deformation to impart negative curvature and membrane addition at a rate commensurate with F-actin polymerization would enable outward TNT elongation. Extrinsic tactic cues, along with cognate intrinsic signaling, would be required to guide and stabilize the elongating TNT towards its intended target, followed by membrane fusion to create a functional TNT. Selected cargoes must be transported between connected cells through the action of molecular motors, before the TNT is retracted or destroyed. This review summarizes the current understanding of the molecular mechanisms regulating these steps, also highlighting areas that deserve future attention.

An antisense oligonucleotide (ASO) is a short single-stranded deoxyribonucleotide complementary to the sense strand of a selected nucleic acid. As a result, an ASO can modulate gene expression through several mechanisms. The technology based on ASO has already been applied in studies on gene function in mammalian cells and selective therapeutic strategies for many diseases. The conceptual simplicity and low cost of this method, and the developments in the field of plant genome sequencing observed in the last decades, have paved the way for the ASO method also in plant biology. It is applied in gene function analysis as well as the development of non-invasive plant production technology involving gene modifications without transgenesis. Therefore, the first part of this review provides a comprehensive overview of the structure, mechanism of action and delivery methods of ASOs in plants and shows the most important features essential for the proper design of individual experiments. We also discuss potential issues and difficulties that may arise during practical ASO implementation. The second part of this article contains an analysis of ASO applications in various studies in the field of plant biology. We presented for the first time that ASOs were also successfully applied in cucumber.

Nuage are RNA-rich condensates that assemble around the nuclei of developing germ cells. Many proteins required for the biogenesis and function of silencing small RNAs (sRNAs) enrich in nuage, and it is often assumed that nuage is the cellular site where sRNAs are synthesized and encounter target transcripts for silencing. Using C. elegans as a model, we examine the complex multicondensate architecture of nuage and review evidence for compartmentalization of silencing pathways. We consider the possibility that nuage condensates balance the activity of competing sRNA pathways and serve to limit, rather than enhance, sRNA amplification to protect transcripts from dangerous runaway silencing.

Brain transcriptional regulatory network for behavior demonstrates that brain gene expression in the honey bee can be accurately predicted from the expression transcription factors (TFs), but roles for specific TFs are less understood. Mushroom bodies (MBs) are important for learning, memory and sensory integration in the honey bee brain. A transcription factor, Mblk-1, expressed preferentially in the large-type Kenyon cells of the honeybee MBs is predicted to be involved in brain function by regulating transcription of its target genes in honey bee. However its function and the mechanism of regulation in behavior of honey bee is still obscure. Here we show that Mblk-1 had significantly higher expression in the brains of forager bees relative to nurse bees. Mblk-1 was significantly inhibited in bees fed siRNA. In addition, inhibition of Mblk-1 decreased sucrose responsiveness in foragers. Finally, we determined that Mblk-1 regulated the mRNA of AmGR1. These findings suggest that Mblk-1 may target AmGR1 to regulate the sucrose responsiveness of foragers. This article is protected by copyright. All rights reserved.

The CIDE domain was initially identified in apoptotic nucleases and now forms a highly conserved family with diverse functions ranging from cell death to lipid metabolism. Based on structural determination of the DREP3 domain, it is suggested that the head-to-tail helical filament structure might be a unified mechanism of CIDE-domain assembly and represents a critical higher-order scaffolding structure that is important for the function of CIDE-domain-containing proteins in DNA fragmentation and lipid-droplet fusion., The cell-death-inducing DFF45-like effector (CIDE) domain is a protein-interaction module comprising ∼80 amino acids and was initially identified in several apoptotic nucleases and their regulators. CIDE-domain-containing proteins were subsequently identified among proteins involved in lipid metabolism. Given the involvement of CIDE-domain-containing proteins in cell death and lipid homeostasis, their structure and function have been intensively studied. Here, the head-to-tail helical filament structure of the CIDE domain of DNA fragmentation factor-related protein 3 (DREP3) is presented. The helical filament structure was formed by opposing positively and negatively charged interfaces of the domain and was assembled depending on protein and salt concentrations. Although conserved filament structures are observed in CIDE family members, the structure elucidated in this study and its comparison with previous structures indicated that the size and the number of molecules used in one turn vary. These findings suggest that this charged-surface-based head-to-tail helical filament structure represents a unified mechanism of CIDE-domain assembly and provides insight into the function of various forms of the filament structure of the CIDE domain in higher-order assembly for apoptotic DNA fragmentation and control of lipid-droplet size.

Individual recognition via communication signals is a critical component of social behavior, and provides the basis of conflict resolution, territorial behavior, and mate choice. However, the function of chemical signals in mammalian individual recognition and conflict resolution has largely been unexplored despite olfaction being a dominant sensory modality in many mammalian species. Here, we describe behavioral tests designed to evaluate the potential role of forehead gland secretions during conflict related to territorial defense in male Great Himalayan leaf-nosed bats. We used gas chromatography-mass spectrometry to quantify the chemical composition. Our results showed that forehead gland secretions contain 16 categories of compounds, including 84 volatile compounds. The concentrations of compounds and their categories differed significantly among individuals. Moreover, behavioral studies indicated that males can use chemical signals for individual recognition. Contests were staged between males with or without functioning forehead glands. Paired males without functioning forehead glands displayed more physical contact and longer contest duration compared with pairs with functioning glands. Moreover, males with a functioning gland were more likely to win in contests when paired with males without a functioning gland. These findings support a growing amount of evidence that chemical signals play a vital role in conflict resolution in mammals.

Lipids are integral cellular components that act as substrates for energy provision, signaling molecules, and essential constituents of biological membranes along with a variety of other biological functions. Despite their significance, lipid accumulation may result in lipotoxicity, impair autophagy, and lysosomal function that may lead to certain diseases and metabolic syndromes like obesity and even cell death. Therefore, these lipids are continuously recycled and redistributed by the process of selective autophagy specifically termed as lipophagy. This selective form of autophagy employs lysosomes for the maintenance of cellular lipid homeostasis. In this review, we have reviewed the current literature about how lipid droplets (LDs) are recruited towards lysosomes, cross-talk between a variety of autophagy receptors present on LD surface and lysosomes, and lipid hydrolysis by lysosomal enzymes. In addition to it, we have tried to answer most of the possible questions related to lipophagy regulation at different levels. Moreover, in the last part of this review, we have discussed some of the pathological states due to the accumulation of these LDs and their possible treatments under the light of currently available findings.

Although type 1 diabetes is thought to be an organ-specific autoimmune disease, mediated by effective CD4+ and CD8+ T cells, it has recently become clear that B cells participate in the initiation and progress of this disease. Indeed, B cell deletion can prevent or reverse autoimmune diabetes in nonobese diabetic mice and even result in partially remaining β cell function in patients with new-onset type 1 diabetes. This review summarizes the dual role of B cells in this process not only of pathogenic effect but also of immunoregulatory function in type 1 diabetes. We focus on the impact that B cells have on regulating the activation, proliferation, and cytokine production of self-reactive T cells along with regulatory T cells, with the aim of providing a better understanding of the interactions between T and B cells in immunopathogenesis and improving the efficacy of interventions for clinical practice.

Super-enhancers (SEs) govern macrophage polarization and function. However, the mechanism underlying the signal-dependent latent SEs remodeling in macrophages remains largely undefined. Here we show that the epigenetic reader ZMYND8 forms liquid compartments with NF-κB/p65 to silence latent SEs and restrict macrophage-mediated inflammation. Mechanistically, the fusion of ZMYND8 and p65 liquid condensates is reinforced by signal-induced acetylation of p65. Then acetylated p65 guides the ZMYND8 redistribution onto latent SEs de novo generated in polarized macrophages, and consequently, recruit LSD1 to decommission latent SEs. The liquidity characteristic of ZMYND8 is critical for its regulatory effect since mutations coagulating ZMYND8 into solid compartments disable the translocation of ZMYND8 and its suppressive function. Thereby, ZMYND8 serves as a molecular rheostat to switch off latent SEs and control the magnitude of the immune response. Meanwhile, we propose a phase separation model by which the latent SEs are fine-tuned in a spatiotemporal manner., Macrophages employ epigenetic remodeling, especially the regulation of superenhancers (SEs), to promote classical polarization and function; whether liquid-liquid phase separation (LLPS) is involved is not known. Here, the authors show the epigenetic reader ZMYND8 forms condensates to deactivate latent SEs in a spatiotemporal manner and thereby restrict macrophage-mediated inflammation.