Mechanisms Of Pathogenesis Research Articles

Expanded ATXN1 alters transcription and calcium signaling in SCA1 human motor neurons differentiated from induced pluripotent stem cells

Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited and lethal neurodegenerative disease caused by the abnormal expansion of CAG repeats in the ATAXIN-1 (ATXN1) gene. Pathological studies identified dysfunction and loss of motor neurons (MNs) in the brain stem and spinal cord, which are thought to contribute to premature lethality by affecting the swallowing and breathing of SCA1 patients. However, the molecular and cellular mechanisms of MN pathogenesis remain unknown.To study SCA1 pathogenesis in human MNs, we differentiated induced pluripotent stem cells (iPSCs) derived from SCA1 patients and their unaffected siblings into MNs. We examined proliferation of progenitor cells, neurite outgrowth, spontaneous and glutamate-induced calcium activity of SCA1 MNs to investigate cellular mechanisms of pathogenesis. RNA sequencing was then used to identify transcriptional alterations in iPSC-derived MN progenitors (pMNs) and MNs which could underlie functional changes in SCA1 MNs. We found significantly decreased spontaneous and evoked calcium activity and identified dysregulation of genes regulating calcium signaling in SCA1 MNs. These results indicate that expanded ATXN1 causes dysfunctional calcium signaling in human MNs.

Somatic mutations in arteriovenous malformations in hereditary hemorrhagic telangiectasia support a bi-allelic two-hit mutation mechanism of pathogenesis

Hereditary hemorrhagic telangiectasia (HHT) is an inherited disorder of vascular malformations characterized by mucocutaneous telangiectases and arteriovenous malformations (AVMs) in internal organs. HHT is caused by inheritance of a loss of function mutation in one of three genes. Although individuals with HHT are haploinsufficient for one of these genes throughout their entire body, rather than exhibiting a systemic vascular phenotype, vascular malformations occur as focal lesions in discrete anatomic locations. The inconsistency between genotype and phenotype has provoked debate over whether haploinsufficiency or a different mechanism gives rise to the vascular malformations. We previously showed that HHT-associated skin telangiectases develop by a two-hit mutation mechanism in an HHT gene. However, somatic mutations were identified in only half of the telangiectases, raising the question whether a second-hit somatic mutation is a necessary (required) event in HHT pathogenesis. Here, we show that another mechanism for the second hit is loss of heterozygosity across the chromosome bearing the germline mutation. Secondly, we investigate the two-hit mutation mechanism for internal organ AVMs, the source of much of the morbidity of HHT. Here, we identified somatic molecular genetic events in eight liver telangiectases, including point mutations and a loss of heterozygosity event. We also identified somatic mutations in one pulmonary AVM and two brain AVMs, confirming that mucocutaneous and internal organ vascular malformations undergo the same molecular mechanisms. Together, these data argue that bi-allelic loss of function in an HHT gene is a required event in the pathogenesis of HHT-associated vascular malformations.

Essential genes for Haemophilus parainfluenzae survival and biofilm growth.

Haemophilus parainfluenzae (Hp) is a Gram-negative, highly prevalent, and abundant commensal in the human oral cavity, and an infrequent extraoral opportunistic pathogen. Hp occupies multiple niches in the oral cavity, including the supragingival plaque biofilm. Little is known about how Hp interacts with its neighbors in healthy biofilms nor its mechanisms of pathogenesis as an opportunistic pathogen. To address this, we identified the essential genome and conditionally essential genes in in vitro biofilms aerobically and anaerobically. Using transposon insertion sequencing (TnSeq) with a highly saturated mariner transposon library in two strains, the ATCC33392 type-strain (Hp 392) and oral isolate EL1 (Hp EL1), we show that the essential genomes of Hp 392 and Hp EL1 are composed of 395 (20%) and 384 (19%) genes, respectively. The core essential genome, consisting of 341 (17%) essential genes conserved between both strains, was composed of genes associated with genetic information processing, carbohydrate, protein, and energy metabolism. We also identified conditionally essential genes for aerobic and anaerobic biofilm growth, which were associated with carbohydrate and energy metabolism in both strains. RNAseq analysis determined that most genes upregulated during anaerobic growth are not essential for Hp 392 anaerobic survival. The completion of this library and analysis under these conditions gives us a foundational insight into the basic biology of H. parainfluenzae in differing oxygen conditions, similar to its in vivo habitat. This library presents a valuable tool for investigation into conditionally essential genes for an organism that lives in close contact with many microbial species in the human oral habitat.IMPORTANCEHaemophilus parainfluenzae is a highly abundant human commensal microbe, present in most healthy individuals where it colonizes the mouth. H. parainfluenzae correlates with good oral health and may play a role in preservation of healthy host status. Also, H. parainfluenzae can cause opportunistic infections outside of the oral cavity. To date, little is known about how H. parainfluenzae colonizes the human host, despite being such a frequent and abundant part of our human microbiome. Here, we demonstrate the creation and use of a powerful tool, a TnSeq library, used to identify genes necessary for both the outright growth of this organism and also genes conditionally essential for growth in varying oxygen status which it can encounter in the human host. This tool and these data serve as a foundation for further study of this relatively unknown organism that may play a role in preserving human health.

The impact of sex on HIV immunopathogenesis and therapeutic interventions.

Globally, the majority of people living with HIV are women or girls, but they have been a minority of participants in clinical trials and observational studies of HIV. Despite this underrepresentation, differences in the pathogenesis of HIV have been observed between men and women, with contributions from both gender- and sex-based factors. These include differences in the risk of HIV acquisition, in viral load set point and immune activation in responses to viremia, and differences in HIV reservoir maintenance. These differences obligate adequate study in both males and females in order to optimize treatments, but also provide a powerful leverage point for delineating the mechanisms of HIV pathogenesis. The shifts in exposure to sex steroid hormones across a lifespan introduce additional complexity, which again can be used to focus on either genetic or hormonal influences as the driver of an outcome. In this Review, we discuss consistent and reproducible differences by sex across the spectrum of HIV, from acquisition through pathogenesis, treatment, and cure, and explore potential mechanisms and gaps in knowledge.

Liver cirrhosis: molecular mechanisms and therapeutic interventions.

Liver cirrhosis is the end-stage of chronic liver disease, characterized by inflammation, necrosis, advanced fibrosis, and regenerative nodule formation. Long-term inflammation can cause continuous damage to liver tissues and hepatocytes, along with increased vascular tone and portal hypertension. Among them, fibrosis is the necessary stage and essential feature of liver cirrhosis, and effective antifibrosis strategies are commonly considered the key to treating liver cirrhosis. Although different therapeutic strategies aimed at reversing or preventing fibrosis have been developed, the effects have not be more satisfactory. In this review, we discussed abnormal changes in the liver microenvironment that contribute to the progression of liver cirrhosis and highlighted the importance of recent therapeutic strategies, including lifestyle improvement, small molecular agents, traditional Chinese medicine, stem cells, extracellular vesicles, and gut remediation, that regulate liver fibrosis and liver cirrhosis. Meanwhile, therapeutic strategies for nanoparticles are discussed, as are their possible underlying broad application and prospects for ameliorating liver cirrhosis. Finally, we also reviewed the major challenges and opportunities of nanomedicine‒biological environment interactions. We hope this review will provide insights into the pathogenesis and molecular mechanisms of liver cirrhosis, thus facilitating new methods, drug discovery, and better treatment of liver cirrhosis.

Combination of trehalose and botulinum toxin type A in REVITOX skin treatment protocols

This article presents the REVITOX protocol, developed by the author, which includes the combination of REVI products (native hyaluronic acid + trehalose) and botulinum toxin type A (BTA) for the treatment of rosacea and correction of age-related changes. A plethora of studies has demonstrated that trehalose, an exceptional stabilizer of proteins, contributes to maintaining cellular integrity, exhibits antioxidant and angioprotective effects, and has been shown to induce autophagy. In combination with the proven effects of hyaluronic acid and BTA, these properties facilitate the optimal environment for cellular structure functioning, influencing the basic mechanisms of rosacea pathogenesis and mitigating the severity of age-related changes through the balanced elimination of dynamic and static rhytides, stimulation of neocollagenesis and improvement of the mechanical properties of the dermis. By targeting the multifactorial processes of facial aging, improving skin hydration and elasticity, the REVITOX Beauty protocol has ensured the balanced rejuvenation of the perioral and periorbital skin, resulting in a significant improvement in skin quality, as confirmed by the results of 3D diagnostics. After 3 treatment sessions of the REVITOX Derma program, the patients showed a general improvement of facial skin, a visible reduction in erythema and telangiectasia severity, regression of papulopustular elements, enhanced skin hydration and elasticity, and no recurrences at the follow-up. Further studies on the combined use of BTA and REVI will investigate the potential for using these protocols in the treatment of other dermatological conditions, including in combination with energy-based devices and beauty injections.

Concomitant presence of a novel ARPP21 variant and CNVs in Chinese familial amyotrophic lateral sclerosis-frontotemporal dementia patients.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder marked by the degeneration of motor neurons and progressive muscle weakness. Heredity plays an important part in the pathogenesis of ALS. Recently, with the emergence of the oligogenic pathogenic mechanism in ALS and the ongoing discovery of new mutated genes and genomic variants, there is an emerging need for larger-scale and more comprehensive genetic screenings in higher resolution. In this study, we performed whole-genome sequencing (WGS) on 34 familial ALS probands lacking the most common disease-causing mutations to explore the genetic landscape of Chinese ALS patients further. Among them, we identified a novel ARPP21 c.1231G > A (p.Glu411Lys) variant and two copy number variations (CNVs) affecting the PFN1 and RBCK1 genes in a patient with ALS-frontotemporal dementia (FTD). This marks the first report of an ARPP21 variant in Chinese ALS-FTD patients, providing fresh evidence for the association between ARPP21 and ALS. Our findings also underscore the potential role of CNVs in ALS-FTD, suggesting that the cumulative effect of multiple rare variants may contribute to disease onset. Furthermore, compared to the averages in our cohort and the reported Chinese ALS population, this patient displayed a shorter survival time and more rapid disease progression, suggesting the possibility of an oligogenic mechanism in disease pathogenesis. Further research will contribute to a deeper understanding of the rare mutations and their interactions, thus advancing our understanding of the genetic mechanisms underlying ALS and ALS-FTD.

Diffuse Gastric Cancer: A Comprehensive Review of Molecular Features and Emerging Therapeutics.

Diffuse-type gastric cancer (DGC) accounts for approximately one-third of gastric cancer diagnoses but is a more clinically aggressive disease with peritoneal metastases and inferior survival compared with intestinal-type gastric cancer (IGC). The understanding of the pathogenesis of DGC has been relatively limited until recently. Multiomic studies, particularly by The Cancer Genome Atlas, have better characterized gastric adenocarcinoma into molecular subtypes. DGC has unique molecular features, including alterations in CDH1, RHOA, and CLDN18-ARHGAP26 fusions. Preclinical models of DGC characterized by these molecular alterations have generated insight into mechanisms of pathogenesis and signaling pathway abnormalities. The currently approved therapies for treatment of gastric cancer generally provide less clinical benefit in patients with DGC. Based on recent phase II/III clinical trials, there is excitement surrounding Claudin 18.2-based and FGFR2b-directed therapies, which capitalize on unique biomarkers that are enriched in the DGC populations. There are numerous therapies targeting Claudin 18.2 and FGFR2b in various stages of preclinical and clinical development. Additionally, there have been preclinical advancements in exploiting unique therapeutic vulnerabilities in several models of DGC through targeting of the focal adhesion kinase (FAK) and Hippo pathways. These preclinical and clinical advancements represent a promising future for the treatment of DGC.

324 Use of organoids as in vitro model to study intestinal function

Abstract Organoids are tridimensional structures cultured in the lab from stem cells. Organoids have been developed for many different organs, particularly those with Lgr5+ stem cells. The organs of the digestive system belong to this group of organs and to date, organoids have been established from all the digestive tract tissues and organs including liver, gall bladder and pancreas. Although most protocols to generate organoids have focused on human and mouse organs, organoids from domestic and production animals like dogs, cats, rabbits, pigs, chickens, turkeys, and horses are actively used in research. In this presentation, the principles of developing intestinal organoids will be covered, along with a summary of how they have been used to address intestinal function and disease in our lab and by others. In our lab, we use swine enteroids (intestinal organoids) to study the intestinal epithelial responses to nutrients and pathogens. We have explored differential responses of the intestinal epithelium to organic and inorganic sources of dietary zinc, and we are currently investigating the mechanism of pathogenesis of Lawsonia intracellularis, the causative agent of porcine intestinal adenopathy. We will also discuss methods for modeling intestinal physiology using enteroids, and the advantages and challenges of working with swine enteroids.

The aryl hydrocarbon receptor and FOS mediate cytotoxicity induced by Acinetobacter baumannii

Acinetobacter baumannii is a pathogenic and multidrug-resistant Gram-negative bacterium that causes severe nosocomial infections. To better understand the mechanism of pathogenesis, we compare the proteomes of uninfected and infected human cells, revealing that transcription factor FOS is the host protein most strongly induced by A. baumannii infection. Pharmacological inhibition of FOS reduces the cytotoxicity of A. baumannii in cell-based models, and similar results are also observed in a mouse infection model. A. baumannii outer membrane vesicles (OMVs) are shown to activate the aryl hydrocarbon receptor (AHR) of host cells by inducing the host enzyme tryptophan-2,3-dioxygenase (TDO), producing the ligand kynurenine, which binds AHR. Following ligand binding, AHR is a direct transcriptional activator of the FOS gene. We propose that A. baumannii infection impacts the host tryptophan metabolism and promotes AHR- and FOS-mediated cytotoxicity of infected cells.

The Comparative Characterization of a Hypervirulent Acinetobacter baumannii Bacteremia Clinical Isolate Reveals a Novel Mechanism of Pathogenesis.

Acinetobacter baumannii is an opportunistic Gram-negative pathogen with exquisite survival capabilities under various environmental conditions and displays widespread resistance to common antibiotics. A. baumannii is a leading cause of nosocomial infections that result in high morbidity and mortality rates. Accordingly, when multidrug resistance rates surpass threshold levels, the percentage of A. baumannii clinical isolates surges. Research into A. baumannii has increased in the past decade, and multiple mechanisms of pathogenesis have been identified, including mechanisms underlying biofilm development, quorum sensing, exotoxin production, secretion system utilization, and more. To date, the two gold-standard strains used to investigate different aspects of A. baumannii pathogenesis include ATCC 17978 and ATCC 19606. Here, we report a comparative characterization study of three additional A. baumannii clinical isolates obtained from different infection types and derived from different anatomical regions of infected patients. The comparison of three clinical isolates in addition to the ATCC strains revealed that the hypervirulent bacteremia clinical isolate, known as HUMC1, employs a completely different mechanism of pathogenesis when compared to all its counterparts. In stark contrast to the other genetic variants, the hypervirulent HUMC1 isolate does not form biofilms, is antibiotic-susceptible, and has the capacity to reach higher levels of quorum compared to the other clinically relevant strains. Our data also reveal that HUMC1 does not shed endotoxin into the extracellular milieu, rather secretes the evolutionarily conserved, host-mimicking, Zonula occludens toxin (Zot). Taken together, our hypothesis that HUMC1 cells have the ability to reach higher levels of quorum and lack biofilm production and endotoxin shedding, accompanied by the substantial elaboration of Zot, suggests a novel mechanism of pathogenesis that appears to afford the hypervirulent pathogen with stealth-like capabilities when disseminating through the circulatory system in a state of bacteremia.

Junctional Epidermolysis Bullosa in Sprague Dawley Rats Caused by a Frameshift Mutation of Col17a1 Gene

Junctional epidermolysis bullosa is an intractable cutaneous disorder in humans causing skin fragility and blistering due to mutations in genes encoding essential molecules adhering epidermis and dermis including collagen XVII. However, the pathogenesis still remains to be not fully understood perhaps because of a lack of appropriate animal models. In this study, we report novel mutant rats experiencing junctional epidermolysis bullosa, which was confirmed to be caused by a frameshift mutation of Col17a1 gene, as a rat model for investigating the underlying mechanism of pathogenesis. The mutant rats completely lacked the expression of collagen XVII and had blisters leading to infantile deaths as a homozygous condition, although their skin was apparently normal at birth by light microscopic evaluation except that immunohistochemical examination could not detect collagen XVII in any organs. These observations suggest that collagen XVII is not essential for the development of skin during the prenatal period but is indispensable for keeping epidermal-dermal connections stable after birth. Subsequent electron microscopic examinations further revealed an absence of hemidesmosomal inner plaques being composed of BP230, a binding partner of collagen XVII, and plectin in Col17a1-null newborns, albeit mRNA expressions of these molecules seemed to be unaffected at least during the fetal period. These results suggest that the lack of collagen XVII induces attenuation of hemidesmosomal inner plaques, which in turn destabilizes the epidermis-dermis connection and results in deterioration of epidermal physiology with formation of blisters after birth.

Bilinear Perceptual Fusion Algorithm Based on Brain Functional and Structural Data for ASD Diagnosis and Regions of Interest Identification.

Autism spectrum disorder (ASD) is a serious mental disorder with a complex pathogenesis mechanism and variable presentation among individuals. Although many deep learning algorithms have been used to diagnose ASD, most of them focus on a single modality of data, resulting in limited information extraction and poor stability. In this paper, we propose a bilinear perceptual fusion (BPF) algorithm that leverages data from multiple modalities. In our algorithm, different schemes are used to extract features according to the characteristics of functional and structural data. Through bilinear operations, the associations between the functional and structural features of each region of interest (ROI) are captured. Then the associations are used to integrate the feature representation. Graph convolutional neural networks (GCNs) can effectively utilize topology and node features in brain network analysis. Therefore, we design a deep learning framework called BPF-GCN and conduct experiments on publicly available ASD dataset. The results show that the classification accuracy of BPF-GCN reached 82.35%, surpassing existing methods. This demonstrates the superiority of its classification performance, and the framework can extract ROIs related to ASD. Our work provides a valuable reference for the timely diagnosis and treatment of ASD.

Novel Therapeutic Approaches in Alzheimer's Disease

Alzheimer's disease (AD) is a neurological condition associated with a decrease in levels of acetylcholine and diminished cholinergic functions. This may be caused by the degeneration of cholinergic neurons in the brain, leading to cognitive deficits. Due to the difficulty and invasiveness of collecting cerebrospinal fluid (CSF) required for assessing conventional biomarkers, researchers are currently exploring less intrusive, less expensive, and more straightforward methods for diagnosing AD. Additionally, conventional interventions such as cholinesterase inhibitors like rivastigmine, donepezil, and galantamine are US FDA-approved drugs that are still effective for managing AD. The goal of this therapy is to increase acetylcholine levels in the brain by inhibiting the enzymes that degrade acetylcholine. Therefore, this therapeutic approach is useful for treating mild-to-moderate AD. However, only symptomatic treatment is currently available, and it can lead to serious adverse effects from conventional therapy. Thus, novel therapies for AD are needed in a growing global population. This manuscript provides information on various biomarkers with possible pathogenesis mechanisms, novel treatment strategies such as microalgae, HupA, cannabinoids, and the beneficial effects of coenzyme Q10, bacterial probiotics, omega-3 fatty acids, vitamin B12, and D3 in memory impairment for managing AD. Non-pharmacological treatments such as music therapy, Electroacupuncture (EA), or manual acupuncture (MA) also play an important role in enhancing the effectiveness of conventional pharmacological treatments for AD.

Iron-depleting nutritional immunity controls extracellular bacterial replication in Legionella pneumophila infections

The accidental human pathogen Legionella pneumophila (Lp) is the etiological agent for a severe atypical pneumonia known as Legionnaires’ disease. In human infections and animal models of disease alveolar macrophages are the primary cellular niche that supports bacterial replication within a unique intracellular membrane-bound organelle. The Dot/Icm apparatus—a type IV secretion system that translocates ~300 bacterial proteins within the cytosol of the infected cell—is a central virulence factor required for intracellular growth. Mutant strains lacking functional Dot/Icm apparatus are transported to and degraded within the lysosomes of infected macrophages. The early foundational work from Dr. Horwitz’s group unequivocally established that Legionella does not replicate extracellularly during infection—a phenomenon well supported by experimental evidence for four decades. Our data challenges this paradigm by demonstrating that macrophages and monocytes provide the necessary nutrients and support robust Legionella extracellular replication. We show that the previously reported lack of Lp extracellular replication is not a bacteria intrinsic feature but rather a result of robust restriction by serum-derived nutritional immunity factors. Specifically, the host iron-sequestering protein Transferrin is identified here as a critical suppressor of Lp extracellular replication in an iron-dependent manner. In iron-overload conditions or in the absence of Transferrin, Lp bypasses growth restriction by IFNγ-primed macrophages though extracellular replication. It is well established that certain risk factors associated with development of Legionnaires’ disease, such as smoking, produce a chronic pulmonary environment of iron-overload. Our work indicates that iron-overload could be an important determinant of severe infection by allowing Lp to overcome nutritional immunity and replicate extracellularly, which in turn would circumvent intracellular cell intrinsic host defenses. Thus, we provide evidence for nutritional immunity as a key underappreciated host defense mechanism in Legionella pathogenesis.

On the issue of the syndromic forms of pyoderma gangrenosum

Gangrenous pyoderma (PG) is an autoinflammatory polygenic neutrophilic dermatosis characterized by the formation of painful ulcerative skin defects with boldly raised undercut edges of purplish-cyanotic coloration and an erythema zone around the focus. Gangrenous pyoderma can manifest as an isolated dermatosis, and be associated with various autoinflammatory syndromes: PASH (gangrenous pyoderma, conglobate acne and purulent hydradenitis), PAPA (gangrenous pyoderma, pyogenic arthritis and conglobate acne), PAPASH (gangrenous pyoderma, pyogenic arthritis, conglobate acne and purulent hydradenitis), PAPASC (gangrenous pyoderma, pyogenic arthritis, conglobate acne, purulent hydradenitis and ulcerative colitis), etc. A number of genetic mutations have been found in the syndromic forms of gangrenous pyoderma (MEFV, NOD2, LPIN2, NLRP3, NLRP12, PSMB8, MVK, IL1RN, PSTPIP1) affecting inflammatory regulatory proteins, which contributes to the development of an autoaggressive process. Neutrophilic autoinflammatory syndromes have a common pathogenesis mechanism, which is an excessive activation of the innate link of the immune system, with hyperproduction of proinflammatory IL-1, IL-17 and chemokines, leading to aseptic neutrophilic inflammation of the skin. At the moment, the treatment of syndromic conditions remains a difficult task. Systemic glucocorticosteroids, immunosuppressants, antimetabolites, and sulfone preparations are used in complex therapy, however, more and more studies indicate the possibility of therapy with genetically engineered biological drugs with TNF inhibitors, IL-1 and IL-17. We present two clinical observations of rare forms of autoinflammatory neutrophilic syndromic conditions PASH and PAPASC in patients aged 20 and 21 years

Alzheimer's Disease Pathology and Assistive Nanotheranostic Approaches for Its Therapeutic Interventions.

Alzheimer's disease (AD) still prevails and continues to increase indiscriminately throughout the 21st century, and is thus responsible for the depreciating quality of health and associated sectors. AD is a progressive neurodegenerative disorder marked by a significant amassment of beta-amyloid plaques and neurofibrillary tangles near the hippocampus, leading to the consequent loss of cognitive abilities. Conventionally, amyloid and tau hypotheses have been established as the most prominent in providing detailed insight into the disease pathogenesis and revealing the associative biomarkers intricately involved in AD progression. Nanotheranostic deliberates rational thought toward designing efficacious nanosystems and strategic endeavors for AD diagnosis and therapeutic implications. The exceeding advancements in this field enable the scientific community to envisage and conceptualize pharmacokinetic monitoring of the drug, sustained and targeted drug delivery responses, fabrication of anti-amyloid therapeutics, and enhanced accumulation of the targeted drug across the blood-brain barrier (BBB), thus giving an optimistic approach towards personalized and precision medicine. Current methods idealized on the design and bioengineering of an array of nanoparticulate systems offer higher affinity towards neurocapillary endothelial cells and the BBB. They have recently attracted intriguing attention to the early diagnostic and therapeutic measures taken to manage the progression of the disease. In this article, we tend to furnish a comprehensive outlook, the detailed mechanism of conventional AD pathogenesis, and new findings. We also summarize the shortcomings in diagnostic, prognostic, and therapeutic approaches undertaken to alleviate AD, thus providing a unique window towards nanotheranostic advancements without disregarding potential drawbacks, side effects, and safety concerns.

Exploring the Frontier of Wheat Rust Resistance: Latest Approaches, Mechanisms, and Novel Insights.

Wheat rusts, including leaf, stripe, and stem rust, have been a threat to global food security due to their devastating impact on wheat yields. In recent years, significant strides have been made in understanding wheat rusts, focusing on disease spread mechanisms, the discovery of new host resistance genes, and the molecular basis of rust pathogenesis. This review summarizes the latest approaches and studies in wheat rust research that provide a comprehensive understanding of disease mechanisms and new insights into control strategies. Recent advances in genetic resistance using modern genomics techniques, as well as molecular mechanisms of rust pathogenesis and host resistance, are discussed. In addition, innovative management strategies, including the use of fungicides and biological control agents, are reviewed, highlighting their role in combating wheat rust. This review also emphasizes the impact of climate change on rust epidemiology and underscores the importance of developing resistant wheat varieties along with adaptive management practices. Finally, gaps in knowledge are identified and suggestions for future research are made. This review aims to inform researchers, agronomists, and policy makers, and to contribute to the development of more effective and sustainable wheat rust control strategies.

Pharmacological Strategies and Surgical Management of Posthemorrhagic Hydrocephalus Following Germinal Matrix-Intraventricular Hemorrhage in Preterm Infants.

Germinal matrix-intraventricular hemorrhage (GM-IVH) is a detrimental neurological complication that occurs in preterm infants, especially in babies born before 32 weeks of gestation and in those with a very low birth weight. GM-IVH is defined as a rupture of the immature and fragile capillaries located in the subependymal germinal matrix zone of the preterm infant brain, and it can lead to detrimental neurological sequelae such as posthemorrhagic hydrocephalus (PHH), cerebral palsy, and other cognitive impairments. PHH following GM-IVH is difficult to treat in the clinic, and no levelone strategies have been recommended to pediatric neurosurgeons. Several cellular and molecular mechanisms of PHH following GM-IVH have been studied in animal models, but no effective pharmacological strategies have been used in the clinic. Thus, a comprehensive understanding of molecular mechanisms, potential pharmacological strategies, and surgical management of PHH is urgently needed. The present review presents a synopsis of the pathogenesis, diagnosis, and cellular and molecular mechanisms of PHH following GM-IVH and explores pharmacological strategies and surgical management.

The Role of Host Genetics and Intestinal Microbiota and Metabolome as a New Insight into IBD Pathogenesis.

Inflammatory bowel disease (IBD) is an incurable, chronic disorder of the gastrointestinal tract whose incidence increases every year. Scientific research constantly delivers new information about the disease and its multivariate, complex etiology. Nevertheless, full discovery and understanding of the complete mechanism of IBD pathogenesis still pose a significant challenge to today's science. Recent studies have unanimously confirmed the association of gut microbial dysbiosis with IBD and its contribution to the regulation of the inflammatory process. It transpires that the altered composition of pathogenic and commensal bacteria is not only characteristic of disturbed intestinal homeostasis in IBD, but also of viruses, parasites, and fungi, which are active in the intestine. The crucial function of the microbial metabolome in the human body is altered, which causes a wide range of effects on the host, thus providing a basis for the disease. On the other hand, human genomic and functional research has revealed more loci that play an essential role in gut homeostasis regulation, the immune response, and intestinal epithelial function. This review aims to organize and summarize the currently available knowledge concerning the role and interaction of crucial factors associated with IBD pathogenesis, notably, host genetic composition, intestinal microbiota and metabolome, and immune regulation.