Integrated Proteomic and Metabolomic Analyses of the Mitochondrial Neurodegenerative Disease MELAS

MELAS (mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes) is a progressive neurodegenerative disease caused by pathogenic mitochondrial DNA variants. The pathogenic mechanism of MELAS remains enigmatic due to the exceptional clinical...

Research Progress on the pathogenic mechanism of Streptococcus suis 2

Streptococcus suis (S.suis) is an important zoonotic pathogen that can cause many diseases in pigs, such as sepsis, arthritis, endocarditis, and meningitis, of which meningitis is the most serious. There are 35 serotypes, and serotype two is the most virulent. At the same time, Streptococcus suis serotype 2(SS2) can also infect humans, causing severe public health problems. Although SS2 has attracted significant attention worldwide, the research on its pathogenesis is still limited. The adhesion of pathogenic bacteria to the surface of host cells or tissues and its subsequent invasion and diffusion are the critical steps of pathogenic bacteria. Moreover, the interaction between pathogen and host is involved in these processes. Therefore, to study the pathogenic mechanism of pathogenic bacteria is to study the interaction between pathogenic bacteria and host. This paper described several common virulence factors, such as CPS, SLY, MRP, EF, SAO, Srt, FBPS, SadP, and Eno. Under the actions of virulence factors, SS2 adheres and colonizes to the mucosal and epithelial surface of host cells. Then SS2 invades into deeper tissues and bloodstream. If SS2 in the blood does not cause fatal sepsis, It can go to the third stage. The third stage is to cross the BBB and access the CNS and ultimately causes meningitis. During pathogenesis, SS2 interacts with multiple host cells, such as neutrophils, macrophages, epithelial cells, and microvascular endothelial cells to evade the innate or adaptive immunity of the host.

Genomic analysis of Elsinoë arachidis reveals its potential pathogenic mechanism and the biosynthesis pathway of elsinochrome toxin

Elsinochromes (ESCs) are virulence factors produced by Elsinoë arachidis which is the cause of peanut scab. However, the biosynthesis pathway of ESCs in E. arachidis has not been elucidated and the potential pathogenic mechanism of E. arachidis is poorly understood. In this study, we report a high-quality genome sequence of E. arachidis. The size of the E. arachidis genome is 33.18Mb, which is comparable to the Ascomycota genome (average 36.91 Mb), encoding 9174 predicted genes. The self-detoxification family including transporters and cytochrome P450 enzymes were analysis, candidate effectors and cell wall degrading enzymes were investigated as the pathogenicity genes by using PHI and CAZy databases. Additionally, the E. arachidis genome contains 24 secondary metabolism gene clusters, in which ESCB1 was identified as the core gene of ESC biosynthesis. Taken together, the genome sequence of E. arachidis provides a new route to explore its potential pathogenic mechanism and the biosynthesis pathway of ESCs.

Alterations in SLC4A2, SLC26A7 and SLC26A9 Drive Acid–Base Imbalance in Gastric Neuroendocrine Tumors and Uncover a Novel Mechanism for a Co-Occurring Polyautoimmune Scenario

Autoimmune polyendocrine syndrome (APS) is assumed to involve an immune system malfunction and entails several autoimmune diseases co-occurring in different tissues of the same patient; however, they are orphans of its accurate diagnosis, as its genetic basis and pathogenic mechanism are not understood. Our previous studies uncovered alterations in the ATPase H+/K+ Transporting Subunit Alpha (ATP4A) proton pump that triggered an internal cell acid–base imbalance, offering an autoimmune scenario for atrophic gastritis and gastric neuroendocrine tumors with secondary autoimmune pathologies. Here, we propose the genetic exploration of APS involving gastric disease to understand the underlying pathogenic mechanism of the polyautoimmune scenario. The whole exome sequencing (WES) study of five autoimmune thyrogastric families uncovered different pathogenic variants in SLC4A2, SLC26A7 and SLC26A9, which cotransport together with ATP4A. Exploratory in vitro studies suggested that the uncovered genes were involved in a pathogenic mechanism based on the alteration of the acid–base balance. Thus, we built a custom gene panel with 12 genes based on the suggested mechanism to evaluate a new series of 69 APS patients. In total, 64 filtered putatively damaging variants in the 12 genes of the panel were found in 54.17% of the studied patients and none of the healthy controls. Our studies reveal a constellation of solute carriers that co-express in the tissues affected with different autoimmune diseases, proposing a unique genetic origin for co-occurring pathologies. These results settle a new-fangled genetics-based mechanism for polyautoimmunity that explains not only gastric disease, but also thyrogastric pathology and disease co-occurrence in APS that are different from clinical incidental findings. This opens a new window leading to the prediction and diagnosis of co-occurring autoimmune diseases and clinical management of patients.

Mortality of Patients Infected by COVID-19 with and without Deep-Vein Thrombosis

Background: Current evidence points to a state of hypercoagulability (consequence of hyperinflammation) as an important pathogenic mechanism that contributes to the increase in mortality in cases of COVID-19. The aim of the present study was to investigate the influence of deep-vein thrombosis on mortality patient’s infected with SARS-CoV-2. Method: A clinical trial was conducted involving 200 consecutive patients with COVID-19—100 patients who were positive for deep-vein thrombosis (venous Doppler ultrasound) and 100 who were negative for deep-vein thrombosis at a public hospital. Results: The mortality rate was 67% in the group positive for DVT and 31% in the group negative for DVT. Conclusion: Deep-vein thrombosis is associated with an increase in mortality in patients with COVID-19 and failures can occur with conventional prophylaxis for deep-vein thrombosis.

Cooperative Mechanism of ADAMTS/ ADAMTSL and Fibrillin-1 in the Marfan Syndrome and Acromelic Dysplasias

The term “fibrillinopathies” gathers various diseases with a wide spectrum of clinical features and severity but all share mutations in the fibrillin genes. The first described fibrillinopathy, Marfan syndrome (MFS), is a multisystem disease with a unique combination of skeletal, thoracic aortic aneurysm (TAA) and ocular features. The numerous FBN1 mutations identified in MFS are located all along the gene, leading to the same pathogenic mechanism. The geleophysic/acromicric dysplasias (GD/AD), characterized by short stature, short extremities, and joint limitation are described as “the mirror image” of MFS. Previously, in GD/AD patients, we identified heterozygous FBN1 mutations all affecting TGFβ-binding protein-like domain 5 (TB5). ADAMTS10, ADAMTS17 and, ADAMTSL2 are also involved in the pathogenic mechanism of acromelic dysplasia. More recently, in TAA patients, we identified mutations in THSD4, encoding ADAMTSL6, a protein belonging to the ADAMTSL family suggesting that ADAMTSL proteins are also involved in the Marfanoid spectrum. Together with human genetic data and generated knockout mouse models targeting the involved genes, we provide herein an overview of the role of fibrillin-1 in opposite phenotypes. Finally, we will decipher the potential biological cooperation of ADAMTS-fibrillin-1 involved in these opposite phenotypes.

Inability to switch from ARID1A-BAF to ARID1B-BAF impairs exit from pluripotency and commitment towards neural crest formation in ARID1B-related neurodevelopmental disorders

Subunit switches in the BAF chromatin remodeler are essential during development. ARID1B and its paralog ARID1A encode for mutually exclusive BAF subunits. De novo ARID1B haploinsufficient mutations cause neurodevelopmental disorders, including Coffin-Siris syndrome, which is characterized by neurological and craniofacial features. Here, we leveraged ARID1B+/− Coffin-Siris patient-derived iPSCs and modeled cranial neural crest cell (CNCC) formation. We discovered that ARID1B is active only during the first stage of this process, coinciding with neuroectoderm specification, where it is part of a lineage-specific BAF configuration (ARID1B-BAF). ARID1B-BAF regulates exit from pluripotency and lineage commitment by attenuating thousands of enhancers and genes of the NANOG and SOX2 networks. In iPSCs, these enhancers are maintained active by ARID1A-containing BAF. At the onset of differentiation, cells transition from ARID1A- to ARID1B-BAF, eliciting attenuation of the NANOG/SOX2 networks and triggering pluripotency exit. Coffin-Siris patient cells fail to perform the ARID1A/ARID1B switch, and maintain ARID1A-BAF at the pluripotency enhancers throughout all stages of CNCC formation. This leads to persistent NANOG/SOX2 activity which impairs CNCC formation. Despite showing the typical neural crest signature (TFAP2A/SOX9-positive), ARID1B-haploinsufficient CNCCs are also aberrantly NANOG-positive. These findings suggest a connection between ARID1B mutations, neuroectoderm specification and a pathogenic mechanism for Coffin-Siris syndrome.

The Expression and Function of Circadian Rhythm Genes in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is among the most common and lethal form of cancer worldwide. However, its diagnosis and treatment are still dissatisfactory, due to limitations in the understanding of its pathogenic mechanism. Therefore, it is important to elucidate the molecular mechanisms and identify novel therapeutic targets for HCC. Circadian rhythm-related genes control a variety of biological processes. These genes play pivotal roles in the initiation and progression of HCC and are potential diagnostic markers and therapeutic targets. This review gives an update on the research progress of circadian rhythms, their effects on the initiation, progression, and prognosis of HCC, in a bid to provide new insights for the research and treatment of HCC.

Genome-Wide Identification of Ralstonia solanacearum Genes Required for Survival in Tomato Plants

Tomato plant xylem is a nutritionally limiting and dynamically changing habitat. Studies on how R. solanacearum survives in this hostile environment are important for our full understanding of the pathogenic mechanism of this bacterium.