[Clinicopathological and molecular genetic features of Crohn's disease].

Objective: To investigate the clinicopathological and molecular genetic characteristics of Crohn's disease (CD). Methods: A retrospective analysis was conducted on 52 CD patients who underwent surgical resection at the First Affiliated Hospital of Nanjing Medical University between January 2014 and June 2023. Clinical presentations and histopathological features were assessed. Whole-genome sequencing was performed on 17 of the samples, followed by sequencing and pathway enrichment analyses. Immunohistochemistry was used to assess the expression of frequently mutated genes. Results: Among the 52 patients, 34 were males and 18 were females, male-to-female ratio was 1.9∶1.0, with a median age of 45 years at surgery and 35 years at diagnosis. According to the Montreal classification, A3 (51.9%,27/52), B2 (61.5%, 32/52), and L3 (50.0%,26/52) subtypes were the most predominant. Abdominal pain and diarrhea were the common symptoms. Histopathological features seen in all 52 patients included transmural inflammation, disruption of cryptal architecture, lymphoplasmacytic infiltration, varying degrees of submucosal fibrosis and thickening, increased enteric nerve fibers and neuronal proliferation. Mucosal defects, fissure ulcers, abscesses, pseudopolyps, and adenomatous proliferation were also observed in 51 (98.1%), 38 (73.1%), 28 (53.8%), 45 (86.5%), and 28 (53.8%) cases, respectively. Thirty-one (59.6%) cases had non-caseating granulomas, and 3 (5.8%) cases had intestinal mucosal glandular epithelial dysplasia. Molecular analysis showed that 12/17 CD patients exhibited mutations in at least one mucin family gene (MUC2, MUC3A, MUC4, MUC6, MUC12, MUC17), and MUC4 was the most frequently mutated in 7/17 of cases. Immunohistochemical stains showed reduced MUC4 expression in epithelial cells, with increased MUC4 expression in the epithelial surface, particularly around areas of inflammatory cell aggregation; and minimal expression in the lower half of the epithelium. Conclusions: CD exhibits diverse clinical and pathological features, necessitating a comprehensive multidimensional analysis for diagnosis. Mutations and expression alterations in mucin family genes, particularly MUC4, may play crucial roles in the pathogenesis of CD.

[Analysis of clinical characteristics and molecular genetics in eighteen patients with 1q21.1 microdeletion syndrome].

OBJECTIVE: To explore the clinical characteristics of 1q21.1 microdeletion by using single nucleotide polymorphism microarrays (SNP array). METHODS: Eighteen cases of 1q21.1 microdeletion syndrome diagnosed at the Longgang District Maternal and Child Health Care Hospital of Shenzhen City from June 2017 to December 2022 were selected as the study subjects. Clinical data of the patients were collected. Results of chromosomal karyotyping and SNP assay were retrospectively analyzed. RESULTS: Among the 18 cases with 1q21.1 microdeletions, 13 had a deletion between BP3 and BP4, 4 had a deletion between BP1/BP2 and BP4, whilst 1 had a proximal 1q21.1 deletion (between BP2 and BP3) involving the Thrombocytopenia-absent radius (TAR) region. The deletions had spanned from 360 kb to 3.9 Mb, which encompassed the GJA5, GJA8, CHD1L, RBM8AB and other morbid genes. In three families, the proband child has inherited the same 1q21.1 microdeletion from their parents, whose clinical phenotype was normal or slightly abnormal. The clinical phenotypes of 1q21.1 microdeletion had included cognitive or behavioral deficits in 9 cases (9/18, 50.0%), growth retardation in 8 cases (8/18, 44.4%), craniofacial deformities in 7 cases (7/18, 38.8%), cardiovascular malformations in 5 cases (5/18, 27.8%), and microcephaly in 3 cases (3/18, 16.7%). CONCLUSION: 1q21.1 microdeletion syndrome has incomplete penetrance and varied expression such as intellectual impairment, growth and development delay, and microcephaly, with a wide range of non-specific phenotypes.

The Molecular Genetics and Genomics of Plant-Pathogen Interactions.

Plants have evolved an intricate immune system to protect themselves from potential pathogens [...].

[Molecular biology analysis of 2 rare RhD variant individuals with RHD*DEL37].

The Rh blood grouping system is a critical standardized test in transfusion medicine, especially for the cases related to haemolytic transfusion reactions and neonatal haemolytic disease caused by clinical RhD blood group incompatibility. In the present case report, we presented two cases with the uncommon RHD gene variation RHD*DEL37. The blood samples of the two subjects were mistakenly identified as RhD-negative through conventional serological testing. Firstly, both blood samples were tested negative for the RhD antigen using traditional tube test and gel microcolumn methods. The phenotyping of RhCE were identified as ccEe and ccee for each sample, respectively. Secondly, genetic analysis was performed using polymerase chain reaction-sequence specific prime (PCR-SSP) which revealed that neither sample belonging to the several common RHD gene variants which was found in Asia. Moreover, they turned out to be positive for the RHD haplotype, which indicated that exons 1-10 on one of the RHD alleles were entirely absent. In addition, a T>C mutation was observed at bases 1154-31 in intron 8 of the other allele, which was located at the intron 8 breakpoint. This result was obtained after further Sanger sequencing of exons 1-10 of the RHD gene. The mutant allele was designated as RHD*DEL37 by the International Society of Blood Transfusion (ISBT) and was identified as D-elute(Del) by phenotype ana-lysis. Both samples were genotyped as RHD*DEL37 and showed positive results. In summary, the true genotype of the two blood samples, of which the screening results only using serological testing method was negative, were RHD*DEL37 /RHD-(RHD*01N.01). Notably, this kind of genotype was reported for the first time in Chinese population. Moreover, the two individuals did not have ties of consanguinity, indicating that some of the Chinese individuals could be carriers of the genetic mutation. Therefore, it might be necessary to further confirm the frequency of this mutation in the Chinese population and the possibility of homozygosity for this mutation. This report identifies infrequent RHD gene mutation samples by coupling molecular biology and serological methods to prevent misclassification of blood groups. Combining serological and molecular biology test results to determine blood group is critical in protecting patients during clinical transfusion procedures.

Deciphering the molecular biology of inflammatory breast cancer through molecular characterization of patient samples and preclinical models.

Inflammatory breast cancer is an aggressive subtype of breast cancer with dismal patient prognosis and a unique clinical presentation. In the past two decades, molecular profiling technologies have been used in order to gain insight into the molecular biology of IBC and to search for possible targets for treatment. Although a gene signature that accurately discriminates between IBC and nIBC patient samples and preclinical models was identified, the overall genomic and transcriptomic differences are small and ambiguous, mainly due to the limited sample sizes of the evaluated patient series and the failure to correct for confounding effects of the molecular subtypes. Nevertheless, data collected over the past 20 years by independent research groups increasingly support the existence of several IBC-specific biological characteristics. In this review, these features are classified as established, emerging and conceptual hallmarks based on the level of evidence reported in the literature. In addition, a synoptic model is proposed that integrates all hallmarks and that can explain how cancer cell intrinsic mechanisms (i.e. NF-κB activation, genomic instability, MYC-addiction, TGF-ß resistance, adaptive stress response, chromatin remodeling, epithelial-to-mesenchymal transition) can contribute to the establishment of the dynamic immune microenvironment associated with IBC. It stands to reason that future research projects are needed to further refine (parts of) this model and to investigate its clinical translatability.

Toward Robust Self-Training Paradigm for Molecular Prediction Tasks.

Molecular prediction tasks normally demand a series of professional experiments to label the target molecule, which suffers from the limited labeled data problem. One of the semisupervised learning paradigms, known as self-training, utilizes both labeled and unlabeled data. Specifically, a teacher model is trained using labeled data and produces pseudo labels for unlabeled data. These labeled and pseudo-labeled data are then jointly used to train a student model. However, the pseudo labels generated from the teacher model are generally not sufficiently accurate. Thus, we propose a robust self-training strategy by exploring robust loss function to handle such noisy labels in two paradigms, that is, generic and adaptive. We have conducted experiments on three molecular biology prediction tasks with four backbone models to gradually evaluate the performance of the proposed robust self-training strategy. The results demonstrate that the proposed method enhances prediction performance across all tasks, notably within molecular regression tasks, where there has been an average enhancement of 41.5%. Furthermore, the visualization analysis confirms the superiority of our method. Our proposed robust self-training is a simple yet effective strategy that efficiently improves molecular biology prediction performance. It tackles the labeled data insufficient issue in molecular biology by taking advantage of both labeled and unlabeled data. Moreover, it can be easily embedded with any prediction task, which serves as a universal approach for the bioinformatics community.

Evolution of Virology: Science History through Milestones and Technological Advancements.

The history of virology, which is marked by transformative breakthroughs, spans microbiology, biochemistry, genetics, and molecular biology. From the development of Jenner's smallpox vaccine in 1796 to 20th-century innovations such as ultrafiltration and electron microscopy, the field of virology has undergone significant development. In 1898, Beijerinck laid the conceptual foundation for virology, marking a pivotal moment in the evolution of the discipline. Advancements in influenza A virus research in 1933 by Richard Shope furthered our understanding of respiratory pathogens. Additionally, in 1935, Stanley's determination of viruses as solid particles provided substantial progress in the field of virology. Key milestones include elucidation of reverse transcriptase by Baltimore and Temin in 1970, late 20th-century revelations linking viruses and cancer, and the discovery of HIV by Sinoussi, Montagnier, and Gallo in 1983, which has since shaped AIDS research. In the 21st century, breakthroughs such as gene technology, mRNA vaccines, and phage display tools were achieved in virology, demonstrating its potential for integration with molecular biology. The achievements of COVID-19 vaccines highlight the adaptability of virology to global health.

Phage proteins target and co-opt host ribosomes immediately upon infection.

Bacteriophages must seize control of the host gene expression machinery to replicate. To bypass bacterial anti-phage defence systems, this host takeover occurs immediately upon infection. A general understanding of phage mechanisms for immediate targeting of host transcription and translation processes is lacking. Here we introduce an integrative high-throughput approach to uncover phage-encoded proteins that target the gene expression machinery of Pseudomonas aeruginosa immediately upon infection with the jumbo phage ΦKZ. By integrating biochemical, genetic and structural analyses, we identify an abundant and conserved phage factor ΦKZ014 that targets the large ribosomal subunit by binding the 5S ribosomal RNA, and rapidly promotes replication in several clinical isolates. ΦKZ014 is among the earliest ΦKZ proteins expressed after infection and remains bound to ribosomes during the entire translation cycle. Our study provides a strategy to decipher molecular components of phage-mediated host takeover and argues that phage genomes represent an untapped discovery space for proteins that modulate the host gene expression machinery.

Undifferentiated Carcinoma with Osteoclast-like Giant Cells of the Pancreas: Molecular Genetic Analysis of 13 Cases.

Undifferentiated carcinoma with osteoclast-like giant cells (UCOGC) of the pancreas is a rare malignancy regarded as a subvariant of pancreatic ductal carcinoma (PDAC) characterized by variable prognosis. UCOGC shows a strikingly similar spectrum of oncogenic DNA mutations to PDAC. In the current work, we analyzed the landscape of somatic mutations in a set of 13 UCOGC cases via next-generation sequencing (NGS). We detected a spectrum of pathogenic or likely pathogenic mutations similar to those observed in PDAC following previously published results (10 KRAS, 9 TP53, 4 CDKN2A, and 1 SMAD4, CIC, GNAS, APC, ATM, NF1, FBXW7, ATR, and FGFR3). Our results support the theory that UCOGC is a variant of PDAC, despite its unique morphology; however, a UCOGC-specific genomic signature as well as predictive markers remain mainly unknown. Programmed death ligand 1 (PD-L1) status remains an important predictive marker based on previous studies.

Insulin Secretion Defect in Children and Adolescents with Obesity: Clinical and Molecular Genetic Characterization.

Introduction: Childhood obesity is increasing worldwide and presents as a global health issue due to multiple metabolic comorbidities. About 1% of adolescents with obesity develop type 2 diabetes (T2D); however, little is known about the genetic and pathophysiological background at young age. The objective of this study was to assess the prevalence of impaired glucose regulation (IGR) in a large cohort of children and adolescents with obesity and to characterize insulin sensitivity and insulin secretion. We also wanted to investigate adolescents with insulin secretion disorder more closely and analyze possible candidate genes of diabetes in a subcohort. Methods: We included children and adolescents with obesity who completed an oral glucose tolerance test (OGTT, glucose + insulin) in the outpatient clinic. We calculated Matsuda index, the area under the curve (AUC (Ins/Glu)), and an oral disposition index (ISSI-2) to estimate insulin resistance and beta-cell function. We identified patients with IGR and low insulin secretion (maximum insulin during OGTT < 200 mU/l) and tested a subgroup using next generation sequencing to identify possible mutations in 103 candidate genes. Results: The total group consisted of 903 children and adolescents with obesity. 4.5% showed impaired fasting glucose, 9.4% impaired glucose tolerance, and 1.2% T2D. Matsuda index and Total AUC (Ins/Glu) showed a hyperbolic relationship. Out of 39 patients with low insulin secretion, we performed genetic testing on 12 patients. We found five monogenetic defects (ABCC8 (n = 3), GCK (n = 1), and GLI2/PTF1A (n = 1)). Conclusion: Using surrogate parameters of beta-cell function and insulin resistance can help identify patients with insulin secretion disorder. A prevalence of 40% mutations of known diabetes genes in the subgroup with low insulin secretion suggests that at least 1.7% of patients with adolescent obesity have monogenic diabetes. A successful molecular genetic diagnosis can help to improve individual therapy.

Life and fate of Ervin Bauer (1890-1938), the eminent scholar and foundational theoretical biologist.

Ervin Bauer (1890-1938) was the first to build a general molecular-based biological theory. He defined the basic principles of theoretical biology from a thermodynamic perspective, focusing on the capacity of biological systems to produce and support the state of sustainable non-equilibrium. His central work "Theoretical Biology" (1935) was written long before modern advances in molecular biology, genetics, and information theory. Ervin Bauer and his wife Stefánia were executed in Stalin's Great Terror. This paper presents a brief introduction to Ervin Bauer's life and includes his short biography.

Structural determination and modeling of ciliary microtubules.

The axoneme, a microtubule-based array at the center of every cilium, has been the subject of structural investigations for decades, but only recent advances in cryo-EM and cryo-ET have allowed a molecular-level interpretation of the entire complex to be achieved. The unique properties of the nine doublet microtubules and central pair of singlet microtubules that form the axoneme, including the highly decorated tubulin lattice and the docking of massive axonemal complexes, provide opportunities and challenges for sample preparation, 3D reconstruction and atomic modeling. Here, the approaches used for cryo-EM and cryo-ET of axonemes are reviewed, while highlighting the unique opportunities provided by the latest generation of AI-guided tools that are transforming structural biology.

Gaps in parasitological research in the molecular era.

We live in the age of molecular biology and '-omics', and molecular methods have opened up unimagined possibilities for biological research, including parasitology. However, too one-sided a focus on new approaches can lead to major gaps as less 'cool' topics are neglected. Selected areas of research are briefly discussed to highlight the gaps caused by the current excessive focus on molecular and '-omics' methods. It is crucial to combine both 'classical' and modern methods without neglecting the complexity of the interactions of parasites with their hosts and the environment (One Health concept), which is even more urgent in today's rapidly changing world. Parasitologists should be more involved in field studies and multidisciplinary assessment of parasites.

[Is hematological cytology outdated at the age of molecular biology and flow cytometry ? Report of a VEXAS syndrome clinical case]. / Cas clinique. La cytologie hématologique désuète à l'heure de la biologie moléculaire et de la cytométrie en flux ? Illustration au travers d'un syndrome de VEXAS.

VEXAS syndrome is a new entity, described as the first one of a new class of hemato-inflammatory diseases. Through this article and based on the first case highlighted at the CHU of Liege, we offer you a review of the literature as well as an overview of different laboratory techniques used for the diagnosis of this syndrome.

Le syndrome de VEXAS est une nouvelle entité, décrite comme pionnière d'une nouvelle classe de maladies hémato-inflammatoires. Au travers de cet article et sur base du premier cas mis en évidence au CHU de Liège, nous vous proposons une revue de la littérature ainsi qu'un aperçu des différentes techniques de laboratoire permettant le diagnostic de ce syndrome.

The landscape of cytogenetic and molecular genetic methods in diagnostics for hematologic neoplasia.

Improvements made during the last decades in the management of patients with hematologic neoplasia have resulted in increase of overall survival. These advancements have become possible through progress in our understanding of genetic basis of different hematologic malignancies and their role in the current risk-adapted treatment protocols. In this review, we provide an overview of current cytogenetic and molecular genetic methods, commonly used in the genetic characterization of hematologic malignancies, describe the current developments in the cytogenetic and molecular diagnostics, and give an outlook into their future development. Furthermore, we give a brief overview of the most important public databases and guidelines for sequence variant interpretation.

Clinicopathological and molecular genetic alterations in monomorphic-epitheliotropic intestinal T-cell lymphoma of the small intestine.

BACKGROUND: Small intestinal monomorphic-epitheliotropic intestinal T-cell lymphoma (MEITL) is a rare aggressive T-cell lymphoma originating in the gastrointestinal tract. This study aimed to investigate the clinicopathological features, immunophenotypes, and molecular genetic changes of MEITL. METHODS: The clinicopathological data for three patients with surgically resected MEITL of the small intestine were collected. Next, immunohistochemical labeling, Epstein-Barr virus (EBV) in situ hybridization, assessment of clonal rearrangement of T-cell receptor (TCR) genes, and next-generation sequencing (NGS) were performed. RESULTS: Of the three patients, two were male and one was female, with ages of 61, 67, and 73 years, respectively. Clinical manifestations were predominantly abdominal pain and distension. Histopathology revealed infiltrative growth of small-to-medium-sized lymphocytes with a consistent morphology between the intestinal walls, accompanied by an obvious pro-epithelial phenomenon. The expression of CD3, CD8, CD43, CD56, TIA-1, CD103, H3K36me3, and Bcl-2 was detected, and the Ki-67 proliferation index ranged from 50% to 80%. All three patients tested negative for EBER. However, monoclonal rearrangement of the TCR gene was detected in them. NGS testing showed a JAK3 mutation in all three cases. Further, STAT5B, SETD2, and TP53 mutations were each observed in two cases, and a BCOR mutation was found in one case. All patients were treated with chemotherapy after surgery. Two patients died 7 and 15 month post-operation, and one patient survived for 5 months of follow-up. CONCLUSIONS: Our findings demonstrate that mutations in JAK3 and STAT5B of the JAK/STAT pathway and inactivation of the oncogene SETD2 markedly contribute to the lymphomagenesis of MEITL.

X-Ray Crystallography for Macromolecular Complexes.

X-ray crystallography has for most of the last century been the standard technique to determine the high-resolution structure of biological macromolecules, including multi-subunit protein-protein and protein-nucleic acids as large as the ribosome and viruses. As such, the successful application of X-ray crystallography to many biological problems revolutionized biology and biomedicine by solving the structures of small molecules and vitamins, peptides and proteins, DNA and RNA molecules, and many complexes-affording a detailed knowledge of the structures that clarified biological and chemical mechanisms, conformational changes, interactions, catalysis and the biological processes underlying DNA replication, translation, and protein synthesis. Now reaching well into the first quarter of the twenty-first century, X-ray crystallography shares the structural biology stage with cryo-electron microscopy and other innovative structure determination methods, as relevant and central to our understanding of biological function and structure as ever. In this chapter, we provide an overview of modern X-ray crystallography and how it interfaces with other mainstream structural biology techniques, with an emphasis on macromolecular complexes.