Follicular lymphoma regulatory T-cell origin and function.

Introduction: Follicular Lymphoma (FL) results from the malignant transformation of germinal center (GC) B cells. FL B cells display recurrent and diverse genetic alterations, some of them favoring their direct interaction with their cell microenvironment, including follicular helper T cells (Tfh). Although FL-Tfh key role is well-documented, the impact of their regulatory counterpart, the follicular regulatory T cell (Tfr) compartment, is still sparse. Methods: The aim of this study was to characterize FL-Tfr phenotype by cytometry, gene expression profile, FL-Tfr origin by transcriptomic analysis, and functionality by in vitro assays. Results: CD4+CXCR5+CD25hiICOS+ FL-Tfr displayed a regulatory program that is close to classical regulatory T cell (Treg) program, at the transcriptomic and methylome levels. Accordingly, Tfr imprinting stigmata were found on FL-Tfh and FL-B cells, compared to their physiological counterparts. In addition, FL-Tfr co-culture with autologous FL-Tfh or cytotoxic FL-CD8+ T cells inhibited their proliferation in vitro. Finally, although FL-Tfr shared many characteristics with Treg, TCR sequencing analyses demonstrated that part of them derived from precursors shared with FL-Tfh. Discussion: Altogether, these findings uncover the role and origin of a Tfr subset in FL niche and may be useful for lymphomagenesis knowledge and therapeutic management.

MicroRNA biosensors for detection of glioblastoma.

Glioblastoma (GBM) is the most common type of malignant brain tumor.The discovery of microRNAs and their unique properties have made them suitable tools as biomarkers for cancer diagnosis, prognosis, and evaluation of therapeutic response using different types of nanomaterials as sensitive and specific biosensors. In this review, we discuss microRNA-based electrochemical biosensing systems and the use of nanoparticles in the evolving development of microRNA-based biosensors in glioblastoma.

MicroRNA biosensors for the detection of liver cancer.

Liver cancer is one of the deadliest types worldwide and early diagnosis is highly important for successful treatment. Therefore, it is necessary to develop rapid, sensitive, simple, and inexpensive analytical tools for its detection. MicroRNAs (miRNA) represent unique biomarkers whose expression in biofluids is strongly associated with cancer in general and miR-21, -31, -122, -145, -146a, -200c, -221, -222, and -223 in liver cancer, specifically. Various biosensors for miRNA detection have been developed. These include electrochemical biosensors based on amperometric, potentiometric, conductometric and impedimetric technology. Furthermore, the use of advanced nanomaterials with enhanced chemical stability, conductivity and electrocatalytic activity have greatly increased the sensitivity and specificity of these devices. The present review focuses on recent advances in electrochemical biosensors for miRNA detection in liver cancer.

Characterization of 43 novel HLA-H alleles.

Forty-three novel HLA-H alleles, including 32 identified in cohorts of French donors for Hematopoietic Stem Cell Transplantation, have been characterized by Next-Generation Sequencing (NGS) using a long range PCR approach. A phylogenetic study confirms three main HLA-H clades.

Polarimetric second harmonic generation microscopy of partially oriented fibers II: Imaging study.

Polarimetric second harmonic generation (SHG) microscopy imaging is employed to investigate the ultrastructural organization of biological and biomimetic partially oriented fibrillar structures. The linear polarization-in polarization-out SHG microscopy measurements are conducted with rat tail tendon, rabbit cornea, pig cartilage, and biomimetic meso-tetra(4-sulfonatophenyl)porphine (TPPS4) cylindrical aggregates, which represent different two- and three-dimensional (2D and 3D) configurations of C6 symmetry fibril structures in the focal volume (voxel) of the microscope. The polarization-in polarization-out imaging of rat tail tendon reveals that SHG intensity is affected by parallel/antiparallel arrangements of the fibers, and achiral (R) and chiral (C) susceptibility component ratio values change by tilting the tendon fibers out of image plane. The R ratio changes for the 2D crossing fibers observed in cornea tissue. The 3D crossing of fibers also affects R ratio in cartilage tissue. The distinctly different dependence of R on crossing and tilting of fibers is demonstrated in collagen and TPPS4 aggregates, due to the achiral molecular susceptibility ratio having values below and above 3, respectively. The polarimetric microscopy results correspond well with the analytical expressions of amplitude and R and C ratios dependence on the crossing angle of the fibers. The experimentally measured SHG intensity and R and C ratio maps are consistent with the computational modeling of various fiber configurations presented in the preceding article. The demonstrated SHG intensity and R and C ratio dependencies on fibril configurations provide the basis for interpreting polarimetric SHG microscopy images in terms of 3D ultrastructural organization of fibers in each voxel of the samples.

Polarimetric second-harmonic generation microscopy of partially oriented fibers I: Digital modeling.

Second-harmonic generation (SHG) in biological tissues originates predominantly from noncentrosymmetric fibrillar structures partially oriented within a focal volume (voxel) of a multiphoton excitation microscope. This study is aimed to elucidate fibrillar organization factors influencing SHG intensity, as well as achiral, R, and chiral, C, nonlinear susceptibility tensor component ratios. SHG response is calculated for various configurations of fibrils in a voxel using the digital nonlinear microscope. The R and C ratios are calculated using linear incident and outgoing polarization states that simulate polarization-in polarization-out polarimetric measurements. The investigation shows strong SHG intensity dependence on parallel/antiparallel fiber organization. The R and C ratios are strongly influenced by the fiber chirality, tilting of the fibers out of the image plane, and crossing of the fibers. The computational modeling provides the basis for the interpretation of polarimetric SHG microscopy images in terms of the ultrastructural organization of fibers in each voxel of the samples. The modeling results are employed in the accompanying paper to investigate the ultrastructures with parallel/antiparallel fibers and two-dimensional and tree-dimensional crossing fibers in biological and biomimetic structures.

High numerical aperture imaging allows chirality measurement in individual collagen fibrils using polarization second harmonic generation microscopy.

Second harmonic generation (SHG) microscopy is a commonly used technique to study the organization of collagen within tissues. However, individual collagen fibrils, which have diameters much smaller than the resolution of most optical systems, have not been extensively investigated. Here we probe the structure of individual collagen fibrils using polarization-resolved SHG (PSHG) microscopy and atomic force microscopy. We find that longitudinally polarized light occurring at the edge of a focal volume of a high numerical aperture microscope objective illuminated with linearly polarized light creates a measurable variation in PSHG signal along the axis orthogonal to an individual collagen fibril. By comparing numerical simulations to experimental data, we are able to estimate parameters related to the structure and chirality of the collagen fibril without tilting the sample out of the image plane, or cutting tissue at different angles, enabling chirality measurements on individual nanostructures to be performed in standard PSHG microscopes. The results presented here are expected to lead to a better understanding of PSHG results from both collagen fibrils and collagenous tissues. Further, the technique presented can be applied to other chiral nanoscale structures such as microtubules, nanowires, and nanoribbons.

Supportive care in a patient with Alstrom syndrome with hyperphenylalaninemia and sleep problems.

Alstrom syndrome is a rare genetic disorder with an autosomal recessive mutation in the ALMS1 gene. The disease's manifestations include ophthalmic problems, hearing loss, obesity, and cardiovascular disorders. In addition, medical cases include other organ complications. However, the overlapping variety of such symptoms with other diseases may delay the diagnosis. In this article, we describe the case of a 7-year-old female patient with Alstrom syndrome, and cardiovascular and hyperphenylalaninemia diseases since birth. Other symptoms included diabetes and ophthalmologic problems with skeletal disability. Blindness and hearing impairment were diagnosed, along with recurrence of respiratory problems at the age of 7 years. The patient's obesity-induced snoring predisposed her to uncontrolled blood glucose. In fact, respiratory tract problems and sleep disorders had occurred as a degraded cycle and left her with a severe disability for years. The similarity of the symptoms with other diseases had misled the physician in diagnosis. However, a polysomnography test (because of complaints of short sleep duration) recognized the source of the patient's sleep disorders and breathing problems. Eventually, we delivered a portable ventilator to the child for continuous positive airway pressure (CPAP) therapy. The child's breathing and oxygenation conditions improved. Using the ventilator and the CPAP system, we discharged her from the hospital without requiring oxygenation, in a stable condition. The procedure could prevent the patient from hypoxia and retinal problem.

Non-coding RNAs in gynecologic cancer.

The term "gynecologic cancer" pertains to neoplasms impacting the reproductive tissues and organs of women encompassing the endometrium, vagina, cervix, uterus, vulva, and ovaries. The progression of gynecologic cancer is linked to various molecular mechanisms. Historically, cancer research primarily focused on protein-coding genes. However, recent years have unveiled the involvement of non-coding RNAs (ncRNAs), including microRNAs, long non-coding RNAs (LncRNAs), and circular RNAs, in modulating cellular functions within gynecological cancer. Substantial evidence suggests that ncRNAs may wield a dual role in gynecological cancer, acting as either oncogenic or tumor-suppressive agents. Numerous clinical trials are presently investigating the roles of ncRNAs as biomarkers and therapeutic agents. These endeavors may introduce a fresh perspective on the diagnosis and treatment of gynecological cancer. In this overview, we highlight some of the ncRNAs associated with gynecological cancers.

Distinct B-Cell Specific Transcriptional Contexts of the BCL2 Oncogene Impact Pre-Malignant Development in Mouse Models.

Upregulated expression of the anti-apoptotic BCL2 oncogene is a common feature of various types of B-cell malignancies, from lymphoma to leukemia or myeloma. It is currently unclear how the various patterns of deregulation observed in pathology eventually impact the phenotype of malignant B cells and their microenvironment. Follicular lymphoma (FL) is the most common non-Hodgkin lymphoma arising from malignant germinal center (GC) B-cells, and its major hallmark is the t(14:18) translocation occurring in B cell progenitors and placing the BCL2 gene under the control of the immunoglobulin heavy chain locus regulatory region (IgH 3'RR), thus exposing it to constitutive expression and hypermutation. Translocation of BCL2 onto Ig light chain genes, BCL2 gene amplification, and other mechanisms yielding BCL2 over-expression are, in contrast, rare in FL and rather promote other types of B-cell lymphoma, leukemia, or multiple myeloma. In order to assess the impact of distinct BCL2 deregulation patterns on B-cell fate, two mouse models were designed that associated BCL2 and its full P1-P2 promoter region to either the IgH 3'RR, within a "3'RR-BCL2" transgene mimicking the situation seen in FL, or an Ig light chain locus context, through knock-in insertion at the Igκ locus ("Igκ-BCL2" model). While linkage to the IgH 3' RR mostly yielded expression in GC B-cells, the Igκ-driven up-regulation culminated in plasmablasts and plasma cells, boosting the plasma cell in-flow and the accumulation of long-lived plasma cells. These data demonstrate that the timing and level of BCL2 deregulation are crucial for the behavior of B cells inside GC, an observation that could strongly impact the lymphomagenesis process triggered by secondary genetic hits.

Viable healthcare supply chain network design for a pandemic.

The recent COVID-19 pandemic revealed that healthcare networks must have a flexible and effective structure. In this study, we develop a viable healthcare network design for a pandemic using a multi-stage stochastic approach. We propose a multi-level network that includes health centers, computed tomography scan centers, hospitals, and clinics. Patients have conditions to returning to normal life or quarantining at home. Three objectives are defined: maximizing the probability of patient recovery, minimizing the costs of all centers in the network, and minimizing the Coronavirus death rate. We investigate a real case study in Iran to demonstrate the model's applicability. Finally, we compare the healthcare supply chain network design in a pandemic with a normal situation to advise how the network can continue to remain viable.

Phylogenetic analysis and antibiotic resistance of Shigella sonnei isolates.

Shigellosis is one of the most important gastric infections caused by different species of Shigella, and has been regarded as a serious threat to public health. Lineage/sublineage profile of Shigella sonnei is strongly associated with the antibiotic resistance and population structure of this pathogen. In this study, we determined the phylogeny and antibiotic resistance profiles of S. sonnei strains, isolated from 1246 stool and 580 food samples, using multiplex PCR-HRMA genotyping and Kirby-Bauer disk diffusion methods, respectively. A total of 64 S. sonnei strains were isolated (13 food and 51 clinical isolates). Multiplex PCR-HMR assay was able to differentiate the lineages II and III, and sublineages IIIb and IIIc strains successfully considering the definite melting curves and temperatures. Lineage I and sublineage IIIa strain were not isolated in this study. We also demonstrated that most of the S. sonnei strains isolated from both food and clinical samples clustered within the lineage III and sublineage IIIc. Resistance against trimethoprim-sulfamethoxazole, tetracycline, chloramphenicol, and streptomycin antibiotics were the most prevalent phenotypes among the S. sonnei lineage III and sublineage IIIc strains.

RNA-based immunoglobulin repertoire sequencing is a new tool for the management of monoclonal gammopathy of renal (kidney) significance.

The diagnostic approach of monoclonal gammopathy of renal significance is based on the detection of a monoclonal immunoglobulin in the blood and urine, and the identification of the underlying clone through bone marrow and/or peripheral blood cytologic and flow cytometry analysis. However, the monoclonal component and its corresponding clone may be undetectable using these routine techniques. Since clone identification is the cornerstone for guiding therapy and assessing disease response, more sensitive methods are required. We recently developed a high-throughput sequencing assay from bone marrow mRNA encoding immunoglobulins (RACE-RepSeq). This technique provides both full-length V(D)J region (variable, diversity and joining genes that generate unique receptors as antigen receptors) of the monoclonal immunoglobulin and the dominant immunoglobulin repertoire. This allows analysis of mutational patterns, immunoglobulin variable gene frequencies and diversity due to somatic hypermutation. Here, we evaluated the diagnostic performance of RACE-RepSeq in 16 patients with monoclonal-associated kidney lesions, and low serum monoclonal immunoglobulin and free light chain levels at diagnosis. Bone marrow immunohistochemical analysis was negative in all 11 patients so tested and 7 of 12 patients had no detectable clone matching the kidney deposits using flow cytometry analysis. By contrast, RACE-RepSeq detected a dominant clonal light chain sequence of matched isotype with respect to kidney deposits in all patients. Thus, high throughput mRNA sequencing appears highly sensitive to detect subtle clonal disorders in monoclonal gammopathy of renal significance and suggest this novel approach could help improve the management of this kidney disease.

Ecotourism supply chain during the COVID-19 pandemic: A real case study.

The coronavirus (COVID-19) disease has caused serious and irreversible damage to the ecotourism industry, posing serious challenges to all parts of the ecotourism supply chain. The ecotourism supply chain is made up of various components, the most important of which are ecotourism centers. During these pandemic times, the primary concerns of these centers are to improve their deplorable economic conditions and retain customers for the post-coronavirus era. As a result, an investigation should be conducted to address these concerns and provide appropriate solutions to help them overcome the challenges that have emerged. To achieve the research goal, a bi-objective mathematical model for the ecotourism supply chain in an uncertain environment is developed, accounting for the effects of COVID-19. The first objective function minimizes the total cost of the supply chain, while the second maximizes customer satisfaction. The proposed mathematical model is solved using a fuzzy goal programming (FGP) method. A sensitivity analysis study is also carried out to examine the performance of some basic parameters. Furthermore, the model is tested in a real case study to determine its efficacy. Finally, some effective managerial insights are proposed to improve the situation of the centers during the pandemic.

Association of M55L and Q192R polymorphisms of paraoxonase 1 gene (PON1) with recurrent pregnancy loss risk: A case-control study.

BACKGROUND: Recurrent pregnancy loss (RPL) refers to the incidence of two or more abortions before the first half of pregnancy. Oxidative stress has been hypothesized to play a central role in RPL. OBJECTIVE: To investigate the relationship between Q192R and L55M polymorphisms of PON1 as antioxidant enzyme and the risk of RPL. MATERIALS AND METHODS: In this case-control study, 110 women with RPL (case) and 110 healthy fertile women (control) referred to the Research and Clinical Center for Infertility, Shiraz, Iran were enrolled. Genomic DNA was extracted from the peripheral blood in all participants. Polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: Statistical analysis of Q192R polymorphism showed a significant difference for the RR genotype between the case and control group (OR = 11, CI = 1.39-86.87, p = 0.005) but none for the QR and QQ genotypes. No significant association was observed between the R and Q allelic frequency in the RPL participants compared to the control group (p = 0.53). Also, statistical analysis of the L55M polymorphism for MM genotype in the case group compared with the control group showed a significant difference (OR = 3.59, CI = 0.97-13.30, p = 0.042), but none for the LM and LL genotypes. CONCLUSION: The findings showed a significant correlation between the Q192R polymorphisms and the L55M PON1 enzyme and RPL in this study population.

Non-linear associations between retinal nerve fibre layer (RNFL) and positive and negative symptoms among men with acute and chronic schizophrenia spectrum disorder.

BACKGROUND: Schizophrenia Spectrum Disorder (SSD) is a chronic psychiatric disorder with modest treatment outcomes. Changes in neuronal morphology may be associated with the symptomatology of SSD. In the present study, we compared the retinal nerve fibre layer thickness (RNFLT) of typically developed adults with that of individuals with SSD in both acute and chronic stages. METHODS: Fifteen healthy adult males (mean age: 36.40 years) and 30 individuals with SSD (mean age: 37.9 years) took part in the study. Among the latter, 15 had a chronic mean SSD for 15.33 years, while 15 were in an acute psychotic phase with a mean illness duration of 12.20 years. Experts rated positive and negative symptoms of SSD. Retinal nerve fibre layer thickness (RNFLT) of all participants was measured with optical coherence tomography (OCT). RESULTS: Compared to healthy controls, individuals with acute SSD had the lowest macula thickness in the right eye. For nerve fiber layer atrophy, participants with acute SSD showed the largest atrophy (right eye, inferior quadrant). For retinal thickness and macular volume cube, compared to healthy controls, participants with acute SSD had the lowest thickness in the subfield of the right eye. Non-linear associations were observed between RNFL and positive and negative symptoms: e.g., for macula central and subfoveal thickness (left and right eye) and for participants with both acute and chronic SSD, exclusively positive and exclusively negative symptoms (as opposed to prevalently negative with some positive symptoms or prevalently positive with some negative symptoms) were associated with lower volumes. In participants with acute SSD, a longer disease duration was associated with thicker RNFL, while in participants with a chronic SSD a longer disease duration was associated with a thinner RNFL. CONCLUSION: The present results confirm previous findings that specific neuronal morphological abnormalities can be observed among individuals with SSD. The non-linear associations between neuronal alterations and positive and negative symptomatology suggested that higher pronounced SSD severity appears to be particularly related to morphological changes. Disease duration and RNFL thickness were linearly associated, though, in opposite directions depending on the chronic or acute state.

Integration of CNN, CBMIR, and Visualization Techniques for Diagnosis and Quantification of Covid-19 Disease.

Diagnosis techniques based on medical image modalities have higher sensitivities compared to conventional RT-PCT tests. We propose two methods for diagnosing COVID-19 disease using X-ray images and differentiating it from viral pneumonia. The diagnosis section is based on deep neural networks, and the discriminating uses an image retrieval approach. Both units were trained by healthy, pneumonia, and COVID-19 images. In COVID-19 patients, the maximum intensity projection of the lung CT is visualized to a physician, and the CT Involvement Score is calculated. The performance of the CNN and image retrieval algorithms were improved by transfer learning and hashing functions. We achieved an accuracy of 97% and an overall prec@10 of 87%, respectively, concerning the CNN and the retrieval methods.

Al-Masa'il fi al-tibb: Hunain ibn Ishaq's historic medical text with a distinctive style of Islamic medical education.

The golden age of Islamic medicine (800 to 1300 CE) is a notable period in medical history. Medical education in this period of time was significant and systematic in Islamic territory. In the early Golden Age of Islamic Medicine, Abu Zayd Hunain ibn Ishaq al-'Ibadi, an exceptional scholar and translator, emerged. He was known as Johannitius in medieval Europe. Al-Masa'il fi al-tibb lil-Mutallimin (Questions on Medicine for Students) was written by Hunain ibn Ishaq. This book remains a definitive text on Islamic medicine and has been printed and published widely in Europe. Al-Masa'il fi al-tibb is written in the style of questions and answers which is distinct from the conventional writing style of medical books on Islamic medicine. The current article reviews Al-Masa'il fi al-tibb and its distinguishing style, the question and answer format. Today, the question-and-answer method is a popular method of medical education, and clinical teachers tend to use it in medical education because of the advantages it offers. The use of this method in Al-Masa'il fi al-tibb for education and examination of medical students by Hunain ibn Ishaq reflects a great improvisation in medical education and introduces him as the leading developer of the question-and-answer method in Islamic medical education.

Thymolipoma associated with lymphocytosis in a 6-year-old girl: A case report.

Thymolipoma is a benign and rare tumor that could be found at any age. Thymolipoma associated with the myasthenia gravis, Graves disease, aplastic anemia, and hypogammaglobulinemia was reported previously, but in this case, thymolipoma is associated with lymphocytosis. A 6-year-old girl was brought to the hospital because of a chronic cough. Her evaluation revealed a 130 × 160× 160 mm fat-containing soft tissue mass arising from anterior mediastinum with complete left lung collapse and contralateral mediastinal shift. Her past medical history showed that she had been evaluated and treated unsuccessfully due to severe lymphocytosis two years earlier. Her peripheral blood and bone marrow cell morphology were normal; in contrast, blood cell count and CD flow cytometry showed severe lymphocytosis. The patient's tumor was excised entirely without any complications, and lymphocytosis resolved during the follow-up period. Because the T lymphocytes are developed in the thymus, and more than 80% of cells in CD flow cytometry were T lymphocytes, and the lymphocytosis resolved with tumor removal; therefore, the authors suggested that Thymolipoma could be associated with lymphocytosis.

Centromeric KIR AA Individuals Harbor Particular KIR Alleles Conferring Beneficial NK Cell Features with Implications in Haplo-Identical Hematopoietic Stem Cell Transplantation.

We have recently shown a broad disparity of Natural Killer (NK) cell responses against leukemia highlighting good and bad responders resting on the Killer cell Immunoglobulin-like Receptors (KIR) and HLA genetics. In this study, we deeply studied KIR2D allele expression, HLA-C recognition and functional effect on NK cells in 108 blood donors in combining high-resolution KIR allele typing and multicolor flow cytometry. The KIR2DL1*003 allotype is associated with centromeric (cen) AA motif and confers the highest NK cell frequency, expression level and strength of KIR/HLA-C interactions compared to the KIR2DL1*002 and KIR2DL1*004 allotypes respectively associated with cenAB and BB motifs. KIR2DL2*001 and *003 allotypes negatively affect the frequency of KIR2DL1+ and KIR2DL3+ NK cells. Altogether, our data suggest that cenAA individuals display more efficient KIR2DL alleles (L1*003 and L3*001) to mount a consistent frequency of KIR2DL+ NK cells and to confer an effective NK cell responsiveness. The transposition of our in vitro observations in the T-replete haplo-identical HSCT context led us to observe that cenAA HSC grafts limit significantly the incidence of relapse in patients with myeloid diseases after T-replete haplo-identical HSCT. As NK cells are crucial in HSCT reconstitution, one could expect that the consideration of KIR2DL1/2/3 allelic polymorphism could help to refine scores used for HSC donor selection.