Loss of TET2 in human hematopoietic stem cells alters the development and function of neutrophils.

Somatic mutations commonly occur in hematopoietic stem cells (HSCs). Some mutant clones outgrow through clonal hematopoiesis (CH) and produce mutated immune progenies shaping host immunity. Individuals with CH are asymptomatic but have an increased risk of developing leukemia, cardiovascular and pulmonary inflammatory diseases, and severe infections. Using genetic engineering of human HSCs (hHSCs) and transplantation in immunodeficient mice, we describe how a commonly mutated gene in CH, TET2, affects human neutrophil development and function. TET2 loss in hHSCs produce a distinct neutrophil heterogeneity in bone marrow and peripheral tissues by increasing the repopulating capacity of neutrophil progenitors and giving rise to low-granule neutrophils. Human neutrophils that inherited TET2 mutations mount exacerbated inflammatory responses and have more condensed chromatin, which correlates with compact neutrophil extracellular trap (NET) production. We expose here physiological abnormalities that may inform future strategies to detect TET2-CH and prevent NET-mediated pathologies associated with CH.

Infecting human hematopoietic stem and progenitor cells with SARS-CoV-2.

Determining how hematopoietic stem and progenitor cells (HSPCs) can be infected by viruses is necessary to understand and predict how the immune system will drive the host response. We present here a protocol to analyze the capacity of SARS-CoV-2 to infect different subsets of human HSPCs, inlcuding procedures for SARS-CoV-2 production and titration, isolation of human HSPCs from different sources (bone marrow, umbilical cord, or peripheral blood), and quantification of SARS-Cov-2 infection capacity by RT-qPCR and colony forming unit assay. For complete details on the use and execution of this protocol, please refer to Huerga Encabo et al. (2021).

Variants in PCSK7, PNPLA3 and TM6SF2 are risk factors for the development of cirrhosis in hereditary haemochromatosis.

BACKGROUND: Cirrhosis develops in <10% of individuals homozygous for the C282Y variant in the homeostatic iron regulator (HFE) gene. Carriage of PCSK7:rs236918 is associated with an increased risk of cirrhosis in this population. AIM: To determine if genetic variants significantly associated with the risk of alcohol- and NAFLD-related cirrhosis also modulate the cirrhosis risk in C282Y homozygotes. METHODS: Variants in PCSK7, PNPLA3, TM6SF2, MBOAT7 and HSD17B13 were genotyped in 1319 C282Y homozygotes, from six European countries, of whom 171 (13.0%) had cirrhosis. Genotypic and allelic associations with the risk for developing cirrhosis were assessed, adjusting for age and sex. Fixed effects meta-analyses of the adjusted summary data for each country were performed. Post hoc association testing was undertaken in the 131 (76.6%) cases and 299 (26.0%) controls with available liver histology. RESULTS: Significant associations were observed between PCSK7:rs236918 (OR = 1.52 [95% CI 1.06-2.19]; P = 0.022; I2  = 0%); PNPLA3:rs738409 (OR = 1.60 [95% CI 1.22-2.11]; P = 7.37 × 10-4 ; I2  = 45.5%) and TM6SF2:rs58542926 (OR = 1.94 [95% CI 1.28-2.95]; P = 1.86 × 10-3 ; I2  = 0%) and the cirrhosis risk in C282Y homozygotes. These findings remained significant in the subpopulation with available liver histology. The population-attributable fractions were 5.6% for PCSK7:rs236918, 13.8% for PNPLA3:rs738409, 6.5% for TM6SF2:rs58542926 and 24.0% for carriage of all three variants combined. CONCLUSIONS: The risk of cirrhosis associated with carriage of PCSK7:rs236918 was confirmed in this much larger population of C282Y homozygotes. In addition, PNPLA3:rs738409 and TM6SF2:rs58542926 were established as significant additional risk factors. More detailed genetic testing of C282Y homozygotes would allow risk stratification and help guide future management.

The impossibility of low-rank representations for triangle-rich complex networks.

The study of complex networks is a significant development in modern science, and has enriched the social sciences, biology, physics, and computer science. Models and algorithms for such networks are pervasive in our society, and impact human behavior via social networks, search engines, and recommender systems, to name a few. A widely used algorithmic technique for modeling such complex networks is to construct a low-dimensional Euclidean embedding of the vertices of the network, where proximity of vertices is interpreted as the likelihood of an edge. Contrary to the common view, we argue that such graph embeddings do not capture salient properties of complex networks. The two properties we focus on are low degree and large clustering coefficients, which have been widely established to be empirically true for real-world networks. We mathematically prove that any embedding (that uses dot products to measure similarity) that can successfully create these two properties must have a rank that is nearly linear in the number of vertices. Among other implications, this establishes that popular embedding techniques such as singular value decomposition and node2vec fail to capture significant structural aspects of real-world complex networks. Furthermore, we empirically study a number of different embedding techniques based on dot product, and show that they all fail to capture the triangle structure.

Clinical study of Agnikarma and Panchatikta Guggulu in the management of Sandhivata (osteoartheritis of knee joint).

BACKGROUND: Sandhivata is a disease described under Vatavyadhi and resembles osteoarthritis (OA) in respect to etiology, pathology, and clinical features. Knee joints are more prone to be affected by this disease because it is the most frequently involved joint in daily works. Acharya Sushruta has indicated Agnikarma, when severe pain occurs in Twak, Mamsa, Sira, Snayu, Sandhi, and Asthi due to Vata Prakopa. Panchatikta Guggulu is a formulation mentioned in Chakradatta and Bhaishajya Ratnavali in the context of Kushtha Roga where it is also indicated for Sandhigata Vata and Asthigata Vata. AIMS: The aim of this study is to evaluate the comparative effect of Agnikarma alone and Agnikarma along with Panchatikta Guggulu orally in Janugata Sandhivata (OA of knee joint). MATERIALS AND METHODS: Thirty-three patients of Janugata Sandhivata were registered and randomly divided into two groups. In Group A (n = 18), Agnikarma was done with Panchadhatu Shalaka once every week for one month while in Group B (n = 15), Agnikarma along with Panchatikta Guggulu orally was given for one month. Weekly assessment was done for relief in Sandhishula (pain), Sparshaasahyata (tenderness), Sandhisphutana (crepitus), Sandhigraha (stiffness) by subjective gradation, and range of movement (ROM) was recorded in research proforma. RESULTS: In Sandhishula, 86% relief was found in Group A whereas 77.78% relief was obtained in Group B. Sparshaasahyata was reduced by 69% in Group A while 87.78% in Group B. Nearly 39% improvement was seen in Sandhisphutana in Group A while 46.67% in Group B. In Sandhigraha, 63% relief was obtained in each of the groups. The patients got relief from the pain after first sitting of Agnikarma in both the groups. The relief was sustained for more than 3 months in most of the patients. There was no significant difference in radiological findings before and after treatment in both the groups. CONCLUSION: It was concluded that Agnikarma is effective in the management of pain in the Sandhivata. However, the addition of Panchatikta Guggulu in the treatment provides better efficacy on joint stiffness and crepitus. Further analysis showed that better relief in pain was observed in Group A while relief in tenderness, crepitus, and stiffness was found better in Group B.

Centralized data recording for a distributed surgical skills trainer to facilitate automated proficiency evaluation.

Virtual reality simulators have the capability to automatically record user performance data in an unbiased, cost effective manner that is also less error prone than manual methods. Centralized data recording simplifies proficiency evaluation even more; however is not commonly available to date for surgical skills trainers. We will detail our approach in implementing a framework for distributed score recording over the Internet using a database for persistent storage.