Microheterogeneity in the Kinetics and Sex-Specific Response to Type I IFN.

The response to type I IFNs involves the rapid induction of prototypical IFN signature genes (ISGs). It is not known whether the tightly controlled ISG expression observed at the cell population level correctly represents the coherent responses of individual cells or whether it masks some heterogeneity in gene modules and/or responding cells. We performed a time-resolved single-cell analysis of the first 3 h after in vivo IFN stimulation in macrophages and CD4+ T and B lymphocytes from mice. All ISGs were generally induced in concert, with no clear cluster of faster- or slower-responding ISGs. Response kinetics differed between cell types: mostly homogeneous for macrophages, but with far more kinetic diversity among B and T lymphocytes, which included a distinct subset of nonresponsive cells. Velocity analysis confirmed the differences between macrophages in which the response progressed throughout the full 3 h, versus B and T lymphocytes in which it was rapidly curtailed by negative feedback and revealed differences in transcription rates between the lineages. In all cell types, female cells responded faster than their male counterparts. The ISG response thus seems to proceed as a homogeneous gene block, but with kinetics that vary between immune cell types and with sex differences that might underlie differential outcomes of viral infections.

Change in HIV-related characteristics of children hospitalised with infectious diseases in Western Cape, South Africa, 2008-2021: a time trend analysis.

INTRODUCTION: With the scaling up of vertical HIV transmission prevention programmes, the HIV-related population profile of children in South Africa has shifted. We described temporal changes in HIV-related characteristics of children, aged ≤3 years (up to the third birthday), with infectious disease hospitalisations across the Western Cape province. METHODS: We used routinely collected electronic data to identify children born in the Western Cape with infectious disease hospital records for lower respiratory tract infections, diarrhoea, meningitis and tuberculous meningitis, from 2008 to 2021. Linked maternal and child unique identifiers were used to extract pregnancy, HIV-related, laboratory, pharmacy and hospitalisation data. We described temporal changes in child HIV exposure and acquisition status, timing of maternal HIV diagnosis and antiretroviral therapy (ART) start, infant exposure to maternal ART and timing thereof, and maternal CD4 and HIV viral load closest to delivery. We used logistic and multinomial regression to assess changes in characteristics between the Pre-Option B+ (2008-2013), Option B+ (2013-2016) and Universal ART periods (2016-2021). RESULTS: Among 52,811 children aged ≤3 years with hospitalisations, the proportion living with HIV dreased from 7.0% (2008) to 1.1% (2021), while those exposed to HIV and uninfected increased from 14.0% (2008) to 16.1% (2021) with a peak of 18.3% in 2017. Among mothers with HIV (n = 9873), the proportion diagnosed with HIV and starting ART before pregnancy increased from 20.2% to 69.2% and 5.8% to 59.0%, respectively, between 2008 and 2021. Children hospitalised during the Universal ART period had eight times higher odds (Odds Ratio: 8.41; 95% CI: 7.36-9.61) of exposure to maternal ART versus children admitted Pre-Option B+. Among mothers of children exposed to HIV and uninfected with CD4 records (n = 7523), the proportion with CD4 <350 cells/µl decreased from 90.6% (2008) to 27.8% (2021). CONCLUSIONS: In recent years, among children hospitalised with infectious diseases, there were fewer children with perinatally acquired HIV, while an increased proportion of those without HIV acquisition are exposed to maternal HIV and ART. There is a need to look beyond paediatric HIV prevalence and consider child exposure to HIV and ART among children without HIV, when assessing the HIV epidemic's impact on child health services.

Genetics of Sex Differences in Immunity.

Women have a stronger immune response and a higher frequency of most autoimmune diseases than men. While much of the difference between men and women is due to the effect of gonadal hormones, genetic differences play a major role in the difference between the immune response and disease frequencies in women and men. Here, we focus on the immune differences between the sexes that are not downstream of the gonadal hormones. These differences include the gene content of the sex chromosomes, the inactivation of chromosome X in women, the consequences of non-random X inactivation and escape from inactivation, and the states that are uniquely met by the immune system of women-pregnancy, birth, and breast feeding. While these female-specific states are temporary and involve gonadal hormonal changes, they may leave a long-lasting footprint on the health of women, for example, by fetal cells that remain in the mother's body for decades. We also briefly discuss the immune phenotype of congenital sex chromosomal aberrations and experimental models that enable hormonal and the non-hormonal effects of the sex chromosomes to be disentangled. The increasing human life expectancy lengthens the period during which gonadal hormones levels are reduced in both sexes. A better understanding of the non-hormonal effects of sex chromosomes thus becomes more important for improving the life quality during that period.

Adipocytes regulate fibroblast function, and their loss contributes to fibroblast dysfunction in inflammatory diseases.

Fibroblasts play critical roles in tissue homeostasis, but in pathologic states can drive fibrosis, inflammation, and tissue destruction. In the joint synovium, fibroblasts provide homeostatic maintenance and lubrication. Little is known about what regulates the homeostatic functions of fibroblasts in healthy conditions. We performed RNA sequencing of healthy human synovial tissue and identified a fibroblast gene expression program characterized by enhanced fatty acid metabolism and lipid transport. We found that fat-conditioned media reproduces key aspects of the lipid-related gene signature in cultured fibroblasts. Fractionation and mass spectrometry identified cortisol in driving the healthy fibroblast phenotype, confirmed using glucocorticoid receptor gene ( NR3C1 ) deleted cells. Depletion of synovial adipocytes in mice resulted in loss of the healthy fibroblast phenotype and revealed adipocytes as a major contributor to active cortisol generation via Hsd11 ß 1 expression. Cortisol signaling in fibroblasts mitigated matrix remodeling induced by TNFα- and TGFß, while stimulation with these cytokines repressed cortisol signaling and adipogenesis. Together, these findings demonstrate the importance of adipocytes and cortisol signaling in driving the healthy synovial fibroblast state that is lost in disease.

Chronotype and Social Jetlag Influence Performance and Injury during Reserve Officers' Training Corps Physical Training.

Sleep and circadian rhythms are critically important for optimal physical performance and maintaining health during training. Chronotype and altered sleep may modulate the response to exercise training, especially when performed at specific times/days, which may contribute to musculoskeletal injury. The purpose of this study was to determine if cadet characteristics (chronotype, sleep duration, and social jetlag) were associated with injury incidence and inflammation during physical training. Reserve Officers' Training Corps (ROTC) cadets (n = 42) completed the Morningness/Eveningness Questionnaire to determine chronotype, and 1-week sleep logs to determine sleep duration and social jetlag. Salivary IL-6 was measured before and after the first and fourth exercise sessions during training. Prospective injury incidence was monitored over 14 weeks of training, and Army Physical Fitness Test scores were recorded at the conclusion. Chronotype, sleep duration, and social jetlag were assessed as independent factors impacting IL-6, injury incidence, and APFT scores using ANOVAs, chi-squared tests, and the t-test where appropriate, with significance accepted at p < 0.05. Evening chronotypes performed worse on the APFT (evening = 103.8 ± 59.8 vs. intermediate = 221.9 ± 40.3 vs. morning = 216.6 ± 43.6; p < 0.05), with no difference in injury incidence. Sleep duration did not significantly impact APFT score or injury incidence. Social jetlag was significantly higher in injured vs. uninjured cadets (2:40 ± 1:03 vs. 1:32 ± 55, p < 0.05). Exercise increased salivary IL-6, with no significant effects of chronotype, sleep duration, or social jetlag. Evening chronotypes and cadets with social jetlag display hampered performance during morning APFT. Social jetlag may be a behavioral biomarker for musculoskeletal injury risk, which requires further investigation.

Insights on the Dynamics and Toxicity of Nanoparticles in Environmental Matrices.

The manufacturing rate of nanoparticles (10-100 nm) is steadily increasing due to their extensive applications in the fabrication of nanoproducts related to pharmaceuticals, cosmetics, medical devices, paints and pigments, energy storage etc. An increase in research related to nanotechnology is also a cause for the production and disposal of nanomaterials at the lab scale. As a result, contamination of environmental matrices with nanoparticles becomes inevitable, and the understanding of the risk of nanoecotoxicology is getting larger attention. In this context, focusing on the environmental hazards is essential. Hence, this manuscript aims to review the toxic effects of nanoparticles on soil, water, aquatic, and terrestrial organisms. The effects of toxicity on vertebrates, invertebrates, and plants and the source of exposure, environmental and biological dynamics, and the adverse effects of some nanoparticles are discussed.

Curcumin Is an Iconic Ligand for Detecting Environmental Pollutants.

The rapid increase in industrial revolution and the consequent environmental contamination demands continuous monitoring and sensitive detection of the pollutants. Nanomaterial-based sensing system has proved to be proficient in sensing environmental pollutants. The development of novel ligands for enhancing the sensing efficiency of nanomaterials has always been a challenge. However, the amendment of nanostructure with molecular ligand increases the sensitivity, selectivity, and analytical performance of the resulting novel sensing platform. Organic ligands are capable of increasing the adsorption efficacy, optical properties, and electrochemical properties of nanomaterials by reducing or splitting of band gap. Curcumin (diferuloylmethane) is a natural organic ligand that exhibits inherent fluorescence and electrocatalytic property. Due to keto-enol tautomerism, it is capable of giving sensitive signals such as fluorescence, luminescence, ultraviolet absorption shifts, and electrochemical data. Curcumin probes were also reported to give enhanced meterological performances, such as low detection limit, repeatability, reproducibility, high selectivity, and high storage stability when used with nanosystem. Therefore, research on curcumin-modified nanomaterials in the detection of environmental pollution needs a special focus for prototype and product development to enable practical use. Hence, this article reviews the role of curcumin as a natural fluorophore in optical and electrochemical sensing of environmentally significant pollutants. This review clearly shows that curcumin is an ideal candidate for developing and validating nanomaterials-based sensors for the detection of environmental pollutants such as arsenic, lead, mercury, boron, cyanide, fluoride, nitrophenol, trinitrotoluene, and picric acid and toxic gases such as ammonia and hydrogen chloride. This review will afford references for future studies and enable researchers to translate the lab concepts into industrial products.

DoChaP: the domain change presenter.

Alternative splicing results in multiple transcripts of the same gene, possibly encoding for different protein isoforms with different domains. Whereas it is possible to manually determine the effect of alternative splicing on the domain composition for a single event, the process requires the tedious integration of several data sources; it is error prone and not feasible for genome-wide characterization of domains affected by differential splicing. To fulfill the need for an automated solution, we developed the Domain Change Presenter (DoChaP, https://dochap.bgu.ac.il/), a web server for the visualization of exon-domain associations. DoChaP visualizes all transcripts of a given gene, the encoded proteins and their domains, and enables a comparison between the transcripts and between their protein products. The colors and organization make the structural effect of alternative splicing events on protein structures easily identified. To enable the study of the conservation of exons structure, alternative splicing, and the effect of alternative splicing on protein domains, DoChaP also provides a two-species comparison of exon-domain associations. DoChaP thus provides a unique and easy-to-use visualization of the exon-domain association and conservation, and will facilitate the study of the structural effects of alternative splicing in health and disease.

Cytokinetic abscission is part of the midblastula transition in early zebrafish embryogenesis.

Animal cytokinesis ends with the formation of a thin intercellular membrane bridge that connects the two newly formed sibling cells, which is ultimately resolved by abscission. While mitosis is completed within 15 min, the intercellular bridge can persist for hours, maintaining a physical connection between sibling cells and allowing exchange of cytosolic components. Although cell-cell communication is fundamental for development, the role of intercellular bridges during embryogenesis has not been fully elucidated. In this work, we characterized the spatiotemporal characteristics of the intercellular bridge during early zebrafish development. We found that abscission is delayed during the rapid division cycles that occur in the early embryo, giving rise to the formation of interconnected cell clusters. Abscission was accelerated when the embryo entered the midblastula transition (MBT) phase. Components of the ESCRT machinery, which drives abscission, were enriched at intercellular bridges post-MBT and, interfering with ESCRT function, extended abscission beyond MBT. Hallmark features of MBT, including transcription onset and cell shape modulations, were more similar in interconnected sibling cells compared to other neighboring cells. Collectively, our findings suggest that delayed abscission in the early embryo allows clusters of cells to coordinate their behavior during embryonic development.

Author Correction: γδ T cells producing interleukin-17A regulate adipose regulatory T cell homeostasis and thermogenesis.

In the version of this article initially published, three authors (Hui-Fern Kuoy, Adam P. Uldrich and Dale. I. Godfrey) and their affiliations, acknowledgments and contributions were not included. The correct information is as follows:Ayano C. Kohlgruber1,2, Shani T. Gal-Oz3, Nelson M. LaMarche1,2, Moto Shimazaki1, Danielle Duquette4, Hui-Fern Koay5,6, Hung N. Nguyen1, Amir I. Mina4, Tyler Paras1, Ali Tavakkoli7, Ulrich von Andrian2,8, Adam P. Uldrich5,6, Dale I. Godfrey5,6, Alexander S. Banks4, Tal Shay3, Michael B. Brenner1,10* and Lydia Lynch1,4,9,10*1Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, MA, USA. 2Division of Medical Sciences, Harvard Medical School, Boston, MA, USA. 3Department of Life Sciences, Ben-Gurion University of the Negev, Beersheba, Israel. 4Division of Endocrinology, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. 5Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Australia. 6ARC Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, Australia. 7Department of General and Gastrointestinal Surgery, Brigham and Women's Hospital, Boston, MA, USA. 8Department of Microbiology and Immunology, Harvard Medical School, Boston, MA, USA. 9School of Biochemistry and Immunology, Trinity College, Dublin, Ireland. 10These authors jointly supervised this work: Michael B. Brenner, Lydia Lynch. *e-mail: mbrenner@research.bwh.harvard.edu; llynch@bwh.harvard.eduAcknowledgementsWe thank A.T. Chicoine, flow cytometry core manager at the Human Immunology Center at BWH, for flow cytometry sorting. We thank D. Sant'Angelo (Rutgers Cancer Institute) for providing Zbtb16-/- mice and R. O'Brien (National Jewish Health) for providing Vg4/6-/- mice. Supported by NIH grant R01 AI11304603 (to M.B.B.), ERC Starting Grant 679173 (to L.L.), the National Health and Medical Research Council of Australia (1013667), an Australian Research Council Future Fellowship (FT140100278 for A.P.U.) and a National Health and Medical Research Council of Australia Senior Principal Research Fellowship (1117766 for D.I.G.).Author contributionsA.C.K., L.L., and M.B.B. conceived and designed the experiments, and wrote the manuscript. A.C.K., N.M.L., L.L., H.N.N., M.S., T.P., and D.D. performed the experiments. S.T.G.-O. and T.S. performed the RNA-seq analysis. A.S.B. and A.I.M. provided advice and performed the CLAMS experiments. A.T. provided human bariatric patient samples. Parabiosis experiments were performed in the laboratory of U.v.A. H.-F.K., A.P.U. and D.I.G provided critical insight into the TCR chain usage of PLZF+ γδ T cells. M.B.B., N.M.L., and L.L. critically reviewed the manuscript.The errors have been corrected in the HTML and PDF version of the article.Correction to: Nature Immunology doi:10.1038/s41590-018-0094-2 (2018), published online 18 April 2018.

γδ T cells producing interleukin-17A regulate adipose regulatory T cell homeostasis and thermogenesis.

γδ T cells are situated at barrier sites and guard the body from infection and damage. However, little is known about their roles outside of host defense in nonbarrier tissues. Here, we characterize a highly enriched tissue-resident population of γδ T cells in adipose tissue that regulate age-dependent regulatory T cell (Treg) expansion and control core body temperature in response to environmental fluctuations. Mechanistically, innate PLZF+ γδ T cells produced tumor necrosis factor and interleukin (IL) 17 A and determined PDGFRα+ and Pdpn+ stromal-cell production of IL-33 in adipose tissue. Mice lacking γδ T cells or IL-17A exhibited decreases in both ST2+ Treg cells and IL-33 abundance in visceral adipose tissue. Remarkably, these mice also lacked the ability to regulate core body temperature at thermoneutrality and after cold challenge. Together, these findings uncover important physiological roles for resident γδ T cells in adipose tissue immune homeostasis and body-temperature control.

Chromosomal numerical aberrations in oral lichen planus.

The malignant potential of oral lichen planus (OLP) has been a matter of serious controversy. We aimed to detect chromosomal numerical aberrations in cells of brush samples collected from affected mucosa. The samples were simultaneously analyzed for morphology and fluorescent in situ hybridization (FISH) with chromosomes 2 and 8 centromeric probes. We analyzed 57 persons with OLP and 33 control individuals. A cut-off value of aneuploid cells was determined as 1.1%. Aneuploid cells were found in 16 persons with OLP (28.1%); in 10 individuals (17.5%), over 5% of the cells were aneuploid. Aneuploid cells were also detected in normal-looking mucosa of seven persons with OLP. One person with OLP developed squamous cell carcinoma; 10% of the cells examined were aneuploid. OLP carries an increased risk for chromosomal instability. Identifying aneuploid cells in a brush sample and the combined morphological and FISH analysis can increase the specificity in predicting the malignant potential of OLP.

Emergency tracheostomy following life-threatening hemorrhage in the floor of the mouth during immediate implant placement in the mandibular canine region.

BACKGROUND: The edentulous interforaminal mandibular area is frequently the preferred area for implant placement. METHODS: A case of emergency tracheostomy following life-threatening hemorrhage in the floor of the mouth during immediate implant placement in the mandibular canine region is described. The probable cause was bleeding from the sublingual artery or a branch of that artery following implant perforation of the lingual cortex. RESULTS: Healing was uneventful and the patient was released from the hospital after 11 days. Three years later, CT showed a well-osseointegrated implant with a severe buccolingual inclination. CONCLUSIONS: It is stressed that short implants (14 mm or less) should be used in the mandibular canine region and that effective treatment of this complication is essential.

[Problems in fetal monitoring characteristic of risks for malpractice suits].

Medical malpractice suits in obstetrics comprise about 10% of all claims against medical institutions in Israel. A significant proportion are due to failures relating to fetal monitoring. We studied the characteristics of 102 of 4125 obstetrical cases reported to the Medical Risk Management Co. as being at risk for a malpractice suit. The cases were divided into those with medical management failures (misinterpretation of fetal monitor tracing, failure to respond promptly to fetal monitoring indicating distress, etc.) and technical failures (loss of monitor tracings, interruption in the tracing at a critical time, unreadable tracings, etc.). The monetary quantum in fetal monitoring failures exceeded $30,000,000. The majority of these failures could have been avoided by using central electronic fetal monitoring systems with alerting and archival capabilities.