Foxn1 overexpression promotes thymic epithelial progenitor cell proliferation and mTEC maintenance, but does not prevent thymic involution.

The transcription factor FOXN1 is essential for fetal thymic epithelial cell (TEC) differentiation and proliferation. Postnatally, Foxn1 levels vary widely between TEC subsets, from low/undetectable in putative TEC progenitors to highest in differentiated TEC subsets. Correct Foxn1 expression is required to maintain the postnatal microenvironment; premature downregulation of Foxn1 causes a rapid involution-like phenotype, and transgenic overexpression can cause thymic hyperplasia and/or delayed involution. We investigated a K5.Foxn1 transgene that drives overexpression in mouse TECs, but causes neither hyperplasia nor delay or prevention of aging-related involution. Similarly, this transgene cannot rescue thymus size in Foxn1lacZ/lacZ mice, which undergo premature involution as a result of reduced Foxn1 levels. However, TEC differentiation and cortico-medullary organization are maintained with aging in both K5.Foxn1 and Foxn1lacZ/lacZ mice. Analysis of candidate TEC markers showed co-expression of progenitor and differentiation markers as well as increased proliferation in Plet1+ TECs associated with Foxn1 expression. These results demonstrate that the functions of FOXN1 in promoting TEC proliferation and differentiation are separable and context dependent, and suggest that modulating Foxn1 levels can regulate the balance of proliferation and differentiation in TEC progenitors.

Neurophysiological processes reflecting the effects of the immediate past during the dynamic management of actions.

In recent years, there has been many efforts to establish a comprehensive theoretical framework explaining the working mechanisms involved in perception-action integration. This framework stresses the importance of the immediate past on mechanisms supporting perception-action integration. The present study investigates the neurophysiological principles of dynamic perception-action bindings, particularly considering the influence of the immediate history on action control mechanisms. For this purpose, we conducted an established stimulus-response binding paradigm during EEG recording. The SR-task measures stimulus-response binding in terms of accuracy and reaction time differences depending on the degree of feature overlap between conditions. Alpha, beta and theta band activity in distinct time domains as well as associated brain regions were investigated applying time-frequency analyses, a beamforming approach as well as correlation analyses. We demonstrate, for the first time, interdependencies of neuronal processes relying on the immediate past. The reconfiguration of an action seems to overwrite immediately preceding processes. The analyses revealed modulations of theta (TBA), alpha (ABA) and beta band activity (BBA) in connection with fronto-temporal structures supporting the theoretical assumptions of the considered conceptual framework. The close interplay of attentional modulation by gating irrelevant information (ABA) and binding and retrieval processes (TBA) is reflected by the correlation of ABA in all pre-probe-intervals with post-probe TBA. Likewise, the role of BBA in maintaining the event file until retrieval is corroborated by BBA preceding the TBA-associated retrieval of perception-action codes. Following action execution, TBA shifted towards visual association cortices probably reflecting preparation for upcoming information, while ABA and BBA continue to reflect processes of attentional control and information selection for goal-directed behavior. The present work provides the first empirical support for concepts about the neurophysiological mechanisms of dynamic management of perception and action.

Iguratimod suppresses plasma cell differentiation and ameliorates experimental Sjögren's syndrome in mice by promoting TEC kinase degradation.

Primary Sjögren's syndrome (pSS) is a chronic inflammatory autoimmune disease with an unclear pathogenesis, and there is currently no approved drug for the treatment of this disease. Iguratimod, as a novel clinical anti-rheumatic drug in China and Japan, has shown remarkable efficacy in improving the symptoms of patients with pSS in clinical studies. In this study we investigated the mechanisms underlying the therapeutic effect of iguratimod in the treatment of pSS. Experimental Sjögren's syndrome (ESS) model was established in female mice by immunizing with salivary gland protein. After immunization, ESS mice were orally treated with iguratimod (10, 30, 100 mg·kg-1·d-1) or hydroxychloroquine (50 mg·kg-1·d-1) for 70 days. We showed that iguratimod administration dose-dependently increased saliva secretion, and ameliorated ESS development by predominantly inhibiting B cells activation and plasma cell differentiation. Iguratimod (30 and 100 mg·kg-1·d-1) was more effective than hydroxychloroquine (50 mg·kg-1·d-1). When the potential target of iguratimod was searched, we found that iguratimod bound to TEC kinase and promoted its degradation through the autophagy-lysosome pathway in BAFF-activated B cells, thereby directly inhibiting TEC-regulated B cells function, suggesting that the action mode of iguratimod on TEC was different from that of conventional kinase inhibitors. In addition, we found a crucial role of TEC overexpression in plasma cells of patients with pSS. Together, we demonstrate that iguratimod effectively ameliorates ESS via its unique suppression of TEC function, which will be helpful for its clinical application. Targeting TEC kinase, a new regulatory factor for B cells, may be a promising therapeutic option.

Butyrophilin 2a2 (Btn2a2) expression on thymic epithelial cells promotes central T cell tolerance and prevents autoimmune disease.

Butyrophilins are surface receptors belonging to the immunoglobulin superfamily. While several members of the butyrophilin family have been implicated in the development of unconventional T cells, butyrophilin 2a2 (Btn2a2) has been shown to inhibit conventional T cell activation. Here, we demonstrate that in steady state, the primary source of Btn2a2 are thymic epithelial cells (TEC). Absence of Btn2a2 alters thymic T cell maturation and bypasses central tolerance mechanisms. Furthermore, Btn2a2-/- mice develop spontaneous autoimmunity resembling human primary Sjögren's Syndrome (pSS), including formation of tertiary lymphoid structures (TLS) in target organs. Ligation of Btn2a2 on developing thymocytes is associated with reduced TCR signaling and CD5 levels, while absence of Btn2a2 results in increased TCR signaling and CD5 levels. These results define a novel role for Btn2a2 in promoting central tolerance by modulating TCR signaling strength and indicate a potential mechanism of pSS development.

Cytomegalovirus immune evasion sets the functional avidity threshold for protection by CD8 T cells.

Conflicting hallmarks are attributed to cytomegalovirus (CMV) infections. CMVs are viewed as being master tacticians in "immune evasion" by subverting essentially all pathways of innate and adaptive immunity. On the other hand, CMV disease is undeniably restricted to the immunologically immature or immunocompromised host, whereas an intact immune system prevents virus spread, cytopathogenic tissue infection, and thus pathological organ manifestations. Therefore, the popular term "immune evasion" is apparently incongruous with the control of CMV infections in the immunocompetent human host as well as in experimental non-human primate and rodent models. Here, we review recent work from the mouse model that resolves this obvious discrepancy for the example of the virus-specific CD8 T-cell response. Immune evasion proteins encoded by murine CMV (mCMV) interfere with the cell surface trafficking of antigenic peptide-loaded MHC class-I (pMHC-I) complexes and thereby reduce their numbers available for interaction with T-cell receptors of CD8 T cells; but this inhibition is incomplete. As a consequence, while CD8 T cells with low interaction avidity fail to receive sufficient signaling for triggering their antiviral effector function in the presence of immune evasion proteins in infected cells, a few pMHC-I complexes that escape to the cell surface are sufficient for sensitizing high-avidity CD8 T cells. It is thus proposed that the function of immune evasion proteins is to raise the avidity threshold for activation, so that in the net result, only high-avidity cells can protect. An example showing that immune evasion proteins can make the difference between life and death is the lacking control of infection in a mouse model of MHC-I histoincompatible hematopoietic cell transplantation (allogeneic-HCT). In this model, only low-avidity CD8 T cells become reconstituted by HCT and almost all infected HCT recipients die of multiple-organ CMV disease when immune evasion proteins are expressed. In contrast, lowering the avidity threshold for antigen recognition by deletion of immune evasion proteins allowed control of infection and rescued from death.

Efficacy and safety of oral ritlecitinib for the treatment of active nonsegmental vitiligo: A randomized phase 2b clinical trial.

BACKGROUND: Vitiligo is a chronic autoimmune disorder characterized by depigmented patches of the skin. OBJECTIVE: To evaluate the efficacy and safety of ritlecitinib, an oral JAK3 (Janus kinase)/TEC (tyrosine kinase expressed in hepatocelluar carcinoma) inhibitor, in patients with active nonsegmental vitiligo in a phase 2b trial (NCT03715829). METHODS: Patients were randomized to once-daily oral ritlecitinib ± 4-week loading dose (200/50 mg, 100/50 mg, 30 mg, or 10 mg) or placebo for 24 weeks (dose-ranging period). Patients subsequently received ritlecitinib 200/50 mg daily in a 24-week extension period. The primary efficacy endpoint was percent change from baseline in Facial-Vitiligo Area Scoring Index at week 24. RESULTS: A total of 364 patients were treated in the dose-ranging period. Significant differences from placebo in percent change from baseline in Facial-Vitiligo Area Scoring Index were observed for the ritlecitinib 50 mg groups with (-21.2 vs 2.1; P < .001) or without (-18.5 vs 2.1; P < .001) a loading dose and ritlecitinib 30 mg group (-14.6 vs 2.1; P = .01). Accelerated improvement was observed after treatment with ritlecitinib 200/50 mg in the extension period (n = 187). No dose-dependent trends in treatment-emergent or serious adverse events were observed across the 48-week treatment. LIMITATIONS: Patients with stable vitiligo only were excluded. CONCLUSIONS: Oral ritlecitinib was effective and well tolerated over 48 weeks in patients with active nonsegmental vitiligo.

Comparison of Simulated and Measured Power of the Earth-Space Link for Satellite-Based AIS Signals.

This research aims to analyze the impact of the Earth-Space link on the Automatic Identification System (AIS) signals of ships. To achieve this, we established a simulation system that measures the receiving power of AIS signals via satellite platforms. We validated the system by utilizing observation data from Tiantuo-5. Through this simulation, we quantitatively analyzed the effects of ionospheric TEC (Total Electron Content) and space loss on the received power. During the processing of observation data, we construct a geometric propagation model utilizing the measured positions of both the satellite and the ship. We then calculate the antenna gain and remove any system errors. Additionally, we eliminate the deviation of elevation and azimuth angles caused by satellite motion. This allows us to determine the actual power of different ships reaching the receiving platform. Upon comparing the measured power data with the simulated power, it was noted that both exhibited an increasing trend as the elevation angle increased. This led to an RMSE (Root Mean Square Error) result of approximately one, indicating the accuracy of the simulation system. These findings hold significant implications for analyzing interference factors in satellite-ground links.

Human stem cell-derived thymic epithelial cells enhance human T-cell development in a xenogeneic thymus.

BACKGROUND: Generation of thymic tissue from pluripotent stem cells would provide therapies for acquired and congenital thymic insufficiency states. OBJECTIVES: This study aimed to generate human thymic epithelial progenitors from human embryonic stem cells (hES-TEPs) and to assess their thymopoietic function in vivo. METHODS: This study differentiated hES-TEPs by mimicking developmental queues with FGF8, retinoic acid, SHH, Noggin, and BMP4. Their function was assessed in reaggregate cellular grafts under the kidney capsule and in hybrid thymi by incorporating them into swine thymus (SwTHY) grafts implanted under the kidney capsules of immunodeficient mice that received human hematopoietic stem and progenitor cells (hHSPCs) intravenously. RESULTS: Cultured hES-TEPs expressed FOXN1 and formed colonies expressing EPCAM and both cortical and medullary thymic epithelial cell markers. In thymectomized immunodeficient mice receiving hHSPCs, hES-TEPs mixed with human thymic mesenchymal cells supported human T-cell development. Hypothesizing that support from non-epithelial thymic cells might allow long-term function of hES-TEPs, the investigators injected them into SwTHY tissue, which supports human thymopoiesis in NOD severe combined immunodeficiency IL2Rγnull mice receiving hHSPCs. hES-TEPs integrated into SwTHY grafts, enhanced human thymopoiesis, and increased peripheral CD4+ naive T-cell reconstitution. CONCLUSIONS: This study has developed and demonstrated in vivo thymopoietic function of hES-TEPs generated with a novel differentiation protocol. The SwTHY hybrid thymus model demonstrates beneficial effects on human thymocyte development of hES-TEPs maturing in the context of a supportive thymic structure.

The Role of Glycoside Hydrolases in S. gordonii and C. albicans Interactions.

Candida albicans can coaggregate with Streptococcus gordonii and cocolonize in the oral cavity. Saliva provides a vital microenvironment for close interactions of oral microorganisms. However, the level of fermentable carbohydrates in saliva is not sufficient to support the growth of multiple species. Glycoside hydrolases (GHs) that hydrolyze glycoproteins are critical for S. gordonii growth in low-fermentable-carbohydrate environments such as saliva. However, whether GHs are involved in the cross-kingdom interactions between C. albicans and S. gordonii under such conditions remains unknown. In this study, C. albicans and S. gordonii were cocultured in heart infusion broth with a low level of fermentable carbohydrate. Planktonic growth, biofilm formation, cell aggregation, and GH activities of monocultures and cocultures were examined. The results revealed that the planktonic growth of cocultured S. gordonii in a low-carbohydrate environment was elevated, while that of cocultured C. albicans was reduced. The biomass of S. gordonii in dual-species biofilms was higher than that of monocultures, while that of cocultured C. albicans was decreased. GH activity was observed in S. gordonii, and elevated activity of GHs was detected in S. gordonii-C. albicans cocultures, with elevated expression of GH-related genes of S. gordonii. By screening a mutant library of C. albicans, we identified a tec1Δ/Δ mutant strain that showed reduced ability to promote the growth and GH activities of S. gordonii compared with the wild-type strain. Altogether, the findings of this study demonstrate the involvement of GHs in the cross-kingdom metabolic interactions between C. albicans and S. gordonii in an environment with low level of fermentable carbohydrates. IMPORTANCE Cross-kingdom interactions between Candida albicans and oral streptococci such as Streptococcus gordonii have been reported. However, their interactions in a low-fermentable-carbohydrate environment like saliva is not clear. The current study revealed glycoside hydrolase-related cross-kingdom communications between S. gordonii and C. albicans under the low-fermentable-carbohydrate condition. We demonstrate that C. albicans can promote the growth and metabolic activities of S. gordonii by elevating the activities of cell-wall-anchored glycoside hydrolases of S. gordonii. C. albicans gene TEC1 is critical for this cross-kingdom metabolic communication.

Effect of nucleated cell count and cryopreservation on engraftment post autologous stem cell transplant.

Using 753 collections from 426 adult haematology patients, we conducted a retrospective, analysis into the effects of overnight storage and nucleated cell counts (NCC) on viable, CD34+ (vCD34+) recovery and engraftment kinetics post autologous stem cell, transplant (ASCT) with peripheral blood stem cells (PBSC). There were significant, differences in vCD34 + recovery ( P < 0.01) after cryopreservation associated with, the fresh NCC of ≥ 300 × 10 6 /mL in products stored overnight, but no association, with time to platelet or neutrophil engraftment post-ASCT was observed for these, products. There was no association of vCD34+ numbers or engraftment kinetics with cryopreserved NCC with either below or greater than the local recommended concentration of 400 × 106 /mL of product. However, there was significant difference in engraftment kinetics in relation to the viable CD34+ dose given at ASCT, in relation to the time to early engraftment and the amount of platelet support given during the engraftment period post-ASCT. We conclude the vCD34+ dose at ASCT is of great importance to early engraftment kinetics and that NCC is an important factor during overnight storage, but not for cryopreservation of PBSC. In light of our findings, we recommend that apheresis products collected in a closed system can safely be stored undiluted overnight.

Precision Temperature Control System with Low EMI for Applications in Analyzing Thermal Properties of Highly Sensitive Piezoelectric Sensors.

A low electromagnetic interference (EMI), precision temperature control system for sensitive piezoelectric sensors stabilization and their thermal characteristics research was proposed. Quartz crystal microbalance (QCM) was chosen as the device to be tested. Recently, QCMs found use in many fields of study such as biology, chemistry, and aerospace. They often operate in harsh environments and are exposed to many external factors including temperature fluctuations, to which QCMs are highly susceptible. Such disturbances can cause undesirable resonant frequency shifts resulting in measurement errors that are difficult to eliminate. The proposed solution enables measurements of QCMs thermal characteristics, effectiveness evaluation of temperature compensation methods, and testing of the frequency stability. As a part of the developed solution, two independent temperature regulators were used: first to maintain the QCM crystal at desired temperature, and second to keep the QCM oscillator circuit at fixed temperature. The single regulator consists of a thermoelectric module (TEC) used for both heating and cooling. Two considered TEC driving methods were compared in terms of EMI and their impact on the QCM signal quality. The proposed system was examined for its temperature stabilization capability showing high stability of 11 mKp-p for one hour and the setpoint accuracy of ±15 mK in the full temperature range.

HIV-1 Nef dimers short-circuit immune receptor signaling by activating Tec-family kinases at the host cell membrane.

The HIV-1 virulence factor Nef promotes high-titer viral replication, immune escape, and pathogenicity. Nef interacts with interleukin-2-inducible T-cell kinase (Itk) and Bruton's tyrosine kinase (Btk), two Tec-family kinases expressed in HIV-1 target cells (CD4 T cells and macrophages, respectively). Using a cell-based bimolecular fluorescence complementation assay, here we demonstrate that Nef recruits both Itk and Btk to the cell membrane and induces constitutive kinase activation in transfected 293T cells. Nef homodimerization-defective mutants retained their interaction with both kinases but failed to induce activation, supporting a role for Nef homodimer formation in the activation mechanism. HIV-1 infection up-regulates endogenous Itk activity in SupT1 T cells and donor-derived peripheral blood mononuclear cells. However, HIV-1 strains expressing Nef variants with mutations in the dimerization interface replicated poorly and were significantly attenuated in Itk activation. We conclude that direct activation of Itk and Btk by Nef at the membrane in HIV-infected cells may override normal immune receptor control of Tec-family kinase activity to enhance the viral life cycle.

Structure, function, and inhibitor targeting of HIV-1 Nef-effector kinase complexes.

Antiretroviral therapy has revolutionized the treatment of AIDS, turning a deadly disease into a manageable chronic condition. Life-long treatment is required because existing drugs do not eradicate HIV-infected cells. The emergence of drug-resistant viral strains and uncertain vaccine prospects highlight the pressing need for new therapeutic approaches with the potential to clear the virus. The HIV-1 accessory protein Nef is essential for viral pathogenesis, making it a promising target for antiretroviral drug discovery. Nef enhances viral replication and promotes immune escape of HIV-infected cells but lacks intrinsic enzymatic activity. Instead, Nef works through diverse interactions with host cell proteins primarily related to kinase signaling pathways and endosomal trafficking. This review emphasizes the structure, function, and biological relevance of Nef interactions with host cell protein-tyrosine kinases in the broader context of Nef functions related to enhancement of the viral life cycle and immune escape. Drug discovery targeting Nef-mediated kinase activation has allowed identification of promising inhibitors of multiple Nef functions. Pharmacological inhibitors of Nef-induced MHC-I down-regulation restore the adaptive immune response to HIV-infected cells in vitro and have the potential to enhance immune recognition of latent viral reservoirs as part of a strategy for HIV clearance.

On the functional role of striatal and anterior cingulate GABA+ in stimulus-response binding.

Successful response selection relies on constantly updating stimulus-response associations. The Theory of Event Coding (TEC) proposes that perception and action are conjointly coded in event files, for which fronto-striatal networks seem to play an important role. However, the exact neurobiochemical mechanism behind event file coding has remained unknown. We investigated the functional relevance of the striatal and anterior cingulate (ACC) GABAergic system using magnetic resonance spectroscopy (MRS). Specifically, the striatal and ACC concentrations of GABA+ referenced against N-acetylaspartate (NAA) were assessed in 35 young healthy males, who subsequently performed a standard event file task. As predicted by the TEC, the participants' responses were modulated by pre-established stimulus response bindings in event files. GABA+/NAA concentrations in the striatum and ACC were not correlated with the overall event binding effect. However, higher GABA+/NAA concentrations in the ACC were correlated with stronger event file binding processes in the early phase of the task. This association disappeared by the end of the task. Taken together, our findings show that striatal GABA+ levels does not seem to modulate event file binding, while ACC GABA+ seem to improve event file binding, but only as long as the participants have not yet gathered sufficient task experience. To the best of our knowledge, this is the first study providing direct evidence for the role of striatal and ACC GABA+ in stimulus-response bindings and thus insights into the brain structure-specific neurobiological aspects of the TEC.

Gli3 in fetal thymic epithelial cells promotes thymocyte positive selection and differentiation by repression of Shh.

Gli3 is a Hedgehog (Hh)-responsive transcription factor that can function as a transcriptional repressor or activator. We show that Gli3 activity in mouse thymic epithelial cells (TECs) promotes positive selection and differentiation from CD4+ CD8+ to CD4+ CD8- single-positive (SP4) cells in the fetal thymus and that Gli3 represses Shh Constitutive deletion of Gli3, and conditional deletion of Gli3 from TECs, reduced differentiation to SP4, whereas conditional deletion of Gli3 from thymocytes did not. Conditional deletion of Shh from TECs increased differentiation to SP4, and expression of Shh was upregulated in the Gli3-deficient thymus. Use of a transgenic Hh reporter showed that the Hh pathway was active in thymocytes, and increased in the Gli3-deficient fetal thymus. Neutralisation of endogenous Hh proteins in the Gli3-/- thymus restored SP4 differentiation, indicating that Gli3 in TECs promotes SP4 differentiation by repression of Shh Transcriptome analysis showed that Hh-mediated transcription was increased whereas TCR-mediated transcription was decreased in Gli3-/- thymocytes compared with wild type.

Sub-Auroral and Mid-Latitude GNSS ROTI Performance during Solar Cycle 24 Geomagnetic Disturbed Periods: Towards Storm's Early Sensing.

Geomagnetic storms-triggered by the interaction between Earth's magnetosphere and interplanetary magnetic field, driven by solar activity-are important for many Earth-bound aspects of life. Serious events may impact the electroenergetic infrastructure, but even weaker storms generate noticeable irregularities in the density of ionospheric plasma. Ionosphere electron density gradients interact with electromagnetic radiation in the radiofrequency domain, affecting sub- and trans-ionospheric transmissions. The main objective of the manuscript is to find key features of the storm-induced plasma density behaviour irregularities in regard to the event's magnitude and general geomagnetic conditions. We also aim to set the foundations for the mid-latitude ionospheric plasma density now-casting irregularities. In the manuscript, we calculate the GPS+GLONASS-derived rate of TEC (total electron content) index (ROTI) for the meridional sector of 10-20∘ E, covering the latitudes between 40 and 70∘ N. Such an approach reveals equatorward spread of the auroral TEC irregularities reaching down to mid-latitudes. We have assessed the ROTI performance for 57 moderate-to-severe storms that occurred during solar cycle 24 and analyzed their behaviors in regard to the geomagnetic conditions (described by Kp, Dst, AE, Sym-H and PC indices).

Study of Spatial and Temporal Variations of Ionospheric Total Electron Content in Japan, during 2014-2019 and the 2016 Kumamoto Earthquake.

There are a large number of excellent research cases in Global Navigation Satellite System (GNSS) positioning and disaster prediction in Japan region, where the simulation and prediction of total electron content (TEC) is a powerful research method. In this study, we used the data of the GNSS Earth Observation Network (GEONET) established by the Geographical Survey Institute of Japan (GSI) to compare the performance of two regional ionospheric models in Japan, in which the spherical cap harmonic (SCH) model has the best performance. In this paper, we investigated the spatial and temporal variations of ionospheric TEC in Japan and their relationship with latitude, longitude, seasons, and solar activity. The results show that the TEC in Japan increases as the latitude decreases, with the highest average TEC in spring and summer and the lowest in winter, and has a strong correlation with solar activity. In addition, the observation and analysis of ionospheric disturbances over Japan before the 2016 Kumamoto earthquake and geomagnetic storms showed that GNSS observing of ionospheric TEC seems to be very effective in forecasting natural disasters and monitoring space weather.

Performance Comparison of GeneXpert MTB/RIF and ProbeTec ET Tests for Rapid Molecular Diagnosis of Extrapulmonary Tuberculosis in a Low TB/MDR-TB Incidence Country.

OBJECTIVE: This study evaluated the performance of GeneXpert MTB/RIF (Xpert) and ProbeTec ET (PTec-ET) assays in diagnosing extrapulmonary tuberculosis (EPTB) in Kuwait. MATERIALS AND METHODS: We tested nonrespiratory clinical specimens (n = 3,995) collected from 3,995 patients suspected to have EPTB. These included cavitary fluids (n = 2,054), fine-needle aspirate (FNA)/pus/tissue biopsy (n = 1,461), urine (n = 302), cerebrospinal fluid (CSF, n = 118), and others (n = 60). All specimens were processed for acid-fast bacilli (AFB), culture in mycobacteria growth indicator tube 960 system, and nucleic acid detection by Xpert and PTec-ET according to manufacturer's instructions. RESULTS: Of 3,995 specimens, 95 were AFB-positive, 403 were culture-positive, and an additional 86 samples had histopathology suggestive of TB. Using culture as reference, the sensitivity and specificity values were 88.33 and 97.3% for Xpert and 72.95 and 97.80% for PTec-ET, respectively. Although performance of both tests was comparable in AFB-positive samples, Xpert detected significantly more cases in culture-positive samples. Among culture-negative samples, Xpert detected 18 more cases including 16 with histopathological evidence of TB. Lowest positivity was detected for both tests in cavitary fluids. Xpert performed better than PTec-ET in culture-positive FNA/pus/tissue biopsy and CSF samples. CONCLUSIONS: Although performance of both tests was suboptimal for AFB-negative/culture-positive samples, Xpert performed better than PTec-ET and also detected more cases of AFB-negative/culture-negative/histopathology-positive samples. PTec-ET was positive in 3, while Xpert was positive in all 6 culture-positive CSF specimens for rapid diagnosis of TB meningitis. Xpert was thus superior to PTec-ET or smear microscopy in rapid diagnosis of EPTB.

Lithosphere atmosphere ionosphere coupling associated with the 2019 Mw 7.1 California earthquake using GNSS and multiple satellites.

Global Navigation Satellite System (GNSS)-based Earthquake (EQ) anomalies in the ionosphere and troposphere provide explicit evidences to study the coupling between seismic events, atmosphere, and ionosphere in epicentral breeding regions consequent to the EQ day in the preparation period. EQs are still not predicted, but the space-based EQ anomalies aid in the development of monitoring pre- and post-seismic precursors around the seismogenic zone and associated fault lineament regions. In this paper, tropospheric and ionospheric anomalies are investigated for the July 06, 2019, Mw 7.1 California EQ from GNSS tropospheric delays and Total Electron Content (TEC), respectively. We noticed that atmospheric and ionospheric anomalies from GNSS stations within 5-10 days before the main shock and storm-induced ionospheric variations occur beyond the 5th day after the EQ. Similarly, synchronized and collocated lower atmospheric anomalies are also recorded in the long-term temporal values of SO2 and SO4 within 1-month before and after July 2019, which validates the existence of Lithosphere-Atmosphere-Ionosphere Coupling (LAIC) over the EQ epicenter. On the other hand, EQ anomalies occur during quiet geomagnetic storm activity (Kp < 3; Dst < - 20 nT) and geomagnetic storm triggered high-intensity ionospheric variations during Kp > 3. All these atmospheric and ionospheric perturbations support the development in EQ precursors with satellite measurements, which are indispensable towards the forecasting of future EQ.

Molecular regulatory networks of thymic epithelial cell differentiation.

Functional mature T cells are generated in the thymus. Thymic epithelial cells (TECs) provide the essential microenvironment for T cell development and maturation. According to their function and localization, TECs are roughly divided into cortical TECs (cTECs) and medullary TECs (mTECs), which are responsible for positive and negative selection, respectively. This review summarizes the current understanding of TEC biology, the identification of fetal and adult bipotent TEC progenitors, and the signaling pathways that control the development and maturation of TECs. The understanding of the ontogeny, differentiation, maturation and function of cTECs lags behind that of mTECs. Better understanding TEC biology will provide clues about TEC development and the applications of thymus engineering.