bluuebunny/crossref_metadata_2025 huggingface dataset:
Pre-Digested Protein Enteral Nutritional Supplementation Enhances Recovery of CD4+ T Cells and Repair of Intestinal Barrier in HIV-Infected Immunological Non-Responders
Authors: Geng Shi-Tao , Zhang Jian-Bo , Wang Yue-Xin , Xu Yu , Lu Danfeng , Zhang Zunyue , Gao Ju , Wang Kun-Hua , Kuang Yi-Qun
Published: December 2021

AIDS patients with immune non-response are prone to malnutrition, intestinal barrier damage, thus aggravating chronic immune activation and inflammation. However, nutritional interventions targeting malnutrition may be beneficial to restore immune function, improve clinical outcomes, and reduce mortality remains largely unclear. This work aimed to evaluate the efficacy of a nutritional supplement in HIV-infected immune non-responders (INRs). The subjects received oral supplementation of a pre-digested protein nutrition formula for three months. We show that the CD4+T and CD8+T cell counts were significantly increased after supplementation of the pre-digested enteral nutritional supplement. Among all pro-inflammatory cytokines in the serum, only IL-1β level was significantly decreased, while TNF-β was significantly increased (P< 0.05). The levels of intestinal mucosal damage markers, diamine oxidase (DAO), D-lactic acid (D-lactate), and lipopolysaccharide (LPS), decreased significantly (P< 0.05) after the nutritional intervention. Moreover, at month 3 after the intervention, the body weight, body mass index, albumin, and hemoglobin of all subjects were significantly increased (P < 0.05). The correlation analysis demonstrated a significantly negative correlation of CD4+T cell count with levels of DAO (r = -0.343,P= 0.004), D-lactate (r = -0.250,P= 0.037), respectively, and a significantly positive correlation of IL-1β level with levels of DAO (r = 0.445,P< 0.001), D-lactate (r = 0.523,P< 0.001), and LPS (r = 0.622,P< 0.001). We conclude that the pre-digested enteral nutrition supplement is effective for HIV-infected INRs.
Inborn Errors of Immunity in the Premature Infant: Challenges in Recognition and Diagnosis
Authors: Gordon Scott M. , O’Connell Amy E.
Published: December 2021

Due to heightened awareness and advanced genetic tools, inborn errors of immunity (IEI) are increasingly recognized in children. However, diagnosing of IEI in premature infants is challenging and, subsequently, reports of IEI in premature infants remain rare. This review focuses on how common disorders of prematurity, such as sepsis, necrotizing enterocolitis, and bronchopulmonary dysplasia, can clinically overlap with presenting signs of IEI. We present four recent cases from a single neonatal intensive care unit that highlight diagnostic dilemmas facing neonatologists and clinical immunologists when considering IEI in preterm infants. Finally, we present a conceptual framework for when to consider IEI in premature infants and a guide to initial workup of premature infants suspected of having IEI.
Integrated Lymphopenia Analysis in Younger and Older Patients With Multiple Sclerosis Treated With Cladribine Tablets
Authors: Giovannoni Gavin , Coyle Patricia K. , Vermersch Patrick , Walker Bryan , Aldridge Julie , Nolting Axel , Galazka Andrew , Lemieux Caroline , Leist Thomas P.
Published: December 2021

Cladribine tablets (CladT) preferentially reduce B and T lymphocyte levels. As aging is associated with a decline in immune function, the effect of CladT on lymphocyte levels may differ by age. This post hoc analysis combined data from the Phase 3 CLARITY, CLARITY Extension, and ORACLE-MS studies to examine the effect of age (≤50 or >50 years) on lymphopenia following CladT 3.5 mg/kg (CladT3.5; cumulative dose over 2 years) treatment over 96 weeks. Both CladT3.5 and placebo were given over Weeks 1 and 5 (Year 1 treatment) and Weeks 48 and 52 (Year 2 treatment) from the start of the studies. Absolute lymphocyte count (ALC) and levels of lymphocyte subsets were examined in 1564 patients (Age ≤50 [placebo: N=566; CladT3.5: N=813]; Age >50 [placebo: N=75; CladT3.5: N=110]). In both age groups, following CladT3.5 treatment, nadir for ALC occurred at Week 9 (8 weeks following start of Year 1 treatment) and Week 55 (7 weeks following start of Year 2 treatment) of the 96-week period; for CD19+ B lymphocytes, nadir occurred at Week 9 (Year 1) and Week 52 (Year 2). For CD4+ T lymphocytes, nadir occurred at Week 16 (Year 1) in both age groups, and at Weeks 60 and 72 (Year 2) in the Age ≤50 and >50 groups, respectively. Nadir for CD8+ T lymphocytes occurred at Week 16 (Year 1) and Week 72 (Year 2) in the Age ≤50 group and levels remained in the normal range; nadir occurred at Week 9 (Year 1) and Week 96 (Year 2) in the Age >50 group. Lymphocyte recovery began soon after nadir following CladT3.5 treatment and median levels reached normal range by end of the treatment year in both age groups. By Week 96, ~25% of patients treated with CladT3.5 reported ≥1 episode of Grade ≥3 lymphopenia (Gr≥3L). The rate of certain infections was numerically higher in older versus younger patients who experienced Gr≥3L. In conclusion, CladT3.5 had a similar effect on ALC and lymphocyte subsets in both younger and older patient groups.
The Role of T Lymphocytes in the Pathogenesis of Paroxysmal Nocturnal Hemoglobinuria
Authors: Li Chenyuan , Dong Xifeng , Wang Huaquan , Shao Zonghong
Published: December 2021

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematopoietic stem cell genetic mutation disease that causes defective erythrocyte membrane hemolysis. Its pathologic basis is the mutation of thePIG-Agene, whose product is necessary for the synthesis of glycosylphosphatidylinositol (GPI) anchors; the mutation ofPIG-Agene results in the reduction or deletion of the GPI anchor, which leads to the deficiency of GPI-anchored proteins (GPI-APs), such as CD55 and CD59, which are complement inhibitors. The deficiency of complement inhibitors causes chronic complement-mediated intravascular hemolysis of GPI-anchor-deficient erythrocyte.PIG-Agene mutation could also be found in bone marrow hematopoietic stem cells (HSCs) of healthy people, but they have no growth advantage; only the HSCs withPIG-Agene mutation in PNH patients have this advantage and expand. Besides, HSCs fromPIG-A-knockout mice do not show clonal expansion in bone marrow, soPIG-Amutation cannot explain the clonal advantage of the PNH clone and some additional factors are needed; thus, in recent years, many scholars have put forward the theories of the second hit, and immune escape theory is one of them. In this paper, we focus on how T lymphocytes are involved in immune escape hypothesis in the pathogenesis of PNH.
IgA Plasma Cells Are Long-Lived Residents of Gut and Bone Marrow That Express Isotype- and Tissue-Specific Gene Expression Patterns
Authors: Wilmore Joel R. , Gaudette Brian T. , Gómez Atria Daniela , Rosenthal Rebecca L. , Reiser Sarah Kim , Meng Wenzhao , Rosenfeld Aaron M. , Luning Prak Eline T. , Allman David
Published: December 2021

Antibody secreting plasma cells are made in response to a variety of pathogenic and commensal microbes. While all plasma cells express a core gene transcription program that allows them to secrete large quantities of immunoglobulin, unique transcriptional profiles are linked to plasma cells expressing different antibody isotypes. IgA expressing plasma cells are generally thought of as short-lived in mucosal tissues and they have been understudied in systemic sites like the bone marrow. We find that IgA+ plasma cells in both the small intestine lamina propria and the bone marrow are long-lived and transcriptionally related compared to IgG and IgM expressing bone marrow plasma cells. IgA+ plasma cells show signs of shared clonality between the gut and bone marrow, but they do not recirculate at a significant rate and are found within bone marrow plasma cells niches. These data suggest that systemic and mucosal IgA+ plasma cells are from a common source, but they do not migrate between tissues. However, comparison of the plasma cells from the small intestine lamina propria to the bone marrow demonstrate a tissue specific gene transcription program. Understanding how these tissue specific gene networks are regulated in plasma cells could lead to increased understanding of the induction of mucosal versus systemic antibody responses and improve vaccine design.
Efficient In Vitro Generation of IL-22-Secreting ILC3 From CD34+ Hematopoietic Progenitors in a Human Mesenchymal Stem Cell Niche
Authors: Bennstein Sabrina B. , Weinhold Sandra , Degistirici Özer , Oostendorp Robert A. J. , Raba Katharina , Kögler Gesine , Meisel Roland , Walter Lutz , Uhrberg Markus
Published: December 2021

Innate lymphoid cells (ILCs) and in particular ILC3s have been described to be vital for mucosal barrier functions and homeostasis within the gastrointestinal (GI) tract. Importantly, IL-22-secreting ILC3 have been implicated in the control of inflammatory bowel disease (IBD) and were shown to reduce the incidence of graft-versus-host disease (GvHD) as well as the risk of transplant rejection. Unfortunately, IL-22-secreting ILC3 are primarily located in mucosal tissues and are not found within the circulation, making access to them in humans challenging. On this account, there is a growing desire for clinically applicable protocols for in vitro generation of effector ILC3. Here, we present an approach for faithful generation of functionally competent human ILC3s from cord blood-derived CD34+ hematopoietic progenitors on layers of human mesenchymal stem cells (MSCs) generated in good manufacturing practice (GMP) quality. The in vitro-generated ILC3s phenotypically, functionally, and transcriptionally resemble bona fide tissue ILC3 with high expression of the transcription factors (TF) RorγT, AHR, and ID2, as well as the surface receptors CD117, CD56, and NKp44. Importantly, the majority of ILC3 belonged to the desired effector subtype with high IL-22 and low IL-17 production. The protocol thus combines the advantages of avoiding xenogeneic components, which were necessary in previous protocols, with a high propensity for generation of IL-22-producing ILC3. The present approach is suitable for the generation of large amounts of ILC3 in an all-human system, which could facilitate development of clinical strategies for ILC3-based therapy in inflammatory diseases and cancer.
PD-1 Inhibitors Plus Capecitabine as Maintenance Therapy for Advanced Intrahepatic Cholangiocarcinoma: A Case Report and Review of Literature
Authors: Wang Zhihong , Zeng Tianmei , Li Yong , Zhang Ding , Yuan Zhengang , Huang Mengli , Yang Yuan , Zhou Weiping
Published: December 2021

Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver cancer with a poor prognosis. Recently, an immunotherapy strategy represented by programmed cell death 1 (PD-1) inhibitors has been applied to the systemic treatment of advanced iCCA. However, immunotherapy combined with chemotherapy as first-line maintenance therapy was rarely reported. Our report presented an advanced iCCA patient who had a dramatic response to the PD-1 inhibitor sintilimab combined with gemcitabine plus cisplatin as the first-line therapy and sintilimab combined with capecitabine as maintenance therapy, yielding an ongoing progression-free survival of 16 months.
The Alternative Complement Pathway Is Activated Without a Corresponding Terminal Pathway Activation in Patients With Heart Failure
Authors: Holt Margrethe Flesvig , Michelsen Annika E. , Shahini Negar , Bjørkelund Elisabeth , Bendz Christina Holt , Massey Richard J. , Schjalm Camilla , Halvorsen Bente , Broch Kaspar , Ueland Thor , Gullestad Lars , Nilsson Per H. , Aukrust Pål , Mollnes Tom Eirik , Louwe Mieke C.
Published: December 2021

Objective

Dysregulation of the complement system has been described in patients with heart failure (HF). However, data on the alternative pathway are scarce and it is unknown if levels of factor B (FB) and the C3 convertase C3bBbP are elevated in these patients. We hypothesized that plasma levels of FB and C3bBbP would be associated with disease severity and survival in patients with HF.

Methods

We analyzed plasma levels of FB, C3bBbP, and terminal C5b-9 complement complex (TCC) in 343 HF patients and 27 healthy controls.

Results

Compared with controls, patients with HF had elevated levels of circulating FB (1.6-fold, p < 0.001) and C3bBbP (1.3-fold, p < 0.001). In contrast, TCC, reflecting the terminal pathway, was not significantly increased (p = 0.15 vs controls). FB was associated with NT-proBNP, troponin, eGFR, and i.e., C-reactive protein. FB, C3bBbP and TCC were not associated with mortality in HF during a mean follow up of 4.3 years.

Conclusion

Our findings suggest that in patients with HF, the alternative pathway is activated. However, this is not accompanied by activation of the terminal pathway.
Development of an In Vivo Probe to Track SARS-CoV-2 Infection in Rhesus Macaques
Authors: Madden Patrick J. , Arif Muhammad S. , Becker Mark E. , McRaven Michael D. , Carias Ann M. , Lorenzo-Redondo Ramon , Xiao Sixia , Midkiff Cecily C. , Blair Robert V. , Potter Elizabeth Lake , Martin-Sancho Laura , Dodson Alan , Martinelli Elena , Todd John-Paul M. , Villinger Francois J. , Chanda Sumit K. , Aye Pyone Pyone , Roy Chad J. , Roederer Mario , Lewis Mark G. , Veazey Ronald S. , Hope Thomas J.
Published: December 2021

Infection with the novel coronavirus, SARS-CoV-2, results in pneumonia and other respiratory symptoms as well as pathologies at diverse anatomical sites. An outstanding question is whether these diverse pathologies are due to replication of the virus in these anatomical compartments and how and when the virus reaches those sites. To answer these outstanding questions and study the spatiotemporal dynamics of SARS-CoV-2 infection a method for tracking viral spread in vivo is needed. We developed a novel, fluorescently labeled, antibody-based in vivo probe system using the anti-spike monoclonal antibody CR3022 and demonstrated that it could successfully identify sites of SARS-CoV-2 infection in a rhesus macaque model of COVID-19. Our results showed that the fluorescent signal from our antibody-based probe could differentiate whole lungs of macaques infected for 9 days from those infected for 2 or 3 days. Additionally, the probe signal corroborated the frequency and density of infected cells in individual tissue blocks from infected macaques. These results provide proof of concept for the use of in vivo antibody-based probes to study SARS-CoV-2 infection dynamics in rhesus macaques.
Modelling the Effects of Multiple Fractal Dimensions on the Flocculation and Resuspension Processes of Cohesive Sediment
Authors: Xu Chunyang , Cuthbertson Alan J. S. , Zhou Yan , Dong Ping , Chen Yongping
Published: December 2021

The flocculation of cohesive sediments represents a critical process in coastal sediment transport, with its appropriate representation in numerical models crucial for the prediction of contaminant transport, coastal morphodynamics and engineering problems. In this study, a flocculation model considering the effects of multiple fractal dimensions is incorporated into a two-phase numerical modelling framework and used to investigate the effects of spatio-temporal variations in sediment concentrations on the temporal evolution of local floc sizes. Initially, the model is applied to simulate the aggregation of clay suspensions in a vertical grid-stirred settling column, with results confirming the importance of multiple fractal dimensions when predicting the time evolution of floc sizes. The adoption of multiple fractal dimensions, in particular, allows the two-phase numerical model to better match the measured settling column data with improved overall correlation. This is especially the case when predicting initial floc size growth during the early period of settling when the flocs tend to adjust more rapidly to their equilibrium sizes. The two-phase model is then applied to simulate field measurements of mud resuspension process in a tidally driven channel. Again, by considering multiple fractal dimensions within the flocculation model, better agreement is obtained between observed and modelled suspended sediment concentrations, while predicted floc sizes are also in general accord with previous field measurements made within the same estuary.
Postulating the Modality of Integrative Taxonomy in Describing the Cryptic Congener Pampus griseus (Cuvier) and Systematics of the Genus Pampus (Perciformes: Stromateidae)
Authors: Roul Subal Kumar , Jeena N. S. , Kumar Rajan , Vinothkumar R. , Rahangdale Shikha , Rahuman Summaya , Ghosh Shubhadeep , Rohit Prathibha , Gopalakrishnan Achamveetil
Published: December 2021

Pomfrets (genus Pampus), a highly commercial fishery resource distributed in the Indo-Western Pacific that includes Lessepsian migrants, have witnessed a series of systematic reforms. In this study, based on comprehensive sampling spanning type localities and coevals in the Northern Indian Ocean, the cryptic and valid species Stromateus griseus is resurrected from the synonymy and re-described as Pampus griseus (New Combination) based on 35 specimens from the Bay of Bengal, corroborated by a molecular analysis, which indicated a confined distribution of the species. The Bayesian phylogeny of the genus was reconstructed, incorporating redressed barcodes (582 nucleotides) and concatenated mitochondrial gene sequence data (1,822 nucleotides) generated from the recorded species P. candidus, P. chinensis and the neophyte along with sequences from GenBank entrusting the latest literature. The phylograms differed in topology as for seven valid species, and the one predicated on the concatenated data erected a highly supported polytomous clade for the P. cinereus complex (P. griseus, P. cinereus, and P. candidus) which shares synapomorphies. Pampus argenteus and P. minor, together, formed a sister clade to the rest. Climate-driven vicariant events during glacial epochs and the Indo-Pacific Barrier effect can be the drivers behind the Indian and Pacific Ocean sister lineages in P. chinensis. A multivariate analysis isolated the cryptic species from its congeners. This article portrays the systematics revision of genus Pampus with an integrative taxonomic approach compiling distinctive molecular, morphological, and anatomical features, revised key for species identification, taxonomic archives of Indian stromateids, and winds up with specific remarks.
Association of Prescription With Body Composition and Patient Outcomes in Incident Peritoneal Dialysis Patients
Authors: Verger Christian , Ronco Claudio , Van Biesen Wim , Heaf James , Vrtovsnik François , Vera Rivera Manel , Puide Ilze , Azar Raymond , Gauly Adelheid , Atiye Saynab , De los Ríos Tatiana
Published: December 2021

Objective: The nutritional status of patients on peritoneal dialysis (PD) is influenced by patient- and disease-related factors and lifestyle. This analysis evaluated the association of PD prescription with body composition and patient outcomes in the prospective incident Initiative for Patient Outcomes in Dialysis–Peritoneal Dialysis (IPOD-PD) patient cohort.

Design and Methods: In this observational, international cohort study with longitudinal follow-up of 1,054 incident PD patients, the association of PD prescription with body composition was analyzed by using the linear mixed models, and the association of body composition with death and change to hemodialysis (HD) by means of a competing risk analysis combined with a spline analysis. Body composition was regularly assessed with the body composition monitor, a device applying bioimpedance spectroscopy.

Results: Age, time on PD, and the use of hypertonic and polyglucose solutions were significantly associated with a decrease in lean tissue index (LTI) and an increase in fat tissue index (FTI) over time. Competing risk analysis revealed a U-shaped association of body mass index (BMI) with the subdistributional hazard ratio (HR) for risk of death. High LTI was associated with a lower subdistributional HR, whereas low LTI was associated with an increased subdistributional HR when compared with the median LTI as a reference. High FTI was associated with a higher subdistributional HR when compared with the median as a reference. Subdistributional HR for risk of change to HD was not associated with any of the body composition parameters. The use of polyglucose or hypertonic PD solutions was predictive of an increased probability of change to HD, and the use of biocompatible solutions was predictive of a decreased probability of change to HD.

Conclusion: Body composition is associated with non-modifiable patient-specific and modifiable treatment-related factors. The association between lean tissue and fat tissue mass and death and change to HD in patients on PD suggests developing interventions and patient counseling to improve nutritional markers and, ultimately, patient outcomes.

Study Registration: The study has been registered at Clinicaltrials.gov (NCT01285726).
Development and Validation of a Nomogram Incorporating Colloid Osmotic Pressure for Predicting Mortality in Critically Ill Neurological Patients
Authors: Lv Bo , Hu Linhui , Fang Heng , Sun Dayong , Hou Yating , Deng Jia , Zhang Huidan , Xu Jing , He Linling , Liang Yufan , Chen Chunbo
Published: December 2021

Backgrounds: The plasma colloid osmotic pressure (COP) values for predicting mortality are not well-estimated. A user-friendly nomogram could predict mortality by incorporating clinical factors and scoring systems to facilitate physicians modify decision-making when caring for patients with serious neurological conditions.

Methods: Patients were prospectively recruited from March 2017 to September 2018 from a tertiary hospital to establish the development cohort for the internal test of the nomogram, while patients recruited from October 2018 to June 2019 from another tertiary hospital prospectively constituted the validation cohort for the external validation of the nomogram. A multivariate logistic regression analysis was performed in the development cohort using a backward stepwise method to determine the best-fit model for the nomogram. The nomogram was subsequently validated in an independent external validation cohort for discrimination and calibration. A decision-curve analysis was also performed to evaluate the net benefit of the insertion decision using the nomogram.

Results: A total of 280 patients were enrolled in the development cohort, of whom 42 (15.0%) died, whereas 237 patients were enrolled in the validation cohort, of which 43 (18.1%) died. COP, neurological pathogenesis and Acute Physiology and Chronic Health Evaluation II (APACHE II) score were predictors in the prediction nomogram. The derived cohort demonstrated good discriminative ability, and the area under the receiver operating characteristic curve (AUC) was 0.895 [95% confidence interval (CI), 0.840–0.951], showing good correction ability. The application of this nomogram to the validation cohort also provided good discrimination, with an AUC of 0.934 (95% CI, 0.892–0.976) and good calibration. The decision-curve analysis of this nomogram showed a better net benefit.

Conclusions : A prediction nomogram incorporating COP, neurological pathogenesis and APACHE II score could be convenient in predicting mortality for critically ill neurological patients.
T Cells Targeting SARS-CoV-2: By Infection, Vaccination, and Against Future Variants
Authors: Nguyen Thi H. O. , Cohen Carolyn A. , Rowntree Louise C. , Bull Maireid B. , Hachim Asmaa , Kedzierska Katherine , Valkenburg Sophie A.
Published: December 2021

T cell responses are a key cornerstone to viral immunity to drive high-quality antibody responses, establishing memory for recall and for viral clearance. Inefficient recruitment of T cell responses plays a role in the development of severe COVID-19 and is also represented by reduced cellular responses in men, children, and diversity compared with other epitope-specific subsets and available T cell receptor diversity. SARS-CoV-2-specific T cell responses are elicited by multiple vaccine formats and augmented by prior infection for hybrid immunity. Epitope conservation is relatively well-maintained leading to T cell crossreactivity for variants of concern that have diminished serological responses.
Wound Vitality in Decomposed Bodies: New Frontiers Through Immunohistochemistry
Authors: Bertozzi Giuseppe , Ferrara Michela , La Russa Raffaele , Pollice Giovanni , Gurgoglione Giovanni , Frisoni Paolo , Alfieri Letizia , De Simone Stefania , Neri Margherita , Cipolloni Luigi
Published: December 2021

Background: The question about wound vitality and the estimation of wound age of production are two of the classic investigation fields of forensic sciences. To answer this, the techniques most frequently used in research studies are immunohistochemistry (IHC), molecular biology, and biochemistry. Despite the great data on the literature about the usefulness of IHC in forensic pathology, there is always a request for further studies, especially on tissues altered by putrefactive phenomena. In fact, the degradation of the tissues is intended as the main limiting factor to the use of this technique.

Scope: The aim of this pilot study was to evaluate the immunohistochemical behavior of samples collected from decomposed bodies (in different putrefaction phases) and to relate these findings to wound vitality and postmortem interval.

Materials and Methods: Samples of skin and soft tissues were collected during autopsies, which were executed on decomposed bodies, whose cause of death was concluded to be traumatic. An immunohistochemical study was performed using antibodies against CD15, CD45, IL-15, tryptase, and glycophorin-A MMPs (endopeptidases involved in degrading extracellular matrix proteins: MMP-9 and MMP-2). An immunohistochemistry (IHC) reaction was evaluated according to a qualitative method as the following legend: (0): not expressed, (+): isolated and disseminated expression, (++): expression in groups or widespread foci, and (+++): widespread expression.

Results: Most of the tested markers (tryptase, glycophorin, IL15, CD 15, CD 45, and MMP9) showed to be highly expressed in the tissue of putrefied skin for 15 days.

Discussion and Conclusion: Although certainly inconclusive, this experimental application demonstrated that a nonexclusive but combined use of multiple antibodies is appropriate to verify wound vitality in decomposed bodies. Among them, GPA exhibited major reliability.
Obstructive Sleep Apnea Syndrome: The Effect of Acute and Chronic Responses of Exercise
Authors: Stavrou Vasileios T. , Astara Kyriaki , Tourlakopoulos Konstantinos N. , Papayianni Eirini , Boutlas Stylianos , Vavougios George D. , Daniil Zoe , Gourgoulianis Konstantinos I.
Published: December 2021

Obstructive Sleep Apnea Syndrome (OSAS) is a sleep disorder with high prevalence in general population, but alarmingly low in clinicians' differential diagnosis. We reviewed the literature on PubMed and Scopus from June 1980–2021 in order to describe the altered systematic pathophysiologic mechanisms in OSAS patients as well as to propose an exercise program for these patients. Exercise prevents a dysregulation of both daytime and nighttime cardiovascular autonomic function, reduces body weight, halts the onset and progress of insulin resistance, while it ameliorates excessive daytime sleepiness, cognitive decline, and mood disturbances, contributing to an overall greater sleep quality and quality of life.
The MocR/GabR Ectoine and Hydroxyectoine Catabolism Regulator EnuR: Inducer and DNA Binding
Authors: Hermann Lucas , Dempwolff Felix , Steinchen Wieland , Freibert Sven-Andreas , Smits Sander H. J. , Seubert Andreas , Bremer Erhard
Published: December 2021

The compatible solutes ectoine and 5-hydroxyectoine are widely synthesized by bacteria as osmostress protectants. These nitrogen-rich tetrahydropyrimidines can also be exploited as nutrients by microorganisms. Many ectoine/5-hydroxyectoine catabolic gene clusters are associated with a regulatory gene (enuR: ectoine nutrient utilization regulator) encoding a repressor protein belonging to the MocR/GabR sub-family of GntR-type transcription factors. Focusing on EnuR from the marine bacterium Ruegeria pomeroyi, we show that the dimerization of EnuR is mediated by its aminotransferase domain. This domain can fold independently from its amino-terminal DNA reading head and can incorporate pyridoxal-5′-phosphate (PLP) as cofactor. The covalent attachment of PLP to residue Lys302 of EnuR was proven by mass-spectrometry. PLP interacts with system-specific, ectoine and 5-hydroxyectoine-derived inducers: alpha-acetyldiaminobutyric acid (alpha-ADABA), and hydroxy-alpha-acetyldiaminobutyric acid (hydroxy-alpha-ADABA), respectively. These inducers are generated in cells actively growing with ectoines as sole carbon and nitrogen sources, by the EutD hydrolase and targeted metabolic analysis allowed their detection. EnuR binds these effector molecules with affinities in the low micro-molar range. Studies addressing the evolutionary conservation of EnuR, modelling of the EnuR structure, and docking experiments with the inducers provide an initial view into the cofactor and effector binding cavity. In this cavity, the two high-affinity inducers for EnuR, alpha-ADABA and hydroxy-alpha-ADABA, are positioned such that their respective primary nitrogen group can chemically interact with PLP. Purified EnuR bound with micro-molar affinity to a 48 base pair DNA fragment containing the sigma-70 type substrate-inducible promoter for the ectoine/5-hydroxyectoine importer and catabolic gene cluster. Consistent with the function of EnuR as a repressor, the core elements of the promoter overlap with two predicted EnuR operators. Our data lend themselves to a straightforward regulatory model for the initial encounter of EnuR-possessing ectoine/5-hydroxyectoine consumers with environmental ectoines and for the situation when the external supply of these compounds has been exhausted by catabolism.
Co-circulation of Orthobunyaviruses and Rift Valley Fever Virus in Mauritania, 2015
Authors: Cichon Nicole , Barry Yahya , Stoek Franziska , Diambar Abdellah , Ba Aliou , Ziegler Ute , Rissmann Melanie , Schulz Jana , Haki Mohamed L. , Höper Dirk , Doumbia Baba A. , Bah Mohamed Y. , Groschup Martin H. , Eiden Martin
Published: December 2021

Ngari virus (NRIV) has been mostly detected during concurrent outbreaks of Rift Valley fever virus (RVFV). NRIV is grouped in the genus Orthobunyavirus within the Bunyaviridae family and RVFV in the genus Phlebovirus in the family Phenuiviridae. Both are zoonotic arboviruses and can induce hemorrhagic fever displaying the same clinical picture in humans and small ruminants. To investigate if NRIV and its parental viruses, Bunyamwera virus (BUNV) and Batai virus (BATV), played a role during the Mauritanian RVF outbreak in 2015/16, we analyzed serum samples of sheep and goats from central and southern regions in Mauritania by quantitative real-time RT-PCR, serum neutralization test (SNT) and ELISA. 41 of 458 samples exhibited neutralizing reactivity against NRIV, nine against BATV and three against BUNV. Moreover, complete virus genomes from BUNV could be recovered from two sheep as well as two NRIV isolates from a goat and a sheep. No RVFV-derived viral RNA was detected, but 81 seropositive animals including 22 IgM-positive individuals were found. Of these specimens, 61 samples revealed antibodies against RVFV and at least against one of the three orthobunyaviruses. An indirect ELISA based on NRIV/BATV and BUNV derived Gc protein was established as complement to SNT, which showed high performance regarding NRIV, but decreased sensitivity and specificity regarding BATV and BUNV. Moreover, we observed high cross-reactivity among NRIV and BATV serological assays. Taken together, the data indicate the co-circulation of at least BUNV and NRIV in the Mauritanian sheep and goat populations.
Industrial Composting of Sewage Sludge: Study of the Bacteriome, Sanitation, and Antibiotic-Resistant Strains
Authors: López-González Juan A. , Estrella-González María J. , Lerma-Moliz Rosario , Jurado Macarena M. , Suárez-Estrella Francisca , López María J.
Published: December 2021

Wastewater treatment generates a huge amount of sewage sludge, which is a source of environmental pollution. Among the alternatives for the management of this waste, industrial composting stands out as one of the most relevant. The objective of this study was to analyze the bacterial population linked to this process and to determine its effectiveness for the reduction, and even elimination, of microorganisms and pathogens present in these organic wastes. For this purpose, the bacteriome and the fecal bacteria contamination of samples from different sewage sludge industrial composting facilities were evaluated. In addition, fecal bacteria indicators and pathogens, such as Salmonella, were isolated from samples collected at key stages of the process and characterized for antibiotic resistance to macrolide, β-lactam, quinolone, and aminoglycoside families. 16S rRNA phylogeny data revealed that the process clearly evolved toward a prevalence of Firmicutes and Actinobacteria phyla, removing the fecal load. Moreover, antibiotic-resistant microorganisms present in the raw materials were reduced, since these were isolated only in the bio-oxidative phase. Therefore, industrial composting of sewage sludge results in a bio-safe final product suitable for use in a variety of applications.
Bacteriome of Moist Smokeless Tobacco Products Consumed in India With Emphasis on the Predictive Functional Potential
Authors: Sajid Mohammad , Srivastava Sonal , Kumar Amit , Kumar Anuj , Singh Harpreet , Bharadwaj Mausumi
Published: December 2021

Smokeless tobacco products (STPs) carry assorted microbial population that contributes to carcinogens synthesis like tobacco-specific nitrosamines (TSNAs). Extensive exploration of microbiota-harboring STPs is required to understand their full carcinogenic potential. Here, we applied 16S rRNA gene sequencing to investigate bacteriome present in moist STPs immensely consumed in India (Khaini, Moist-snuff, Qiwam, and Snus). Further, the functional metagenome was speculated by PICRUSt (Phylogenetic Investigation of Communities by Reconstruction of Unobserved States) to assign the abundance of genes related to nitrogen metabolism, bacterial toxins, antibiotic drug resistance and other pro-inflammatory molecules. Highly diverse bacterial communities were observed in all moist STPs. Taxonomic analysis revealed a total of 549 genera belonging to four major phyla Proteobacteria, Firmicutes, Bacteroidetes and Actinobacteria. Overall, the core bacterial genera Acinetobacter, Bacillus, Prevotella, Acetobacter, Lactobacillus, Paracoccus, Flavobacterium, and Bacteroides were significantly abundant in moist STPs. Elevated moisture-holding products like Moist-snuff and Qiwam harbor rich bacterial species diversity and showed similar bacteriome composition. Furthermore, Qiwam products showed the highest level of genes associated with nitrogen metabolism, antibiotic resistance, toxins, and pro-inflammation (predicted by PICRUSt) which can contribute to the synthesis of TSNAs and induction of oral cancer. The present broad investigation of moist STPs-associated bacteriome prevalence and their detailed metabolic potential will provide novel insight into the oral carcinogenesis induced by STPs.
Genome Characteristics Reveal the Biocontrol Potential of Actinobacteria Isolated From Sugarcane Rhizosphere
Authors: Wang Zhen , Solanki Manoj Kumar , Yu Zhuo-Xin , Anas Muhammad , Dong Deng-Feng , Xing Yong-Xiu , Malviya Mukesh Kumar , Pang Fei , Li Yang-Rui
Published: December 2021

To understand the beneficial interaction of sugarcane rhizosphere actinobacteria in promoting plant growth and managing plant diseases, this study investigated the potential role of sugarcane rhizospheric actinobacteria in promoting plant growth and antagonizing plant pathogens. We isolated 58 actinobacteria from the sugarcane rhizosphere, conducted plant growth-promoting (PGP) characteristics research, and tested the pathogenic fungi in vitro. Results showed that BTU6 (Streptomyces griseorubiginosus), the most representative strain, regulates plant defense enzyme activity and significantly enhances sugarcane smut resistance by regulating stress resistance-related enzyme (substances (POD, PAL, PPO, TP) in sugarcane) activity in sugarcane. The genomic evaluation indicated that BTU6 has the ability to biosynthesize chitinase, β-1,3-glucanase, and various secondary metabolites and plays an essential role in the growth of sugarcane plants under biotic stress. Potential mechanisms of the strain in improving the disease resistance of sugarcane plants and its potential in biodegrading exogenous chemicals were also revealed. This study showed the importance of sugarcane rhizosphere actinobacteria in microbial ecology and plant growth promotion.
The Possible Link Between Manufacturing and Probiotic Efficacy; a Molecular Point of View on Bifidobacterium
Authors: Duboux Stéphane , Van Wijchen Myrthe , Kleerebezem Michiel
Published: December 2021

Probiotics for food or supplement use have been studied in numerous clinical trials, addressing a broad variety of diseases, and conditions. However, discrepancies were observed in the clinical outcomes stemming from the use of lactobacillaceae and bifidobacteria strains. These differences are often attributed to variations in the clinical trial protocol like trial design, included target population, probiotic dosage, or outcome parameters measured. However, a contribution of the methods used to produce the live bioactive ingredients should not be neglected as a possible additional factor in the observed clinical outcome variations. It is well established that manufacturing conditions play a role in determining the survival and viability of probiotics, but much less is known about their influence on the probiotic molecular composition and functionality. In this review, we briefly summarize the evidence obtained for Lacticaseibacillus rhamnosus GG and Lactiplantibacillus plantarum WCFS1, highlighting that expression and presence of probiotic niche factor (NF) and/or effector molecules (EM) may be altered during production of those two well-characterized lactobacillaceae probiotic strains. Subsequently, we summarize in more depth what is the present state of knowledge about bifidobacterial probiotic NF and EM; how their expression may be modified by manufacturing related environmental factors and how that may affect their biological activity in the host. This review highlights the importance of gathering knowledge on probiotic NF and EM, to validate them as surrogate markers of probiotic functionality. We further propose that monitoring of validated NF and/or EM during production and/or in the final preparation could complement viable count assessments that are currently applied in industry. Overall, we suggest that implementation of molecular level quality controls (i.e., based on validated NF and EM), could provide mode of action based in vitro tests contributing to better control the health-promoting reliability of probiotic products.
Bioinspired Networks of Communicating Synthetic Protocells
Authors: Grimes Patrick J. , Galanti Agostino , Gobbo Pierangelo
Published: December 2021

The bottom-up synthesis of cell-like entities or protocells from inanimate molecules and materials is one of the grand challenges of our time. In the past decade, researchers in the emerging field of bottom-up synthetic biology have developed different protocell models and engineered them to mimic one or more abilities of biological cells, such as information transcription and translation, adhesion, and enzyme-mediated metabolism. Whilst thus far efforts have focused on increasing the biochemical complexity of individual protocells, an emerging challenge in bottom-up synthetic biology is the development of networks of communicating synthetic protocells. The possibility of engineering multi-protocellular systems capable of sending and receiving chemical signals to trigger individual or collective programmed cell-like behaviours or for communicating with living cells and tissues would lead to major scientific breakthroughs with important applications in biotechnology, tissue engineering and regenerative medicine. This mini-review will discuss this new, emerging area of bottom-up synthetic biology and will introduce three types of bioinspired networks of communicating synthetic protocells that have recently emerged.
Sensitivity of Visual System in 5-Day “Dry” Immersion With High-Frequency Electromyostimulation
Authors: Shoshina Irina , Zelenskaya Inna , Karpinskaia Valeriia , Shilov Yuri , Tomilovskaya Elena
Published: December 2021

The aim of this work was to study the sensitivity of the visual system in 5-day “dry” immersion with a course of high-frequency electromyostimulation (HFEMS) and without it. “Dry” immersion (DI) is one of the most effective models of microgravity. DI reproduces three basic effects of weightlessness: physical inactivity, support withdrawal and elimination of the vertical vascular gradient. The “dry” immersion included in the use of special waterproof and highly elastic fabric on of immersion in a liquid similar in density to the tissues of the human body. The sensitivity of the visual system was assessed by measuring contrast sensitivity and magnitude of the Müller-Lyer illusion. The visual contrast sensitivity was measured in the spatial frequency range from 0.4 to 10.0 cycles/degree. The strength of visual illusion was assessed by means of motor response using “tracking.” Measurements were carried out before the start of immersion, on the 1st, 3rd, 5th days of DI, and after its completion. Under conditions of “dry” immersion without HFEMS, upon the transition from gravity to microgravity conditions (BG and DI1) we observed significant differences in contrast sensitivity in the low spatial frequency range, whereas in the experiment with HFEMS—in the medium spatial frequency range. In the experiment without HFEMS, the Müller-Lyer illusion in microgravity conditions was absent, while in the experiment using HFEMS it was significantly above zero at all stages. Thus, we obtained only limited evidence in favor of the hypothesis of a possible compensating effect of HFEMS on changes in visual sensitivity upon the transition from gravity to microgravity conditions and vice versa. The study is a pilot and requires further research on the effect of HFEMS on visual sensitivity.
Neurotensin Attenuates Nociception by Facilitating Inhibitory Synaptic Transmission in the Mouse Spinal Cord
Authors: Zhang Ming-Ming , Feng Yu-Peng , Qiu Xin-Tong , Chen Tao , Bai Yang , Feng Jia-Ming , Wang Jun-Da , Chen Yan , Zhang Ming-Zhe , Duan Hao-Kai , Zhao Mingwei , Teng Yi-Hui , Cao Jing , Zang Wei-Dong , Yang Kun , Li Yun-Qing
Published: December 2021

Neurotensin (NT) is an endogenous tridecapeptide in the central nervous system. NT-containing neurons and NT receptors are widely distributed in the spinal dorsal horn (SDH), indicating their possible modulatory roles in nociception processing. However, the exact distribution and function of NT, as well as NT receptors (NTRs) expression in the SDH, have not been well documented. Among the four NTR subtypes, NTR2 is predominantly involved in central analgesia according to previous reports. However, the expression and function of NTR2 in the SDH has not yet been directly elucidated. Specifically, it remains unclear how NT-NTR2 interactions contribute to NT-mediated analgesia. In the present study, by using immunofluorescent histochemical staining and immunohistochemical staining with in situ hybridization histochemical staining, we found that dense NT- immunoreactivity (NT-ir) and moderate NTR2-ir neuronal cell bodies and fibers were localized throughout the superficial laminae (laminae I-II) of the SDH at the light microscopic level. In addition, γ-aminobutyric acid (GABA) and NTR2 mRNA were colocalized in some neuronal cell bodies, predominantly in lamina II. Using confocal and electron microscopy, we also observed that NT-ir terminals made both close contacts and asymmetrical synapses with the local GABA-ir neurons. Second, electrophysiological recordings showed that NT facilitated inhibitory synaptic transmission but not glutamatergic excitatory synaptic transmission. Inactivation of NTR2 abolished the NT actions on both GABAergic and glycinergic synaptic release. Moreover, a behavioral study revealed that intrathecal injection of NT attenuated thermal pain, mechanical pain, and formalin induced acute inflammatory pain primarily by activating NTR2. Taken together, the present results provide direct evidence that NT-containing terminals and fibers, as well as NTR2-expressing neurons are widely distributed in the spinal dorsal horn, GABA-containing neurons express NTR2 mainly in lamina II, GABA coexists with NTR2 mainly in lamina II, and NT may directly increase the activity of local inhibitory neurons through NTR2 and induce analgesic effects.
Comparison of Endovascular Embolization Plus Simultaneous Microsurgical Resection vs. Primary Microsurgical Resection for High-Grade Brain Arteriovenous Malformations
Authors: Wang Mingze , Lin Fa , Qiu Hancheng , Cao Yong , Wang Shuo , Zhao Jizong
Published: December 2021

Aim: It remains a challenge in surgical treatments of brain arteriovenous malformations (AVMs) in Spetzler-Martin Grade (SMG) IV and V to achieve both optimal neurological outcomes and complete obliteration. The authors reported a series of patients with AVMs in SMG IV and V who underwent a surgical paradigm of endovascular embolization and simultaneous microsurgical resection based on the one-staged hybrid operation.

Methods: Participants in the multicenter prospective clinical trial (NCT 03774017) between January 2016 and December 2019 were enrolled. Patients who received endovascular embolization plus microsurgical resection (EE+MRS) and those who received intraoperative digital subtraction angiography plus microsurgical resection (iDSA+MRS) were divided into two groups. Information on clinical features, operative details, and clinical outcomes were extracted from the database. Deterioration of neurological deficits (DNDs) was defined as the primary outcome, which represented neurological outcomes. The time of microsurgical operation and blood loss were defined as the secondary outcomes representing microsurgical risks and difficulties. Outcomes and technical details were compared between groups.

Results: Thirty-eight cases (male: female = 23:15) were enrolled, with 24 cases in the EE+MRS group and 14 in the iDSA+MRS group. Five cases (13.2%) were in SMG V and 33 cases (86.8%) were in SMG IV. Fourteen cases (36.8%) underwent the paradigm of microsurgical resection plus intraoperative DSA. Twenty-four cases (63.2%, n = 24) underwent the paradigm of endovascular embolization plus simultaneous microsurgical resection. Degradations of SMG were achieved in 15 cases. Of the cases, two cases got the residual nidus detected via intraoperative DSA and resected. Deterioration of neurological deficits occurred in 23.7% of cases (n = 9) when discharged, and in 13.5, 13.5, 8.1% of cases at the follow-ups of 3, 6, and 12 months, respectively, without significant difference between groups (P > 0.05). Intracranial hemorrhagic complications were reported in three cases (7.9%) of the EE+MRS group only. The embolization did not significantly affect the surgical time and intraoperative blood loss. The subtotal embolization or the degradation of size by 2 points resulted in no DNDs.

Conclusions: The paradigms based on the one-staged hybrid operation were practical and effective in treating high-grade AVMs. Appropriate intraoperative embolization could help decrease operative risks and difficulties and improve neurological outcomes.