bluuebunny/crossref_metadata_2025 huggingface dataset:
Response of Soil Respiration and Its Components to Precipitation Exclusion in Vitex negundo Var. Heterophylla Shrubland of the Middle Taihang Mountain in North China
Authors: Shen Huitao , Zhang Lingkai , Meng Henan , Zheng Zhenhua , Zhao Yanxia , Zhang Tao
Published: July 2021

Assessing the response of soil heterotrophic and autotrophic respiration to climate change is critical for forecasting terrestrial carbon cycle behavior in the future. In the present study, we conducted a drought experiment in Vitexnegundo var. heterophylla shrub ecosystem of the Middle Taihang Mountain. Three precipitation manipulation treatments (natural conditions/ambient precipitation (CK), reduced precipitation by 30% (PE30), and reduced precipitation by 60% (PE60)) were used to study the impact of different levels of precipitation exclusion on total soil respiration (Rs) and its heterotrophic (Rh) and autotrophic (Ra) components. Our results showed that the rates of Rs and its components were significantly decreased under the precipitation exclusion treatments. The proportion of Rh in Rs reduced from 72.6% for CK to 71.9% under PE60. The annual cumulative C fluxes of Rs decreased by 47.8 g C m−2 in PE30 and 106.0 g C m−2 in PE60, respectively. An exponential relationship was observed between the rate of each soil respiration component and soil temperature in all treatments ( p < 0.01). Moreover, each soil respiration component rate was better represented by a quadratic model which included soil moisture ( p < 0.01). However, including both of soil temperature and soil moisture did not explain more variation in soil respiration components compared than the regression model with soil moisture only. In addition, excluding precipitation increased the temperature sensitivity (Q10 values) of Rs and its Ra and Rh components compared to the control. Collectively, our findings suggest that increased drought will inhibit the release of carbon from the soil to the atmosphere, and will likely decrease the contribution of Rh to Rs in this semiarid shrubland ecosystem.
A Novel de novo Mutation in EBF3 Associated With Hypotonia, Ataxia, and Delayed Development Syndrome in a Chinese Boy
Authors: Huang Yanru , Mei Libin , Wang Yangdan , Ye Huiming , Ma Xiaomin , Zhang Jian , Cai Meijiao , Li Ping , Ge Yunsheng , Zhou Yulin
Published: July 2021

Objective

Global developmental delay has markedly high phenotypic and genetic heterogeneity, and is a great challenge for clinical diagnosis. Hypotonia, ataxia, and delayed development syndrome (HADDS), first reported in 2017, is one type of global development delay. The aim of the present study was to investigate the genetic etiology of a Chinese boy with global developmental delay.

Methods

We combined clinical and imaging phenotyping with trio whole-exome sequencing and Sanger sequencing to the patient and his clinically unaffected parents. A luciferase reporter and immunofluorescence were performed to detect the effect of mutation on transcriptional activity and subcellular localization.

Results

The patient presented with several previously unreported symptoms in the patients with HADDS, including hemangiomas, mild hearing abnormalities and tracheomalacia. A novel EBF3 c.589A > G missense mutation (p.Asn197Asp, p.N197D) was identified in the patient but not in his parents. By constructing the plasmid and transfecting HEK293T cells, EBF3-N197D mutant showed impaired activation of luciferase reporter expression of the p21 promoter, and the mutant affected its entry into the nucleus.

Conclusion

To the best of our knowledge, this is the first report of EBF3 pathogenic mutation which associated with HADDS in the Chinese population. Our results expand the phenotypes and pathogenic mutation spectrum of HADDS, thus potentially facilitating the clinical diagnosis and genetic counseling of HADDS patients.
Integrated Analysis of Hepatic miRNA and mRNA Expression Profiles in the Spontaneous Reversal Process of Liver Fibrosis
Authors: Tai Yang , Zhao Chong , Lan Tian , Zhang Linhao , Xiao Yang , Tong Huan , Liu Rui , Tang Chengwei , Gao Jinhang
Published: July 2021

Liver fibrosis results from the imbalance between extracellular matrix (ECM) production and degradation, which is a common pathological consequence of various chronic liver diseases. Although many miRNAs have been reported in liver fibrosis progression, miRNA-mRNA interactions in its reversal process remain to be elucidated. In the current study, we performed an integrated analysis of miRNA and mRNA expression profiles in the mouse model with the spontaneous reversal potency of liver fibrosis. A total of 102 miRNA and 2,845 mRNAs showed significant differential expression in reversal mice compared to fibrotic mice. Moreover, 3,769 putative negatively correlated miRNA-mRNA pairs were revealed to be potentially implicated in the biological function regulation of small molecule metabolism and ECM organization. By integrating miRNA-mRNA regulatory networks, mmu-miR-1843a-5p, mmu-miR-193a-5p, mmu-miR-194-2-3p, and mmu-miR-30c-2-3p were identified as lysyl oxidases-specific miRNAs that were correlated with fibrosis reversal. Our results provided potential candidate targets for the treatment of liver fibrosis.
Genomic and Immunologic Correlates of Indoleamine 2,3-Dioxygenase Pathway Expression in Cancer
Authors: Panda Anshuman , Ganesan Shridar
Published: July 2021

Immune checkpoint blockade leads to unprecedented responses in many cancer types. An alternative method of unleashing anti-tumor immune response is to target immunosuppressive metabolic pathways like the indoleamine 2,3-dioxygenase (IDO) pathway. Despite promising results in Phase I/II clinical trials, an IDO-1 inhibitor did not show clinical benefit in a Phase III clinical trial. Since, a treatment can be quite effective in a specific subset without being effective in the whole cancer type, it is important to identify the subsets of cancers that may benefit from IDO-1 inhibitors. In this study, we looked for the genomic and immunologic correlates of IDO pathway expression in cancer using the Cancer Genome Atlas (TCGA) dataset. Strong CD8+ T-cell infiltration, high mutation burden, and expression of exogenous viruses [Epstein-Barr virus (EBV), Human papilloma virus (HPV), and Hepatitis C virus (HCV)] or endogenous retrovirus (ERV3-2) were associated with over-expression of IDO-1 in most cancer types, IDO-2 in many cancer types, and TDO-2 in a few cancer types. High mutation burden in ER+ HER2− breast cancer, and ERV3-2 expression in ER− HER2− and HER2+ breast, colon, and endometrial cancers were associated with over-expression of all three genes. These results may have important implications for guiding development clinical trials of IDO-1 inhibitors.
Social Connectedness, Excessive Screen Time During COVID-19 and Mental Health: A Review of Current Evidence
Authors: Pandya Apurvakumar , Lodha Pragya
Published: July 2021

With an advancement of digital technology, excessive screen time has become a grave concern. This has pushed researchers and practitioners to focus on digital well-being. Screen time during COVID-19 has further increased as a result of public health measures enforced by governments to curb the pandemic. With the global societies under lockdown, the only medium to stay socio- emotionally connected was the digital one. A lack of comprehensive empirical overviews on screen time in COVID-19 era in the present literature prompted us to conduct this review. The present review attempts to understand the virtual social connectedness, excessive use of digital technology, its consequences and suggest strategies to maintain healthy use of digital technology. Results reveal that screen time has increased drastically during COVID-19. Though there are mixed consequences of prolonged screen time use and blurred understanding between healthy and unhealthy social connectedness over digital media, the suggestions for negative implications on (physical and) mental health warrant a strict need for inculcating healthy digital habits, especially knowing that digital technology is here to stay and grow with time.
Receptor Tyrosine Kinase Inhibitor Sunitinib as Novel Immunotherapy to Inhibit Myeloid-Derived Suppressor Cells for Treatment of Endometriosis
Authors: He Ying , Hung Sze Wan , Liang Bo , Zhang Ruizhe , Gao Yating , Chu Ching Yan , Zhang Tao , Xu Hui , Chung Jacqueline Pui Wah , Wang Chi Chiu
Published: July 2021

Endometriosis is a common, benign, and hormone-dependent gynaecological disorder that displays altered immunoinflammatory profiles. Myeloid-derived suppressor cells (MDSCs) suppressed immunosurveillance in endometriosis in human and mouse model. Receptor tyrosine kinase inhibitor Sunitinib can induce MDSC apoptosis and suppress the progression of cancer. However, the effects of Sunitinib on MDSCs in endometriosis and the underlying mechanism are not clear. In this study, we employed an animal study of the endometriosis model in mice for treatment of Sunitinib. After syngeneic endometrium transplantation and treatment, endometriotic lesion volume, weight, and histology were compared. Peritoneal fluid, peripheral blood, and bone marrow MDSC subsets and their molecular signaling were monitored by flow cytometry. Peritoneal cytokines were assayed by ELISA. The gene expression profiles of isolated CD11b+Ly6G+Ly6Clo cells were studied by RNA sequencing. We found that Sunitinib significantly decreased the endometriotic lesion size and weight after 1 and 3 weeks, and decreased p-STAT3 activation in MDSCs after 1 week of treatment. In the first week, Sunitinib specifically increased the G-MDSC population in peritoneal fluid but the isolated CD11b+Ly6G+Ly6Clo MDSCs after Sunitinib treatment were presented as mature polynuclear MDSCs, while the control group had immature mononuclear MDSCs. Importantly, we found Sunitinib differentially suppressed gene expressions of immunosuppressive function and differentiation in peritoneal G-MDSCs. Apelin signaling pathway associated genes and inflammation related genes were upregulated, and amino acid metabolism regulator genes were downregulated in bone marrow G-MDSCs. For endometriotic lesions, the PPARG gene governing glucose metabolism and fatty acid storage, which is important for the development of endometriosis was upregulated. In conclusion, Sunitinib inhibited endometriotic lesions, by promoting peritoneal fluid MDSCs maturation and inhibiting the immunosuppressive function. These findings suggest that Sunitinib changed the immune microenvironment and inhibited the development of endometriosis, which has potential therapeutic effects as novel immunotherapy to promote MDSCs maturation, differentiation, and metabolism for the treatment of endometriosis.
L-Leucine Promotes STAT1 and ISGs Expression in TGEV-Infected IPEC-J2 Cells via mTOR Activation
Authors: Du Jian , Chen Daiwen , Yu Bing , He Jun , Yu Jie , Mao Xiangbing , Luo Yuheng , Zheng Ping , Luo Junqiu
Published: July 2021

L-leucine (Leu), as one of the effective amino acids to activate the mTOR signaling pathway, can alleviate transmissible gastroenteritis virus (TGEV) infection. However, the underlying mechanism by which Leu alleviates the virus infection has not been fully characterized. In particular, how Leu impacts TGEV replication through mTOR signaling has yet to be elucidated. In the present study, we found that TGEV proliferated efficiently in intestinal porcine epithelial cells (IPEC-J2 cells) as evidenced by the increase in viral contents by flow cytometry, the inhibition of cell proliferation by CCK-8 assay as well as the reduction of PCNA level by western blot. Besides, western blot analysis showed that STAT1 expression was markedly reduced in TGEV-infected cells. The results of ELISA revealed the inhibition of ISGs (ISG56, MxA, and PKR) expressions by TGEV infection. TGEV-induced mTOR and its downstream p70 S6K and 4E-BP1, STAT1 and ISGs downregulation were blocked by an mTOR activator-MHY1485 but not by an mTOR inhibitor-RAPA. Concurrently, mTOR activation by MHY1485 reduced the contents of TGEV and vice versa. Furthermore, Leu reversed the inhibition of STAT1 and ISGs by activating mTOR and its downstream p70 S6K and 4E-BP1 in TEGV-infected cells. Our findings demonstrated that Leu promoted the expressions of STAT1 and ISGs via activating mTOR signaling in IPEC-J2 cells, aiming to prevent TGEV infection.
Novel Host Protein TBC1D16, a GTPase Activating Protein of Rab5C, Inhibits Prototype Foamy Virus Replication
Authors: Yan Jun , Zheng Yingcheng , Yuan Peipei , Wang Shanshan , Han Song , Yin Jun , Peng Biwen , Li Zhi , Sun Yan , He Xiaohua , Liu Wanhong
Published: July 2021

Prototype foamy virus (PFV) is a member of the oldest family of retroviruses and maintains lifelong latent infection in the host. The lifelong latent infection of PFV may be maintained by the restriction factors of viral replication in the host. However, the mechanisms involved in PFV latent infection are poorly understood. Here, we found that TBC1D16, a TBC domain-containing protein, is significantly down-regulated after PFV infection. Tre2/Bub2/Cdc16 (TBC) domain-containing proteins function as Rab GTPase-activating proteins (GAPs) and are participates in the progression of some diseases and many signaling pathways. However, whether TBC proteins are involved in PFV replication has not been determined. Here, we found that TBC1D16 is a novel antiviral protein that targets Rab5C to suppress PFV replication. Overexpression TBC1D16 inhibited the transcription and expression of Tas and Gag, and silencing TBC1D16 enhanced the PFV replication. Moreover, the highly conserved amino acid residues R494 and Q531 in the TBC domain of TBC1D16 were essential for inhibiting PFV replication. We also found that TBC1D16 promoted the production of PFV-induced IFN-β and the transcription of downstream genes. These results suggest that TBC1D16 might be the first identified TBC proteins that inhibited PFV replication and the mechanism by which TBC1D16 inhibited PFV replication could provide new insights for PFV latency.
Characteristics and Management of Autoimmune Disease-Associated Cerebral Venous Sinus Thrombosis
Authors: Zhang Baizhuo , Lang Yue , Zhang Weiguanliu , Cui Li , Deng Fang
Published: July 2021

Cerebral venous sinus thrombosis (CVST) is a central nervous system disease characterised by thrombosis in cerebral venous or dural sinuses. Autoimmune diseases, a series of diseases caused by immune responses to autoantigens, are important causes of CVST. The most common diseases that lead to CVST are Behçet’s syndrome, systemic lupus erythematosus, antiphospholipid syndrome, and Sjögren’s syndrome. Each of these diseases have different clinical and imaging manifestations and treatment for CVST varies by aetiology. This review summarises the characteristics and the current management strategies for autoimmune disease-associated CVST and emphasises controversial therapeutic strategies to provide informative reference information for diagnosis and treatment. Risk factors of autoimmune antigens should not be neglected when unconventional CVST occurs, and both drugs and interventional therapy need further standardisation and discussion with more prospective clinical studies.
Immune2vec: Embedding B/T Cell Receptor Sequences in ℝN Using Natural Language Processing
Authors: Ostrovsky-Berman Miri , Frankel Boaz , Polak Pazit , Yaari Gur
Published: July 2021

The adaptive branch of the immune system learns pathogenic patterns and remembers them for future encounters. It does so through dynamic and diverse repertoires of T- and B- cell receptors (TCR and BCRs, respectively). These huge immune repertoires in each individual present investigators with the challenge of extracting meaningful biological information from multi-dimensional data. The ability to embed these DNA and amino acid textual sequences in a vector-space is an important step towards developing effective analysis methods. Here we present Immune2vec, an adaptation of a natural language processing (NLP)-based embedding technique for BCR repertoire sequencing data. We validate Immune2vec on amino acid 3-gram sequences, continuing to longer BCR sequences, and finally to entire repertoires. Our work demonstrates Immune2vec to be a reliable low-dimensional representation that preserves relevant information of immune sequencing data, such as n-gram properties and IGHV gene family classification. Applying Immune2vec along with machine learning approaches to patient data exemplifies how distinct clinical conditions can be effectively stratified, indicating that the embedding space can be used for feature extraction and exploratory data analysis.
S100A4 Is Critical for a Mouse Model of Allergic Asthma by Impacting Mast Cell Activation
Authors: Wu Tongqian , Ma Lan , Jin Xiaoqian , He Jingjing , Chen Ke , Zhang Dingshan , Yuan Rui , Yang Jun , Zhong Qin , Zhou Haiyan , Xiang Zou , Fang Yu
Published: July 2021

Background

The calcium-binding protein S100A4 demonstrates important regulatory roles in many biological processes including tumorigenesis and inflammatory disorders such as allergy. However, the specific mechanism of the contribution of S100A4 to allergic diseases awaits further clarification.

Objective

To address the effect of S100A4 on the regulation of mast cell activation and its impact on allergy.

Methods

Bone marrow-derived cultured mast cells (BMMCs) were derived from wild-type (WT) or S100A4-/- mice for in vitro investigation. WT and S100A4-/- mice were induced to develop a passive cutaneous anaphylaxis (PCA) model, a passive systemic anaphylaxis (PSA) model, and an ovalbumin (OVA)-mediated mouse asthma model.

Results

Following OVA/alum-based sensitization and provocation, S100A4-/- mice demonstrated overall suppressed levels of serum anti-OVA IgE and IgG antibodies and proinflammatory cytokines in serum, bronchoalveolar lavage fluid (BALF), and lung exudates. S100A4-/- mice exhibited less severe asthma signs which included inflammatory cell infiltration in the lung tissue and BALF, and suppressed mast cell recruitment in the lungs. Reduced levels of antigen reencounter-induced splenocyte proliferation in vitro were recorded in splenocytes from OVA-sensitized and challenged mice that lacked S100A4-/-. Furthermore, deficiency in the S100A4 gene could dampen mast cell activation both in vitro and in vivo, evidenced by reduced β-hexosaminidase release and compromised PCA and PSA reaction. We also provided evidence supporting the expression of S100A4 by mast cells.

Conclusion

S100A4 is required for mast cell functional activation, and S100A4 may participate in the regulation of allergic responses at least partly through regulating the activation of mast cells.
Sexual Dimorphism and Gender in Infectious Diseases
Authors: Gay Laetitia , Melenotte Cléa , Lakbar Ines , Mezouar Soraya , Devaux Christian , Raoult Didier , Bendiane Marc-Karim , Leone Marc , Mège Jean-Louis
Published: July 2021

Epidemiological studies and clinical observations show evidence of sexual dimorphism in infectious diseases. Women are at less risk than men when it comes to developing most infectious diseases. However, understanding these observations requires a gender approach that takes into account an analysis of both biological and social factors. The host’s response to infection differs in males and females because sex differences have an impact on hormonal and chromosomal control of immunity. Estradiol appears to confer protective immunity, while progesterone and testosterone suppress anti-infectious responses. In addition, genetic factors, including those associated with sex chromosomes, also affect susceptibility to infections. Finally, differences in occupational activities, lifestyle, and comorbidities play major roles in exposure to pathogens and management of diseases. Hence, considering sexual dimorphism as a critical variable for infectious diseases should be one of the steps taken toward developing personalized therapeutic approaches.
TIGIT, the Next Step Towards Successful Combination Immune Checkpoint Therapy in Cancer
Authors: Ge Zhouhong , Peppelenbosch Maikel P. , Sprengers Dave , Kwekkeboom Jaap
Published: July 2021

T cell immunoreceptor with Ig and ITIM domains (TIGIT) is an inhibitory receptor expressed on several types of lymphocytes. Efficacy of antibody blockade of TIGIT in cancer immunotherapy is currently widely being investigated in both pre-clinical and clinical studies. In multiple cancers TIGIT is expressed on tumor-infiltrating cytotoxic T cells, helper T cells, regulatory T cells and NK cells, and its main ligand CD155 is expressed on tumor-infiltrating myeloid cells and upregulated on cancer cells, which contributes to local suppression of immune-surveillance. While single TIGIT blockade has limited anti-tumor efficacy, pre-clinical studies indicate that co-blockade of TIGIT and PD-1/PD-L1 pathway leads to tumor rejection, notably even in anti-PD-1 resistant tumor models. Among inhibitory immune checkpoint molecules, a unique property of TIGIT blockade is that it enhances not only anti-tumor effector T-cell responses, but also NK-cell responses, and reduces the suppressive capacity of regulatory T cells. Numerous clinical trials on TIGIT-blockade in cancer have recently been initiated, predominantly combination treatments. The first interim results show promise for combined TIGIT and PD-L1 co-blockade in solid cancer patients. In this review, we summarize the current knowledge and identify the gaps in our current understanding of TIGIT’s roles in cancer immunity, and provide, based on these insights, recommendations for its positioning in cancer immunotherapy.
Antigen-Specific Treg Therapy in Type 1 Diabetes – Challenges and Opportunities
Authors: Serr Isabelle , Drost Felix , Schubert Benjamin , Daniel Carolin
Published: July 2021

Regulatory T cells (Tregs) are key mediators of peripheral self-tolerance and alterations in their frequencies, stability, and function have been linked to autoimmunity. The antigen-specific induction of Tregs is a long-envisioned goal for the treatment of autoimmune diseases given reduced side effects compared to general immunosuppressive therapies. However, the translation of antigen-specific Treg inducing therapies for the treatment or prevention of autoimmune diseases into the clinic remains challenging. In this mini review, we will discuss promising results for antigen-specific Treg therapies in allergy and specific challenges for such therapies in autoimmune diseases, with a focus on type 1 diabetes (T1D). We will furthermore discuss opportunities for antigen-specific Treg therapies in T1D, including combinatorial strategies and tissue-specific Treg targeting. Specifically, we will highlight recent advances in miRNA-targeting as a means to foster Tregs in autoimmunity. Additionally, we will discuss advances and perspectives of computational strategies for the detailed analysis of tissue-specific Tregs on the single-cell level.
Grazing by the Copepod Parvocalanus crassirostris on Picochlorum sp. at Harmful Bloom Densities and the Role of Particle Size
Authors: Ma Xiao , Jacoby Charles A. , Johnson Kevin B.
Published: July 2021

Harmful blooms of nanophytoplankton (2–20 μm) are increasingly common and sometimes severe, but requirements and controls of such blooms (e.g., water quality constraints, requirements for nutrients, and the presence of different guilds of grazers) are poorly understood. Laboratory grazing experiments were conducted to evaluate the potential for top-down control by the copepod Parvocalanus crassirostris on a small harmful algal species (an unidentified chlorophyte Picochlorum, 1–4 μm) and to test the effects of cell sizes on grazing rates. The Picochlorum sp. is a strain isolated from a long-lasting harmful algal bloom in the Indian River Lagoon that reached high densities (>1 × 106 cells ml–1). Experiments contrasted grazing on Picochlorum sp. with grazing on the palatable prymnesiophyte Isochrysis galbana (4–6 μm) in monocultures and mixed cultures. When presented in monocultures, grazing rates on Picochlorum sp. were lower than grazing rates on the palatable alternative. When Picochlorum sp. were presented alongside I. galbana, copepods essentially ceased feeding on the former. In additional experiments, P. crassirostris were fed plastic beads with diameters of 2.0–17.9 μm to control for differences in taste, toxicity, production of mucilage and shape of potential food. Paracalanus crassirostris fed most efficiently on beads with diameters of 7.0–7.9 μm. Results revealed that P. crassirostris can consume Picochlorum sp., but small size and the presence of palatable cells reduces the likelihood of top-down control of blooms of Picochlorum sp.
On Using Lagrangian Drift Simulations to Aid Interpretation of in situ Monitoring Data
Authors: Callies Ulrich , Kreus Markus , Petersen Wilhelm , Voynova Yoana G.
Published: July 2021

One key challenge of marine monitoring programs is to reasonably combine information from different in situ observations spread in space and time. In that context, we suggest the use of Lagrangian transport simulations extending both forward and backward in time to identify the movements of water bodies from the time they were observed to the time of their synopsis. We present examples of how synoptic maps of salinity generated by this method support the identification and tracing of river plumes in coastal regions. We also demonstrate how we can use synoptic maps to delineate different water masses in coastal margins. These examples involve quasi-continuous observations of salinity taken along ferry routes. A third application is the synchronization of measurements between fixed stations and nearby moving platforms. Both observational platforms often see the same water body, but at different times. We demonstrate how the measurements from a fixed platform can be synchronized to measurements from a moving platform by taking into account simulation-based time shifts.
Submesoscale Vorticity and Divergence in the Alboran Sea: Scale and Depth Dependence
Authors: Esposito Giovanni , Berta Maristella , Centurioni Luca , Johnston T.M. Shaun , Lodise John , Özgökmen Tamay , Poulain Pierre-Marie , Griffa Annalisa
Published: July 2021

The statistics of submesoscale divergence and vorticity (kinematic properties, KPs) in the Alboran Sea (Mediterranean Sea) are investigated, using data from drifters released during two experiments in June 2018 and April 2019 in the framework of the Coherent Lagrangian Pathways from the Surface Ocean to Interior (CALYPSO) project. Surface drifters sampling the first meter of water (CARTHE and CODE) and 15 m drifters (SVP) are considered. The area of interest is dominated by processes of strong frontogenesis and eddy formation as well as mixing, related to the high lateral gradients between Mediterranean and Atlantic waters. Drifter coverage and distribution allow to investigate the dependence of KPs on horizontal scales in a range between 1 and 16 km, that effectively bridges submesoscale and mesoscale processes, and at two depths, of 1 and 15 m. For both experiments, the surface flow is highly ageostrophic at 1 km scale, with positive vorticity skewness indicating the presence of submesoscale features. Surface divergence quickly decreases at increasing scales with a slope compatible with a turbulent process with broadband wavenumber spectrum, suggesting the influence of surface boundary layer processes such as wind effects, waves and Langmuir cells at the smaller scales. Vorticity, on the other hand, has a significantly slower decay, suggesting interaction between submesoscale and mesoscale dynamics. Results at 15 m are characterized by reduced ageostrophic dynamics with respect to the surface, especially for divergence. Submesoscale processes are present but appear attenuated in terms of KP magnitude and skewness. The results are generally consistent for the two experiments, despite the observed differences in the mixed layer stratification, suggesting that submesoscale instabilities occur mostly at surface fronts associated with filaments of Atlantic and Mediterranean waters that are present in both cases. The results are compared with previous literature results in other parts of the world ocean and a synthesis is provided. Good agreement with previous surface results is found, suggesting some general properties for divergence and vorticity scale dependence. The importance of further investigating very high resolution frontal processes at scales of tens of meters, as well as processes of interaction with high wind effects is highlighted.
Smoldering and Flaming of Disc Wood Particles Under External Radiation: Autoignition and Size Effect
Authors: Wang Supan , Ding Pengfei , Lin Shaorun , Gong Junhui , Huang Xinyan
Published: July 2021

Wildfires are global issues that cause severe damages to the society and environment. Wood particles and firebrands are the most common fuels in wildfires, but the size effect on the flaming and smoldering ignitions as well as the subsequent burning behavior is still poorly understood. In this work, a well-controlled experiment was performed to investigate smoldering and flaming ignitions of stationary disc-shaped wood particles with different diameters (25–60 mm) and thicknesses (15–25 mm) under varying radiant heat flux. The ignition difficulty, in terms of the minimum heat flux, increases from smoldering ignition to piloted flaming ignition and then to flaming autoignition. As the sample thickness increases, the minimum heat flux, ignition temperature, and burning duration for flaming autoignition all increase, while the peak burning flux decreases, but they are insensitive to the sample diameter. During ignition and burning processes, the disc particle is deformed due to the interaction between chemical reactions and thermomechanical stresses, especially for smoldering. The characteristic thickness of the smoldering front on wood is also found to be 10–15 mm. This study sheds light on the size effect on the ignition of wood particles by wildfire radiation and helps understand the interaction between flaming and smoldering wildfires.
Innate Immune Response to Viral Infections at the Maternal-Fetal Interface in Human Pregnancy
Authors: Espino Ana , El Costa Hicham , Tabiasco Julie , Al-Daccak Reem , Jabrane-Ferrat Nabila
Published: July 2021

The placenta, the first and largest organ to develop after conception, not only nurtures and promotes the development of the conceptus, but, it also functions as a barrier against invading pathogens. Early phases of pregnancy are associated with expansion of specific subsets of Natural Killer cells (dNK) and macrophages (dMφ) at the maternal uterine mucosa, the basal decidua. In concert with cells of fetal origin, dNK cells, and dMφ orchestrate all steps of placenta and fetus development, and provide the first line of defense to limit vertical transmission. However, some pathogens that infect the mother can overcome this protective barrier and jeopardize the fetus health. In this review, we will discuss how members of the classical TORCH family (Toxoplasma, Other, Rubella, Cytomegalovirus, and Herpes simplex virus) and some emerging viruses (Hepatitis E virus, Zika virus, and SARS-CoV2) can afford access to the placental fortress. We will also discuss how changes in the intrauterine environment as a consequence of maternal immune cell activation contribute to placental diseases and devastating pregnancy outcomes.
Case Report: SAPHO Syndrome Mimicking Bone Metastases During Treatment With Pembrolizumab for Non-small Cell Lung Cancer
Authors: Kubo Yuko , Ito Kimiteru , Fujiwara Yutaka , Yoshida Tatsuya , Kusumoto Masahiko
Published: July 2021

A 69-year-old female with recurrent stage IV squamous cell lung carcinoma and metastatic abdominal lymph node but not bone metastases was being treated with pembrolizumab. Four months after starting the recurrent treatment, the tumour reduced in size but she began to complain of back pain and palmar rash. A bone scan showed uptake lesions in the left sternocostal joints and vertebrae, while spine magnetic resonance imaging (MRI) showed multiple lesions in the thoracic vertebrae. Her heterogeneous lesions, such as skin and multiple bone manifestations, were comprehensively diagnosed as SAPHO syndrome by different experts. Furthermore, the SAPHO syndrome was suspected to be an immune-related adverse event induced by pembrolizumab, and pembrolizumab withdrawal and prednisolone treatment were performed. Subsequently, her symptoms improved and the follow-up imaging findings showed that the bone lesions had almost disappeared. This case demonstrates that SAPHO syndrome mimicking bone metastases developed during treatment with pembrolizumab. SAPHO syndrome is rare and bone lesions related to the disease may be misdiagnosed as bone metastases. Therefore, it is important in the future for various physicians to have a better understanding of SAPHO syndrome and to consider the potential relationship between this disease and immunotherapy.
Acute Hemodynamic Effect of Acetazolamide in Patients With Pulmonary Hypertension Whilst Breathing Normoxic and Hypoxic Gas: A Randomized Cross-Over Trial
Authors: Lichtblau Mona , Berlier Charlotte , Saxer Stéphanie , Carta Arcangelo F. , Mayer Laura , Groth Alexandra , Bader Patrick R. , Schneider Simon R. , Furian Michael , Schwarz Esther I. , Swenson Erik R. , Bloch Konrad E. , Ulrich Silvia
Published: July 2021

Aims: To test the acute hemodynamic effect of acetazolamide in patients with pulmonary hypertension (PH) under ambient air and hypoxia.

Methods: Patients with pulmonary arterial or chronic thromboembolic PH (PAH/CTEPH) undergoing right heart catheterization were included in this randomized, placebo-controlled, double-blinded, crossover trial. The main outcome, pulmonary vascular resistance (PVR), further hemodynamics, blood- and cerebral oxygenation were measured 1 h after intravenous administration of 500 mg acetazolamide or placebo-saline on ambient air (normoxia) and at the end of breathing hypoxic gas (FIO2 0.15, hypoxia) for 15 min.

Results: 24 PH-patients, 71% men, mean ± SD age 59 ± 14 years, BMI 28 ± 5 kg/m2, PVR 4.7 ± 2.1 WU participated. Mean PVR after acetazolamide vs. placebo was 5.5 ± 3.0 vs. 5.3 ± 3.0 WU; mean difference (95% CI) 0.2 (−0.2–0.6, p = 0.341). Heart rate was higher after acetazolamide (79 ± 12 vs. 77 ± 11 bpm, p = 0.026), pH was lower (7.40 ± 0.02 vs. 7.42 ± 0.03, p = 0.002) but PaCO2 and PaO2 remained unchanged while cerebral tissue oxygenation increased (71 ± 6 vs. 69 ± 6%, p = 0.017). In acute hypoxia, acetazolamide decreased PVR by 0.4 WU (0.0–0.9, p = 0.046) while PaO2 and PaCO2 were not changed. No adverse effects occurred.

Conclusions: In patients with PAH/CTEPH, i.v. acetazolamide did not change pulmonary hemodynamics compared to placebo after 1 hour in normoxia but it reduced PVR after subsequent acute exposure to hypoxia. Our findings in normoxia do not suggest a direct acute pulmonary vasodilator effect of acetazolamide. The reduction of PVR during hypoxia requires further corroboration. Whether acetazolamide improves PH when given over a prolonged period by stimulating ventilation, increasing oxygenation, and/or altering vascular inflammation and remodeling remains to be investigated.
Point-Of-Care Capillary Refill Technology Improves Accuracy of Peripheral Perfusion Assessment
Authors: Sheridan David C. , Cloutier Robert L. , Samatham Ravi , Hansen Matthew L.
Published: July 2021

Background: Peripheral perfusion assessment is used routinely at the bedside by measuring the capillary refill time (CRT). Recent clinical trials have shown evidence to its ability to recognize conditions with decreased end organ perfusion as well as guiding therapeutic interventions in sepsis. However, the current standard of physician assessment at the bedside has shown large variability. New technology can improve the precision and repeatability of CRT affecting translation of previous high impact research.

Methods: This was a prospective, observational study in the intensive care unit and emergency department at a quaternary care hospital using a non-invasive finger sensor for CRT. The device CRT was compared to the gold standard of trained research personnel assessment of CRT as well as to providers clinically caring for the patient.

Results: Pearson correlations coefficients were performed across 89 pairs of measurements. The Pearson correlation for the device CRT compared to research personnel CRT was 0.693. The Pearson correlation for the provider CRT compared to research personnel CRT was 0.359.

Conclusions: New point-of-care technology shows great promise in the ability to improve peripheral perfusion assessment performed at the bedside in the emergency department triage and during active resuscitation. This standardized approach allows for better translation of prior research that is limited by the subjectivity of manual visual assessment of CRT.
Clinical Features and Long-Term Outcomes After Laparoscopic Surgery in Patients Co-existing With Endometriosis and Adenomyosis
Authors: Sun Ting-Ting , Li Xiao-Yan , Shi Jing-Hua , Wu Yu-Shi , Gu Zhi-Yue , Leng Jin-Hua
Published: July 2021

Objective: To investigate the difference of clinical features and outcomes between EM patients with and without AM after following up for at least 6 years after surgery.

Methods: We retrospectively analyzed 358 EM patients who had a minimum of 6 years follow-up after laparoscopic cystectomy, which was performed by one single doctor at Peking Union Medical College Hospital from January 2009 to April 2013. All women were divided into AM group and non-AM group and analysis was performed in preoperative characteristics, surgical findings and postoperative outcomes during follow-up.

Results: A total of 358 EM patients were recruited, of which 142 (39.7%) were in the AM group and the rest 216 (60.3%) in the non-AM group. Between the two group, the mean age was 34.6 vs. 32.2 years (P < 0.001). The mean operating time in the AM and non-AM group was 73.2 vs. 61.9 min (P < 0.001). According to the revised AFS classification, the mean score of the two group were 60.3 vs. 45.5 (P < 0.001). At the end of the follow-up, though the AM group was with higher rate of disease relapse, yet no significant difference was found between the two groups in statistical comparison (34/142 [23.9%] vs. 34/216 [15.7%], P = 0.053). With a minimum follow-up of 6 years after laparoscopic cystectomy, failed and successful pregnancy were seen in 107/142(75.4%) and 35/142 (24.6%) patients in the AM group vs. 114/216(52.8%) and 102/216 (47.2%) patients in the non-AM group (P < 0.05). As for the successfully pregnant patients, live births, including spontaneous pregnancy and IVF-ET, were seen in 34/35 (97.1) vs. 99/102 (97.1) patients between AM and non-AM groups, while others ended in spontaneous abortion. No significant associations were found between the two groups in infertility, leiomyoma presence, the size of ovarian endometrioma, type of deep infiltrating endometriosis (DIE) or type of recurrence (P > 0.05).

Conclusion: Compared with non-AM group, EM patients with concurrent AM may have higher age, longer mean operating time and higher mean AFS score. In terms of fertility outcomes, patients in the AM group were with lower likelihood of pregnancy after surgery during the long-time follow-up.
The DmsABC Sulfoxide Reductase Supports Virulence in Non-typeable Haemophilus influenzae
Authors: Dhouib Rabeb , Nasreen Marufa , Othman Dk Seti Maimonah Pg , Ellis Daniel , Lee Simon , Essilfie Ama-Tawiah , Hansbro Philip M. , McEwan Alastair G. , Kappler Ulrike
Published: July 2021

Although molybdenum-containing enzymes are well-established as having a key role in bacterial respiration, it is increasingly recognized that some may also support bacterial virulence. Here, we show that DmsABC, a putative dimethylsulfoxide (DMSO) reductase, is required for fitness of the respiratory pathogen Haemophilus influenzae (Hi) in different models of infection. Expression of the dmsABC operon increased with decreasing oxygen availability, but despite this, a Hi2019ΔdmsA strain did not show any defects in anaerobic growth on chemically defined medium (CDM), and viability was also unaffected. Although Hi2019ΔdmsA exhibited increased biofilm formation in vitro and greater resistance to hypochlorite killing compared to the isogenic wild-type strain, its survival in contact with primary human neutrophils, in infections of cultured tissue cells, or in a mouse model of lung infection was reduced compared to Hi2019WT. The tissue cell infection model revealed a two-fold decrease in intracellular survival, while in the mouse model of lung infection Hi2019ΔdmsA was strongly attenuated and below detection levels at 48 h post-inoculation. While Hi2019WT was recovered in approximately equal numbers from bronchoalveolar lavage fluid (BALF) and lung tissue, survival of Hi2019ΔdmsA was reduced in lung tissue compared to BALF samples, indicating that Hi2019ΔdmsA had reduced access to or survival in the intracellular niche. Our data clearly indicate for the first time a role for DmsABC in H. influenzae infection and that the conditions under which DmsABC is required in this bacterium are closely linked to interactions with the host.
The Muscle Activation Differences in Post-Stroke Upper Limb Flexion Synergy Based on Spinal Cord Segments: A Preliminary Proof-of-Concept Study
Authors: Liu Gang , Chia Chin-hsuan , Wang Wei-ning , Cao Yue , Tian Shan , Shen Xue-yan , Chen Ying , Lu Rong-rong , Wu Jun-fa , Zhu Yu-lian , Wu Yi
Published: July 2021

Objective: This study examined the activation difference of muscles innervated by cervical cord 5-6 (C5-C6) and cervical cord 8- thoracic cord 1 (C8-T1) in upper limb flexion synergy after stroke.

Methods: Surface electromyography (sEMG) signals were collected during elbow flexion in stroke patients and healthy controls. The study compared normalized activation of two pairs of muscles that could cause similar joint movement but which dominated different spinal cord segments (clavicular part of the pectoralis major, PC vs. Sternocostal part of the pectoralis major, PS; Flexor carpi radialis, FCR vs. Flexor carpi ulnaris, FCU). In each muscle pair, one muscle was innervated by the same spinal cord segment (C5-C6), dominating the elbow flexion and the other was not. The comparison of the activation of the same muscle between patients and healthy controls was undertaken after standardization based on the activation of the biceps brachii in elbow flexion.

Results: There was no difference between the PC and PS's normalized activation in healthy controls while the PC's normalized activation was higher than PS in stroke patients during elbow flexion. Similarly, there was no significant difference in normalized activation between FCR and FCU in healthy controls, and the same is true for stroke patients. However, the standardized activation of both FCR and FCU in stroke patients was significantly lower than that in healthy controls.

Conclusion: After stroke, the activation of the distal muscles of the upper limb decreased significantly regardless of the difference of spinal cord segments; while the activation of the proximal muscles innervated by the same spinal cord segment (C5-C6) dominating the elbow flexion showed higher activation during flexion synergy. The difference in muscle activation based on spinal cord segments may be the reason for the stereotyped joint movement of upper limb flexion synergy.
SARS-CoV-2 Susceptibility and COVID-19 Mortality Among Older Adults With Cognitive Impairment: Cross-Sectional Analysis From Hospital Records in a Diverse US Metropolitan Area
Authors: Pan Alan P. , Meeks Jennifer , Potter Thomas , Masdeu Joseph C. , Seshadri Sudha , Smith Matthew Lee , Ory Marcia G. , Vahidy Farhaan S.
Published: July 2021

Introduction: Persistent knowledge gaps exist as to the extent that preexisting cognitive impairment is a risk factor for susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and mortality from the coronavirus disease 2019 (COVID-19).

Methods: We conducted a cross-sectional analysis of adults tested for SARS-CoV-2 at a tertiary healthcare system. Cognitive impairment was identified utilizing diagnosis codes (mild cognitive impairment, Alzheimer's disease, vascular, and other dementias) or cognitive impairment-specific medication use. Propensity score (PS) matched analyses were utilized to report odds ratios (OR) and 95% confidence intervals (CI) for association of cognitive impairment with SARS-CoV-2 susceptibility and COVID-19 mortality.

Results: Between March-3rd and December-11th, 2020, 179,979 adults were tested, of whom 21,607 (12.0%) tested positive. We identified 6,364 individuals with preexisting cognitive impairment (mean age: 78.5 years, 56.8% females), among whom 843 (13.2%) tested positive and 139 (19.5%) of those hospitalized died. In the pre-PS matched cohort, cognitive impairment was significantly associated with increased SARS-CoV-2 susceptibility (OR, CI: 1.12, 1.04–1.21) and COVID-19 mortality (OR, CI: 2.54, 2.07–3.12). One-to-one matches were identified for 6,192 of 6,364 (97.3%) individuals with prior cognitive impairment and 687 of 712 (96.5%) hospitalized patients with prior cognitive impairment. In the fully balanced post-matched cohort, preexisting cognitive impairment was significantly associated with higher likelihood of SARS-CoV-2 infection (OR, CI: 1.51, 1.35–1.70); however, cognitive impairment did not confer higher risk of COVID-19 mortality (OR, CI: 0.96, 0.73–1.25).

Discussion: To mitigate the effects of healthcare catastrophes such as the COVID-19 pandemic, strategies for targeted prevention and risk-stratified comorbidity management are warranted among the vulnerable sub-population living with cognitive impairment.
New Frontiers for Deep Brain Stimulation: Directionality, Sensing Technologies, Remote Programming, Robotic Stereotactic Assistance, Asleep Procedures, and Connectomics
Authors: Merola Aristide , Singh Jaysingh , Reeves Kevin , Changizi Barbara , Goetz Steven , Rossi Lorenzo , Pallavaram Srivatsan , Carcieri Stephen , Harel Noam , Shaikhouni Ammar , Sammartino Francesco , Krishna Vibhor , Verhagen Leo , Dalm Brian
Published: July 2021

Over the last few years, while expanding its clinical indications from movement disorders to epilepsy and psychiatry, the field of deep brain stimulation (DBS) has seen significant innovations. Hardware developments have introduced directional leads to stimulate specific brain targets and sensing electrodes to determine optimal settings via feedback from local field potentials. In addition, variable-frequency stimulation and asynchronous high-frequency pulse trains have introduced new programming paradigms to efficiently desynchronize pathological neural circuitry and regulate dysfunctional brain networks not responsive to conventional settings. Overall, these innovations have provided clinicians with more anatomically accurate programming and closed-looped feedback to identify optimal strategies for neuromodulation. Simultaneously, software developments have simplified programming algorithms, introduced platforms for DBS remote management via telemedicine, and tools for estimating the volume of tissue activated within and outside the DBS targets. Finally, the surgical accuracy has improved thanks to intraoperative magnetic resonance or computerized tomography guidance, network-based imaging for DBS planning and targeting, and robotic-assisted surgery for ultra-accurate, millimetric lead placement. These technological and imaging advances have collectively optimized DBS outcomes and allowed “asleep” DBS procedures. Still, the short- and long-term outcomes of different implantable devices, surgical techniques, and asleep vs. awake procedures remain to be clarified. This expert review summarizes and critically discusses these recent innovations and their potential impact on the DBS field.