bluuebunny/crossref_metadata_2025 huggingface dataset:
Depression and Antidepressants During Pregnancy: Craniofacial Defects Due to Stem/Progenitor Cell Deregulation Mediated by Serotonin
Authors: Sánchez Natalia , Juárez-Balarezo Jesús , Olhaberry Marcia , González-Oneto Humberto , Muzard Antonia , Mardonez María Jesús , Franco Pamela , Barrera Felipe , Gaete Marcia
Published: August 2021

Depression is a common and debilitating mood disorder that increases in prevalence during pregnancy. Worldwide, 7 to 12% of pregnant women experience depression, in which the associated risk factors include socio-demographic, psychological, and socioeconomic variables. Maternal depression could have psychological, anatomical, and physiological consequences in the newborn. Depression has been related to a downregulation in serotonin levels in the brain. Accordingly, the most commonly prescribed pharmacotherapy is based on selective serotonin reuptake inhibitors (SSRIs), which increase local serotonin concentration. Even though the use of SSRIs has few adverse effects compared with other antidepressants, altering serotonin levels has been associated with the advent of anatomical and physiological changes in utero, leading to defects in craniofacial development, including craniosynostosis, cleft palate, and dental defects. Migration and proliferation of neural crest cells, which contribute to the formation of bone, cartilage, palate, teeth, and salivary glands in the craniofacial region, are regulated by serotonin. Specifically, craniofacial progenitor cells are affected by serotonin levels, producing a misbalance between their proliferation and differentiation. Thus, it is possible to hypothesize that craniofacial development will be affected by the changes in serotonin levels, happening during maternal depression or after the use of SSRIs, which cross the placental barrier, increasing the risk of craniofacial defects. In this review, we provide a synthesis of the current research on depression and the use of SSRI during pregnancy, and how this could be related to craniofacial defects using an interdisciplinary perspective integrating psychological, clinical, and developmental biology perspectives. We discuss the mechanisms by which serotonin could influence craniofacial development and stem/progenitor cells, proposing some transcription factors as mediators of serotonin signaling, and craniofacial stem/progenitor cell biology. We finally highlight the importance of non-pharmacological therapies for depression on fertile and pregnant women, and provide an individual analysis of the risk–benefit balance for the use of antidepressants during pregnancy
Discovery of Novel Host Molecular Factors Underlying HBV/HCV Infection
Authors: Huang Xubo , Glessner Joseph T. , Huang Jinxia , Zhou Desheng , March Michael E. , Wang Hongna , Xia Qianghua , Hakonarson Hakon , Li Jin
Published: August 2021

Hepatitis is an inflammatory condition of the liver, which is frequently caused by the infection of hepatitis B virus (HBV) or hepatitis C virus (HCV). Hepatitis can lead to the development of chronic complications including cancer, making it a major public health burden. Co-infection of HBV and HCV can result in faster disease progression. Therefore, it is important to identify shared genetic susceptibility loci for HBV and HCV infection to further understand the underlying mechanism. Through a meta-analysis based on genome-wide association summary statistics of HBV and HCV infection, we found one novel locus in the Asian population and two novel loci in the European population. By functional annotation based on multi-omics data, we identified the likely target genes at each novel locus, such as HMGB1 and ATF3, which play a critical role in autophagy and immune response to virus. By re-analyzing a microarray dataset from Hmgb1–/– mice and RNA-seq data from mouse liver tissue overexpressing ATF3, we found that differential expression of autophagy and immune and metabolic gene pathways underlie these conditions. Our study reveals novel common susceptibility loci to HBV and HCV infection, supporting their role in linking autophagy signaling and immune response.
3D Organoid Culture From Adult Salivary Gland Tissues as an ex vivo Modeling of Salivary Gland Morphogenesis
Authors: Kim Donghyun , Yoon Yeo-Jun , Choi Dojin , Kim Jisun , Lim Jae-Yol
Published: August 2021

Lumen formation of salivary glands has been investigated using in vivo or ex vivo rudiment culture models. In this study, we used a three-dimensional (3D) salivary gland organoid culture system and demonstrated that lumen formation could be recapitulated in mouse SMG organoids. In our organoid culture system, lumen formation was induced by vasoactive intestinal peptide and accelerated by treatment with RA. Furthermore, lumen formation was observed in branching duct-like structure when cultured in combination of fibroblast growth factors (FGF) in the presence of retinoic acid (RA). We suggest RA signaling-mediated regulation of VIPR1 and KRT7 as the underlying mechanism for lumen formation, rather than apoptosis in the organoid culture system. Collectively, our results support a fundamental role for RA in lumen formation and demonstrate the feasibility of 3D organoid culture as a tool for studying salivary gland morphogenesis.
3D in vivo Magnetic Particle Imaging of Human Stem Cell-Derived Islet Organoid Transplantation Using a Machine Learning Algorithm
Authors: Sun Aixia , Hayat Hasaan , Liu Sihai , Tull Eliah , Bishop Jack Owen , Dwan Bennett Francis , Gudi Mithil , Talebloo Nazanin , Dizon James Raynard , Li Wen , Gaudet Jeffery , Alessio Adam , Aguirre Aitor , Wang Ping
Published: August 2021

Stem cell-derived islet organoids constitute a promising treatment of type 1 diabetes. A major hurdle in the field is the lack of appropriate in vivo method to determine graft outcome. Here, we investigate the feasibility of in vivo tracking of transplanted stem cell-derived islet organoids using magnetic particle imaging (MPI) in a mouse model. Human induced pluripotent stem cells-L1 were differentiated to islet organoids and labeled with superparamagnetic iron oxide nanoparticles. The phantoms comprising of different numbers of labeled islet organoids were imaged using an MPI system. Labeled islet organoids were transplanted into NOD/scid mice under the left kidney capsule and were then scanned using 3D MPI at 1, 7, and 28 days post transplantation. Quantitative assessment of the islet organoids was performed using the K-means++ algorithm analysis of 3D MPI. The left kidney was collected and processed for immunofluorescence staining of C-peptide and dextran. Islet organoids expressed islet cell markers including insulin and glucagon. Image analysis of labeled islet organoids phantoms revealed a direct linear correlation between the iron content and the number of islet organoids. The K-means++ algorithm showed that during the course of the study the signal from labeled islet organoids under the left kidney capsule decreased. Immunofluorescence staining of the kidney sections showed the presence of islet organoid grafts as confirmed by double staining for dextran and C-peptide. This study demonstrates that MPI with machine learning algorithm analysis can monitor islet organoids grafts labeled with super-paramagnetic iron oxide nanoparticles and provide quantitative information of their presence in vivo.
The Multifaceted Roles of Proline in Cell Behavior
Authors: Patriarca Eduardo J. , Cermola Federica , D’Aniello Cristina , Fico Annalisa , Guardiola Ombretta , De Cesare Dario , Minchiotti Gabriella
Published: August 2021

Herein, we review the multifaceted roles of proline in cell biology. This peculiar cyclic imino acid is:(i)A main precursor of extracellular collagens (the most abundant human proteins), antimicrobial peptides (involved in innate immunity), salivary proteins (astringency, teeth health) and cornifins (skin permeability);(ii)an energy source for pathogenic bacteria, protozoan parasites, and metastatic cancer cells, which engage in extracellular-protein degradation to invade their host;(iii)an antistress molecule (an osmolyte and chemical chaperone) helpful against various potential harms (UV radiation, drought/salinity, heavy metals, reactive oxygen species);(iv)a neural metabotoxin associated with schizophrenia;(v)a modulator of cell signaling pathways such as the amino acid stress response and extracellular signal-related kinase pathway;(vi)an epigenetic modifier able to promote DNA and histone hypermethylation;(vii)an inducer of proliferation of stem and tumor cells; and(viii)a modulator of cell morphology and migration/invasiveness. We highlight how proline metabolism impacts beneficial tissue regeneration, but also contributes to the progression of devastating pathologies such as fibrosis and metastatic cancer.
Thermal Disproportionation for the Synthesis of Silicon Nanocrystals and Their Photoluminescent Properties
Authors: Su Yize , Wang Chenhao , Hong Zijian , Sun Wei
Published: August 2021

In the past decades, silicon nanocrystals have received vast attention and have been widely studied owing to not only their advantages including nontoxicity, high availability, and abundance but also their unique luminescent properties distinct from bulk silicon. Among the various synthetic methods of silicon nanocrystals, thermal disproportionation of silicon suboxides (often with H as another major composing element) bears the superiorities of unsophisticated equipment requirements, feasible processing conditions, and precise control of nanocrystals size and structure, which guarantee a bright industrial application prospect. In this paper, we summarize the recent progress of thermal disproportionation chemistry for the synthesis of silicon nanocrystals, with the focus on the effects of temperature, Si/O ratio, and the surface groups on the resulting silicon nanocrystals’ structure and their corresponding photoluminescent properties. Moreover, the paradigmatic application scenarios of the photoluminescent silicon nanocrystals synthesized via this method are showcased or envisioned.
Proteomic Analysis of Copper Toxicity in Human Fungal Pathogen Cryptococcus neoformans
Authors: Sun Tianshu , Li Yanjian , Li Yingxing , Li Hailong , Gong Yiyi , Wu Jianqiang , Ning Yating , Ding Chen , Xu Yingchun
Published: August 2021

Cryptococcus neoformans is an invasive human fungal pathogen that causes more than 181,000 deaths each year. Studies have demonstrated that pulmonary C. neoformans infection induces innate immune responses involving copper, and copper detoxification in C. neoformans improves its fitness and pathogenicity during pulmonary C. neoformans infection. However, the molecular mechanism by which copper inhibits C. neoformans proliferation is unclear. We used a metallothionein double-knockout C. neoformans mutant that was highly sensitive to copper to demonstrate that exogenous copper ions inhibit fungal cell growth by inducing reactive oxygen species generation. Using liquid chromatography-tandem mass spectrometry, we found that copper down-regulated factors involved in protein translation, but up-regulated proteins involved in ubiquitin-mediated protein degradation. We propose that the down-regulation of protein synthesis and the up-regulation of protein degradation are the main effects of copper toxicity. The ubiquitin modification of total protein and proteasome activity were promoted under copper stress, and inhibition of the proteasome pathway alleviated copper toxicity. Our proteomic analysis sheds new light on the antifungal mechanisms of copper.
Linear and Continuous Flavivirus Epitopes From Naturally Infected Humans
Authors: Fumagalli Marcilio Jorge , Figueiredo Luiz Tadeu Moraes , Aquino Victor Hugo
Published: August 2021

This manuscript is an up-to-date review of experimentally validated linear and continuous epitopes identified from arbovirus members of theFlavivirusgenus. We summarized 153 immunoreactive peptides from the Dengue virus, Zika virus, Japanese encephalitis virus, West Nile virus, and tick-borne encephalitis virus described in studies published from 1989 to 2020. We included peptides from structural (envelope, capsid, and pre-membrane) and nonstructural (Ns1–5) viral proteins that demonstrated relevant immunoreactivity with antibodies from naturally infected or vaccinated humans. We included peptides that demonstrated relevant reactivity features, such as indicators of disease severity related to immunological or immunopathological outcomes, differential or group diagnostic markers, immunotherapy candidates, and potential for vaccine formulation. The majority of immunoreactive peptides were described for DENV probably due to its long-lasting impact on human health and the lack of efficient vaccines and therapeutic methods. Immune landscape data regarding linear immunoreactive and continuous flavivirus peptides are still scarce, and a complete and more detailed map remains to be elucidated. Therefore, this review provides valuable data for those investigating the antibody response against flavivirus infection.
C-Type Natriuretic Peptide Plays an Anti-Inflammatory Role in Rat Epididymitis Induced by UPEC
Authors: Mei Chunlei , Kang Yafei , Zhang Chenlu , He Chunyu , Liao Aihua , Huang Donghui
Published: August 2021

Human epididymitis is mainly caused by retrograde urinary tract infection with uropathogenic Escherichia coli (UPEC). This disease is an important factor (accounting for 20–30%) causing male infertility. C-type natriuretic peptide (CNP), a protein composed of 22 amino acids, is proved to play an immunoregulatory role in respiratory and cardiovascular systems. CNP is expressed extremely high in the epididymis, but whether CNP plays the same role in acute epididymitis is unclear. At first, we established an acute caput epididymitis model in rats with UPEC and treated them with CNP to measure inflammatory damage. Then RNA-seq transcriptome technology was used to reveal potential signal pathways. Secondly, the turbidity and activity of UPEC were assessed using a microplate reader and the amount of UPEC by agar plates after incubation with CNP. Thirdly, macrophages in caput epididymis were tested by immunohistochemistry (IHC). Meanwhile, lipopolysaccharide (LPS) with or without CNP was used to stimulate the macrophage (RAW264.7) in vitro and to detect the expression level of pro-inflammatory factors. Finally, the macrophage (RAW264.7) was treated with CNP, 8-Br-cGMP [cyclic guanosinc monophosphate (cGMP) analog] and KT5823 [protein kinase G (PKG) inhibitor], and the expression level of nuclear factor-k-gene binding (NF-kB) signal pathway was examined. The results showed that the damage of epididymis induced by UPEC as well as the pro-inflammatory factors could be alleviated significantly with CNP treatment. CNP could inhibit the activity and numbers of bacteria in both in vivo and in vitro experiments. Moreover, CNP repressed the invasion, and the expression of pro-inflammatory factors (such as NF-kB, IL-1β, IL-6, TNF-α) in macrophages and its effect could be inhibited by KT5823. Therefore, we drew a conclusion from the above experiments that CNP alleviates the acute epididymitis injury induced by UPEC. On one hand, CNP could inhibit the growth of UPEC. On the other hand, CNP could decrease invasion and inflammatory reaction of macrophages; the mechanism was involved in inhibiting NF-kB signal pathway through the cGMP/PKG in macrophages. This research would open up the possibility of using CNP as a potential treatment for epididymitis.
Trypanosoma cruzi Induces Regulatory B Cell Alterations in Patients With Chronic Chagas Disease
Authors: Girard Magalí C. , Ossowski Micaela S. , Muñoz-Calderón Arturo , Fernández Marisa , Hernández-Vásquez Yolanda , Chadi Raúl , Gómez Karina A.
Published: August 2021

The clinical evolution of patients with chronic Chagas disease (CCD) is mainly associated with an excessive inflammation and a defective immunomodulatory profile caused by the interaction between T. cruzi and the host. Regulatory B (Breg) cells exert immune suppression mostly through IL-10 production (B10 cells), but also through IL-10-independent mechanisms. Previously, we demonstrated that CCD patients with cardiomyopathy show changes in the ex vivo Breg cell phenotypic distribution although maintain IL-10 production capacity. Here, we sought to identify potential alterations on Breg cells upon in vitro stimulation. Isolated B cells from CCD patients with or without cardiomyopathy and non-infected (NI) donors were stimulated with T. cruzi lysate or CpG + CD40L, and characterized by flow cytometry based on the expression of CD24, CD27, CD38, and the regulatory molecules IL-10 and PD-L1. IL-10 and IL-17 secretion in the supernatant of B cells was evaluated by ELISA. Data showed that T. cruzi stimulation diminished the expression of CD24 and CD38 on CD27− B cells while reducing the percentage of CD24high inside CD27+ B cells. Furthermore, T. cruzi induced a regulatory B cell phenotype by increasing B10 cells and IL-10 secretion in all the groups. The innate-like B10 cells expansion observed in patients with cardiomyopathy would be associated with CD27− B10 cell subsets, while no predominant phenotype was found in the other groups. Patients with cardiomyopathy also displayed higher IL-17 secretion levels in T. cruzi–activated B cells. CpG + CD40L stimulation revealed that B cells from CCD patients and NI donors had the same ability to differentiate into B10 cells and secrete IL-10 in vitro. Additionally, CCD patients showed an increased frequency of CD24−CD27− B cells and a reduction in the percentage of CD24highCD27+ Breg cells, which appeared to be inversely correlated with the presence of T. cruzi DNA in blood. Finally, CCD patients exhibited a higher frequency of PD-L1+ B cells in T. cruzi–stimulated samples, suggesting that IL-10-independent mechanisms could also be tangled in the control of inflammation. Altogether, our results provide evidence about the potential role of Breg cells in the immune response developed against T. cruzi and its contribution to chronic Chagas cardiomyopathy.
Adaptation Mechanisms in Human–Agent Interaction: Effects on User’s Impressions and Engagement
Authors: Biancardi Beatrice , Dermouche Soumia , Pelachaud Catherine
Published: August 2021

Adaptation is a key mechanism in human–human interaction. In our work, we aim at endowing embodied conversational agents with the ability to adapt their behavior when interacting with a human interlocutor. With the goal to better understand what the main challenges concerning adaptive agents are, we investigated the effects on the user’s experience of three adaptation models for a virtual agent. The adaptation mechanisms performed by the agent take into account the user’s reaction and learn how to adapt on the fly during the interaction. The agent’s adaptation is realized at several levels (i.e., at the behavioral, conversational, and signal levels) and focuses on improving the user’s experience along different dimensions (i.e., the user’s impressions and engagement). In our first two studies, we aim to learn the agent’s multimodal behaviors and conversational strategies to dynamically optimize the user’s engagement and impressions of the agent, by taking them as input during the learning process. In our third study, our model takes both the user’s and the agent’s past behavior as input and predicts the agent’s next behavior. Our adaptation models have been evaluated through experimental studies sharing the same interacting scenario, with the agent playing the role of a virtual museum guide. These studies showed the impact of the adaptation mechanisms on the user’s experience of the interaction and their perception of the agent. Interacting with an adaptive agent vs. a nonadaptive agent tended to be more positively perceived. Finally, the effects of people’s a priori about virtual agents found in our studies highlight the importance of taking into account the user’s expectancies in human–agent interaction.
Myoglobin Offers Higher Accuracy Than Other Cardiac-Specific Biomarkers for the Prognosis of COVID-19
Authors: Yu Jia-Sheng , Chen Ru-Dong , Zeng Ling-Cheng , Yang Hong-Kuan , Li Hua
Published: August 2021

Although sporadic studies have shown that myoglobin may have better prognostic performance than other cardiac markers in COVID-19, a comprehensive comparative study is lacking. Herein, we retrospectively analyzed the clinical and laboratory data of COVID-19 patients admitted to the Guanggu Campus of Wuhan Tongji Hospital from February 9, 2020 to March 30, 2020, intending to compare the prognostic accuracy of three commonly used cardiac markers on COVID-19 mortality. Our results revealed that abnormal increases in myocardial biomarkers were associated with a significantly increased risk of in-hospital mortality with COVID-19. Interestingly, myoglobin, a non-cardiac-specific biomarker, also expressed in skeletal myocytes, had even higher prognostic accuracy than cardiac-specific biomarkers such as high-sensitivity troponin I (hs-TnI) and creatine kinase-MB (CK-MB). More importantly, multivariate Cox analysis showed that myoglobin, rather than hs-TnI or CK-MB, was independently prognostic for in-hospital mortality in COVID-19. These results were further confirmed by subgroup analyses of patients with severe and critical illnesses and those without a history of cardiovascular disease. Our findings suggest that myoglobin may be a reliable marker of illness reflecting general physiological disturbance and help to assess prognosis and treatment response in patients with COVID-19.
Single-Cell Transcriptomic Analysis Reveals Developmental Relationships and Specific Markers of Mouse Periodontium Cellular Subsets
Authors: Nagata Mizuki , Chu Angel Ka Yan , Ono Noriaki , Welch Joshua D. , Ono Wanida
Published: August 2021

The periodontium is essential for supporting the functionality of the tooth, composed of diversity of mineralized and non-mineralized tissues such as the cementum, the periodontal ligament (PDL) and the alveolar bone. The periodontium is developmentally derived from the dental follicle (DF), a fibrous tissue surrounding the developing tooth bud. We previously showed through in vivo lineage-tracing experiments that DF contains mesenchymal progenitor cells expressing parathyroid hormone-related protein (PTHrP), which give rise to cells forming the periodontal attachment apparatus in a manner regulated by autocrine signaling through the PTH/PTHrP receptor. However, the developmental relationships between PTHrP+ DF cells and diverse cell populations constituting the periodontium remain undefined. Here, we performed single-cell RNA-sequencing (scRNA-seq) analyses of cells in the periodontium by integrating the two datasets, i.e. PTHrP-mCherry+ DF cells at P6 and 2.3kb Col1a1 promoter-driven GFP+ periodontal cells at P25 that include descendants of PTHrP+ DF cells, cementoblasts, osteoblasts and periodontal ligament cells. This integrative scRNA-seq analysis revealed heterogeneity of cells of the periodontium and their cell type-specific markers, as well as their relationships with DF cells. Most importantly, our analysis identified a cementoblast-specific metagene that discriminate cementoblasts from alveolar bone osteoblasts, including Pthlh (encoding PTHrP) and Tubb3. RNA velocity analysis indicated that cementoblasts were directly derived from PTHrP+ DF cells in the early developmental stage and did not interconvert with other cell types. Further, CellPhoneDB cell-cell communication analysis indicated that PTHrP derived from cementoblasts acts on diversity of cells in the periodontium in an autocrine and paracrine manner. Collectively, our findings provide insights into the lineage hierarchy and intercellular interactions of cells in the periodontium at a single-cell level, aiding to understand cellular and molecular basis of periodontal tissue formation.
Post-COVID-19 Adaptations; the Shifts Towards Online Learning, Hybrid Course Delivery and the Implications for Biosciences Courses in the Higher Education Setting
Authors: Bashir Amreen , Bashir Shahreen , Rana Karan , Lambert Peter , Vernallis Ann
Published: August 2021

The Covid-19 pandemic has created challenges and caused disruption across the Higher Education sector; university campuses closed, and face-to-face teaching and assessment shifted to an online format. Learning from our students’ experience during this period will help us shape future hybrid delivery so that it best fits Bioscience students. This pedagogical study explored Aston University’s Bioscience students’ experiences of studying from home, and the impact of the lockdown on mental wellbeing and quality of life. 151 students completed an online survey during August 2020, which included open and closed questions. Analysis of survey data revealed that a majority of students reported positive experiences of online open-book assessments and most would welcome this format in the future. The majority of students faced no technical issues, predominantly stating that they also had good internet connectivity. Shifting to remote learning and online classrooms uncovered conflicting preferences; despite wanting more interactive lectures, only half of the students were comfortable interacting using video cameras. Free text responses provided an insight into how some students reported an inadequate home working space/environment and lacked necessary items such as a desk, highlighting how remote working may intensify social and digital inequality - particularly for students from more deprived households. Wider detrimental experiences of lockdown included dissatisfaction with access to healthcare, decreased concentration, sleeping difficulties and a decline in mental wellbeing. Education strategies going forward will need to address the mental health needs of students who have suffered during the pandemic. Our university, amongst others, is embracing hybrid course delivery, which could offer a solution to ensuring Bioscience students receive hands-on laboratory experience and face-to-face contact to remain motivated and benefit from the on-campus facilities and support, whilst allowing students some of the flexibility afforded by remote study. In the current competitive higher education market where student retention is key, it is important to consider student demographics and digital equity to ensure an appropriate approach is applied to cater for all students.
Human Umbilical Cord Mesenchymal Stem Cell-Derived Exosomes Improve Ovarian Function and Proliferation of Premature Ovarian Insufficiency by Regulating the Hippo Signaling Pathway
Authors: Li Zhongkang , Zhang Mingle , Zheng Jiahua , Tian Yanpeng , Zhang Huihui , Tan Yi , Li Qian , Zhang Jingkun , Huang Xianghua
Published: August 2021

Background

Premature ovarian insufficiency (POI) is associated with severe physical damage and psychological burden on women. Transplantation of exosomes is an encouraging regenerative medicine method, which has the potential for restoring ovarian functions on POI with high efficiency. This study aims at evaluating the therapeutic efficacy of human umbilical cord mesenchymal stem cell-derived exosomes (hUCMSC-Exos) on ovarian dysfunction of POI and the role of Hippo pathway in this exosome-mediated treatment.

Methods

POI mice models were established through intraperitoneal injection of cyclophosphamide. Subsequently, transplantation of hUCMSC-Exos was conducted to administer POI mice. Ovaries and plasma of these mice models were harvested after two weeks of treatment. Ovarian morphology and follicle number were assessed by hematoxylin and eosin staining. Moreover, ELISA was used to detect hormone levels, which are related to ovarian function in serum. To assess the recovery of reproductive ability, we recorded the rate of pregnancy, the amount of offspring, and the time of birth in different groups. To explore the underlying mechanisms of exosome-mediated treatment for ovarian function recovery, the proliferation of ovarian cells in vivo was detected by immunohistochemistry and immunofluorescence staining. Additionally, we conducted EdU and CCK-8 assays to assess the proliferative ability of ovarian granulosa cells (GCs) that were cultured in vitro. Western blot analysis was conducted to estimate the proteins levels of Hippo- and proliferation-associated molecules in vivo and in vitro.

Results

After transplantation of hUCMSC-Exos, the ovarian function-related hormone levels and the number of ovarian follicles returned to nearly normal degrees. Meanwhile, there was a significant improvement in reproductive outcomes after exosomal treatment. Furthermore, the improvement of ovarian function and proliferation was associated with the regulation of Hippo pathway. In vitro, co-culture with exosomes significantly elevated the proliferation of ovarian GCs by regulating Hippo pathway. However, the positive effects on the proliferation of GCs were significantly depressed when key Hippo pathway molecule was inhibited.

Conclusion

This study suggested that hUCMSC-Exos promoted ovarian functions and proliferation by regulating the Hippo pathway. Therefore, exosomal transplantation could be a promising and efficient clinical therapy for POI in the near future.
Free Triiodothyronine Is Associated With Hepatic Steatosis and Liver Stiffness in Euthyroid Chinese Adults With Non-Alcoholic Fatty Liver Disease
Authors: Guo Wen , Qin Pei , Li Xiao-Na , Wu Juan , Lu Jing , Zhu Wen-Fang , Diao Qing-qing , Xu Nian-Zhen , Zhang Qun
Published: August 2021

Objective

The association between non-alcoholic fatty liver disease (NAFLD) and thyroid hormones in euthyroid subjects is unclear. We investigated the relationship between thyroid function and the severity of hepatic steatosis and liver fibrosis in a large cohort of euthyroid Chinese adults.

Methods

A total of 3496 participants were enrolled. Liver ultrasonography was used to define the presence of NAFLD (n=2172) or the absence of NAFLD (n=1324). Anthropometric and biochemical measurements were made and thyroid function parameters including free triiodothyronine (FT3), free thyroxine (FT4), thyroid‐stimulating hormone (TSH) were measured. The severity of hepatic steatosis and liver stiffness was assessed by transient elastography.

Results

Levels of FT3 were significantly higher in the severe NAFLD group and moderate NAFLD group than in the mild NAFLD group (5.18 ± 0.58 vs 5.11 ± 0.57 vs 4.98 ± 0.60 pmol/L, P<0.001). Participants with F4 and F3 liver fibrosis had higher FT3 levels than those with F2 fibrosis (6.33 ± 0.39 vs 5.29 ± 0.48 vs 5.20 ± 0.50 pmol/L, P<0.001). However, FT4 and TSH levels did not correlate with hepatic steatosis or liver fibrosis severity. In addition, the proportions of participants with NAFLD (46.0% vs 63.1% vs 73.3%, P<0.001) and liver fibrosis (11.5% vs 18.6% vs 20.8%, P<0.001) increased as FT3 levels increased. Logistic regression analysis showed that FT3 levels were positively associated with the severity of hepatic steatosis and liver fibrosis presence, even after adjustment for metabolic risk factors including BMI. In non-obese participants, the FT3 level was an independently risk factor for the severity of hepatic steatosis.

Conclusions

There are positive associations of FT3 levels with the severity of hepatic steatosis and the presence of liver fibrosis in NAFLD with euthyroidism.
FGF-Receptors and PD-L1 in Anaplastic and Poorly Differentiated Thyroid Cancer: Evaluation of the Preclinical Rationale
Authors: Adam Pia , Kircher Stefan , Sbiera Iuliu , Koehler Viktoria Florentine , Berg Elke , Knösel Thomas , Sandner Benjamin , Fenske Wiebke Kristin , Bläker Hendrik , Smaxwil Constantin , Zielke Andreas , Sipos Bence , Allelein Stephanie , Schott Matthias , Dierks Christine , Spitzweg Christine , Fassnacht Martin , Kroiss Matthias
Published: August 2021

Background

Treatment options for poorly differentiated (PDTC) and anaplastic (ATC) thyroid carcinoma are unsatisfactory and prognosis is generally poor. Lenvatinib (LEN), a multi-tyrosine kinase inhibitor targeting fibroblast growth factor receptors (FGFR) 1-4 is approved for advanced radioiodine refractory thyroid carcinoma, but response to single agent is poor in ATC. Recent reports of combining LEN with PD-1 inhibitor pembrolizumab (PEM) are promising.

Materials and Methods

Primary ATC (n=93) and PDTC (n=47) tissue samples diagnosed 1997-2019 at five German tertiary care centers were assessed for PD-L1 expression by immunohistochemistry using Tumor Proportion Score (TPS). FGFR 1-4 mRNA was quantified in 31 ATC and 14 PDTC with RNAscope in-situ hybridization. Normal thyroid tissue (NT) and papillary thyroid carcinoma (PTC) served as controls. Disease specific survival (DSS) was the primary outcome variable.

Results

PD-L1 TPS≥50% was observed in 42% of ATC and 26% of PDTC specimens. Mean PD-L1 expression was significantly higher in ATC (TPS 30%) than in PDTC (5%; p<0.01) and NT (0%, p<0.001). 53% of PDTC samples had PD-L1 expression ≤5%. FGFR mRNA expression was generally low in all samples but combined FGFR1-4 expression was significantly higher in PDTC and ATC compared to NT (each p<0.001). No impact of PD-L1 and FGFR 1-4 expression was observed on DSS.

Conclusion

High tumoral expression of PD-L1 in a large proportion of ATCs and a subgroup of PDTCs provides a rationale for immune checkpoint inhibition. FGFR expression is low thyroid tumor cells. The clinically observed synergism of PEM with LEN may be caused by immune modulation.
Outcomes of Minimally Invasive Thyroid Surgery – A Systematic Review and Meta-Analysis
Authors: de Vries Lisa H. , Aykan Dilay , Lodewijk Lutske , Damen Johanna A. A. , Borel Rinkes Inne H. M. , Vriens Menno R.
Published: August 2021

Purpose

Conventional thyroidectomy has been standard of care for surgical thyroid nodules. For cosmetic purposes different minimally invasive and remote-access surgical approaches have been developed. At present, the most used robotic and endoscopic thyroidectomy approaches are minimally invasive video assisted thyroidectomy (MIVAT), bilateral axillo-breast approach endoscopic thyroidectomy (BABA-ET), bilateral axillo-breast approach robotic thyroidectomy (BABA-RT), transoral endoscopic thyroidectomy via vestibular approach (TOETVA), retro-auricular endoscopic thyroidectomy (RA-ET), retro-auricular robotic thyroidectomy (RA-RT), gasless transaxillary endoscopic thyroidectomy (GTET) and robot assisted transaxillary surgery (RATS). The purpose of this systematic review was to evaluate whether minimally invasive techniques are not inferior to conventional thyroidectomy.

Methods

A systematic search was conducted in Medline, Embase and Web of Science to identify original articles investigating operating time, length of hospital stay and complication rates regarding recurrent laryngeal nerve injury and hypocalcemia, of the different minimally invasive techniques.

Results

Out of 569 identified manuscripts, 98 studies met the inclusion criteria. Most studies were retrospective in nature. The results of the systematic review varied. Thirty-one articles were included in the meta-analysis. Compared to the standard of care, the meta-analysis showed no significant difference in length of hospital stay, except a longer stay after BABA-ET. No significant difference in incidence of recurrent laryngeal nerve injury and hypocalcemia was seen. As expected, operating time was significantly longer for most minimally invasive techniques.

Conclusions

This is the first comprehensive systematic review and meta-analysis comparing the eight most commonly used minimally invasive thyroid surgeries individually with standard of care. It can be concluded that minimally invasive techniques do not lead to more complications or longer hospital stay and are, therefore, not inferior to conventional thyroidectomy.
Risks to Fish Populations in Dryland Rivers From the Combined Threats of Drought and Instream Barriers
Authors: Marshall Jonathan C. , Lobegeiger Jaye S. , Starkey Alisa
Published: August 2021

In dryland rivers, flow intermittency means fish populations are often subjected to drought disturbance. The viability of these fish populations depends on the availability of waterhole refuges for individuals to survive drought (resistance) and the ability of surviving fish to repopulate the rivers by recruitment and dispersal once flow returns (resilience). In this study we combined remote-sensed mapping of the locations of waterholes that lasted through an extreme drought in the northern Murray Darling Basin, Australia, with an assessment of the impacts of in-stream barriers on limiting the opportunities for fish to move and repopulate after drought. We found that at the peak of this 2018–2020 drought, the worst on record for some rivers and the most spatially synchronous recorded across the region, waterholes were few and generally small – representing only 11% of the total river channel network. All the fish in the region that survived the drought were concentrated into this limited waterhole refuge habitat. Even small instream structures, such as minor weirs, caused large reductions in the opportunities for fish to move between river segments when there is flow. Almost all the 104 instream structures assessed reduced long-term fish movement opportunities, measured as days with discharge greater than calculated barrier drown out thresholds, by more than 70% and up to 100%, when compared to opportunities for movement if the barrier was not present. This large impact from small instream barriers is a consequence of flow intermittency and is likely to reduce fish population resilience and impact the capacity of fish populations to recover after drought. Combining information on the risks posed by limited refuge habitat availability during drought and from reduced movement opportunity following drought allowed us to identify river segments where these combined threats are the greatest risk to viability of local fish populations. Considering the spatial arrangements of these risks provides a means to systematically prioritize mitigation measures such as weir removal to improve fish movement opportunities and local management of key waterholes to increase drought resistance. The approach used here provides a guide for assessing and prioritizing the management of fish population viability risks from drought and fragmentation by barriers in any non-perennial river setting.
Gall-Inducing Tephritid Flies (Diptera: Tephritidae): Evolution and Host–Plant Relations
Authors: Korneyev Valery A.
Published: August 2021

The molecular-based phylogenetic analysis of the subfamily Tephritinae, the subfamily that contains almost all the cecidogenous species of the family Tephritidae, has reassigned several tribes and groups of genera and modified their concepts based on morphology alone to other tribes and, thus, changed the hypothetical scenarios of evolution of fly/host–plant relations and, in particular, the gall induction in different phylogenetic lineages. Gall induction is shown to arise independently within the Myopitini (in two lineages), Cecidocharini,Tomoplagiagroup of genera, Eurostini,Eutreta, Tephritisgroup of genera, Platensinini,Campiglossagroup of genera, andSphenellagroup of genera independently and more or less synchronously due to the shift to host plants with smaller flower heads and sensitive to larval feeding causing tissue proliferation. This was possibly a result of temporary aridization of the grassy biomes in the Nearctic and Afrotropic regions in the late Miocene or early Pliocene.
Mendelian Randomization in Stroke: A Powerful Approach to Causal Inference and Drug Target Validation
Authors: Acosta Julián N. , Szejko Natalia , Falcone Guido J.
Published: August 2021

Stroke is a leading cause of death and disability worldwide. However, our understanding of its underlying biology and the number of available treatment options remain limited. Mendelian randomization (MR) offers a powerful approach to identify novel biological pathways and therapeutic targets for this disease. Around ~100 MR studies have been conducted so far to explore, confirm, and quantify causal relationships between several exposures and risk of stroke. In this review, we summarize the current evidence arising from these studies, including those investigating ischemic stroke, hemorrhagic stroke, or both. We highlight the different types of exposures that are currently under study, ranging from well-known cardiovascular risk factors to less established inflammation-related mechanisms. Finally, we provide an overview of future avenues of research and novel approaches, including drug target validation MR, which is poised to have a substantial impact on drug development and drug repurposing.
TLR-9 Plays a Role in Mycobacterium leprae-Induced Innate Immune Activation of A549 Alveolar Epithelial Cells
Authors: Dias André Alves , Silva Carlos Adriano de Matos e , Silva Camila Oliveira da , Linhares Natasha Ribeiro Cardoso , Santos João Pedro Sousa , Vivarini Aislan de Carvalho , Marques Maria Ângela de Mello , Rosa Patrícia Sammarco , Lopes Ulisses Gazos , Berrêdo-Pinho Márcia , Pessolani Maria Cristina Vidal
Published: August 2021

The respiratory tract is considered the main port of entry of Mycobacterium leprae, the causative agent of leprosy. However, the great majority of individuals exposed to the leprosy bacillus will never manifest the disease due to their capacity to develop protective immunity. Besides acting as a physical barrier, airway epithelium cells are recognized as key players by initiating a local innate immune response that orchestrates subsequent adaptive immunity to control airborne infections. However, to date, studies exploring the interaction of M. leprae with the respiratory epithelium have been scarce. In this work, the capacity of M. leprae to immune activate human alveolar epithelial cells was investigated, demonstrating that M. leprae-infected A549 cells secrete significantly increased IL-8 that is dependent on NF-κB activation. M. leprae was also able to induce IL-8 production in human primary nasal epithelial cells. M. leprae-treated A549 cells also showed higher expression levels of human β-defensin-2 (hβD-2), MCP-1, MHC-II and the co-stimulatory molecule CD80. Furthermore, the TLR-9 antagonist inhibited both the secretion of IL-8 and NF-κB activation in response to M. leprae, indicating that bacterial DNA sensing by this Toll-like receptor constitutes an important innate immune pathway activated by the pathogen. Finally, evidence is presented suggesting that extracellular DNA molecules anchored to Hlp, a histone-like protein present on the M. leprae surface, constitute major TLR-9 ligands triggering this pathway. The ability of M. leprae to immune activate respiratory epithelial cells herein demonstrated may represent a very early event during infection that could possibly be essential to the generation of a protective response.
Mac-1 Receptor Clustering Initiates Production of Pro-Inflammatory, Antibacterial Extracellular Vesicles From Neutrophils
Authors: Szeifert Viktória , Kolonics Ferenc , Bartos Balázs , Khamari Delaram , Vági Pál , Barna László , Ligeti Erzsébet , Lőrincz Ákos M.
Published: August 2021

Depending on the prevailing environmental conditions, neutrophilic granulocytes release extracellular vesicles (EV) which have either anti-inflammatory effects on other neutrophils or pro-inflammatory and antibacterial effects. In the present study we investigated the molecular mechanisms underlying the biogenesis of functionally heterogenic EVs. We show that selective stimulation of Mac-1 integrin (complement receptor 3) by specific ligands initiates the generation of EVs which are able to impair bacterial growth and to induce the secretion of the pro-inflammatory cytokine IL-8 (aEV). However, direct Mac-1 stimulation results in aEV release only if neutrophils were activated on ligand coated surfaces whereas soluble ligands are ineffective. Using total internal reflection fluorescence (TIRF) microcopy, an increased clustering of Mac-1 molecules could be visualized in neutrophils added to C3bi coated surfaces; moreover antibody induced cluster formation triggers aEV release as well. Mac-1 induced production of aEV apparently necessitates a strong calcium signal as it fully depends on the presence of extracellular calcium. However, initiation of a strong calcium signal by an ionophore only results the generation of EV devoid of any antibacterial or pro-inflammatory effect. Our results thus demonstrate that stimulation and clustering of Mac-1 is necessary and sufficient for initiation of aEV biogenesis. In contrast, an intracellular calcium signal is necessary but by itself not sufficient for the production of antibacterial and pro-inflammatory EVs.
CMV Infection Is Directly Related to the Inflammatory Status in Chronic Heart Failure Patients
Authors: García-Torre Alejandra , Bueno-García Eva , López-Martínez Rocío , Rioseras Beatriz , Díaz-Molina Beatriz , Lambert José Luis , Quirós Covadonga , Alonso-Álvarez Sara , Alonso-Arias Rebeca , Moro-García Marco A.
Published: August 2021

High levels of inflammation play an important role in chronic heart failure (CHF). Patients with CHF have elevated levels of pro-inflammatory cytokines circulating systemically, mainly TNF and IL-6. However, there are almost no studies that relate these levels to the functional status of patients in CHF, much less to their CMV serostatus. In this study, patients with CHF (n=40; age=54.9 ± 6.3; New York Heart Association functional classification (NYHA, I-III) and healthy controls (n=40; age=53.5 ± 7.1) were analyzed. The serum concentrations of nine pro- and anti-inflammatory cytokines were measured by Luminex® xMap Technology and the basal level of mRNA expression of some immune molecules was quantified by TaqMan™ Array in CD4+ T-lymphocytes. The concentration of these cytokines in culture supernatants in response to anti-CD3 and LPS was also measured. The percentage of CD28null T-cells was determined, as well as the antibody titer against CMV. We found a higher concentration of all cytokines studied in CHF serum compared to healthy controls, as well as a direct correlation between functional status in CHF patients and levels of inflammatory cytokines. Moreover, the highest cytokine concentrations were found in patients with higher concentrations of lymphocytes lacking CD28 molecule. The cytokine production was much higher in CMV+ patients, and the production of these cytokines was found mainly in the T-lymphocytes of CMV+ patients in response to anti-CD3. Anti-CMV antibody levels were positively correlated with cytokine levels. The baseline expression of specific mRNA of the main molecules involved in the Th1 response, as well as molecules related to the CD4+CD28 null subset was higher in CMV+ patients. The cytokine concentrations are higher in CHF CMV+ patients and these concentrations are related to the production of antibodies against CMV. These high levels of cytokines are also associated with the more differentiated CD28null lymphocyte populations. All this, together with the dynamics of the pathology itself, makes CMV+ patients present a worse functional status and possibly a worse evolution of the pathology.