bluuebunny/crossref_metadata_2025 huggingface dataset:
A nicotine-induced positive feedback loop between HIF1A and YAP1 contributes to epithelial-to-mesenchymal transition in pancreatic ductal adenocarcinoma
Authors: Ben Qiwen , An Wei , Sun Yunwei , Qian Aihua , Liu Jun , Zou Duowu , Yuan Yaozong
Published: September 2020

Background

Nicotine, an active ingredient in tobacco, can promote epithelial-to-mesenchymal transition (EMT) processes that enhance the aggressiveness of a number of human cancers. In the present study, we investigated whether cigarette smoke/nicotine drives EMT in pancreatic ductal adenocarcinoma (PDAC).

Methods

Quantitative real-time PCR, western blot, immunohistochemistry, and immunofluorescence assays were used to evaluate Yes-associated protein 1 (YAP1) expression associated with cigarette smoking in human PDAC tissue samples and with nicotine exposure in PDAC cell lines. Bioinformatics, loss- and gain- of- function experiments, luciferase reporter assays, chromatin immunoprecipitation (ChIP), and murine tumor xenograft models were performed to examine the function of YAP1 in PDAC and to identify potential mechanisms of action.

Results

Exposure to smoking or nicotine promoted EMT and tumor growth in PDAC cells and in xenograft tumors. Functional studies revealed that YAP1 might drive nicotine-stimulated EMT and oncogenic activity in vitro and in vivo. In human PDAC tissues, upregulation of YAP1 was associated with “ever smoking” status and poor overall survival. In term of mechanism, hypoxia inducible factor (HIF)1A promoted YAP1 nuclear localization and YAP1 transactivation by directly binding to the hypoxia responsive elements of the YAP1 promoter upon nicotine treatment. Nicotine stimulated HIF1A and YAP1 expression by activating cholinergic receptor nicotinic alpha7 (CHRNA7). In addition, YAP1 increased and sustained the protein stability of HIF1A.

Conclusions

These data demonstrate that YAP1 enhances nicotine-stimulated EMT and tumor progression of PDAC through a HIF1A/YAP1 positive feedback loop. Developing inhibitors that specifically target YAP1 may provide a novel therapeutic approach to suppress PDAC growth, especially in PDAC patients who have a history of smoking.
The U2AF2 /circRNA ARF1/miR-342–3p/ISL2 feedback loop regulates angiogenesis in glioma stem cells
Authors: Jiang Yang , Zhou Jinpeng , Zhao Junshuang , Zhang Haiying , Li Long , Li Hao , Chen Lian , Hu Jiangfeng , Zheng Wei , Jing Zhitao
Published: September 2020

Background

Glioma is the most common and lethal primary brain tumor in adults, and angiogenesis is one of the key factors contributing to its proliferation, aggressiveness, and malignant transformation. However, the discovery of novel oncogenes and the study of its molecular regulating mechanism based on circular RNAs (circRNAs) may provide a promising treatment target in glioma.

Methods

Bioinformatics analysis, qPCR, western blotting, and immunohistochemistry were used to detect the expression levels ofISL2, miR-342–3p, circRNA ARF1 (cARF1),U2AF2, andVEGFA. Patient-derived glioma stem cells (GSCs) were established for the molecular experiments. Lentiviral-based infection was used to regulate the expression of these molecules in GSCs. The MTS, EDU, Transwell, and tube formation assays were used to detect the proliferation, invasion, and angiogenesis of human brain microvessel endothelial cells (hBMECs). RNA-binding protein immunoprecipitation, RNA pull-down, dual-luciferase reporter, and chromatin immunoprecipitation assays were used to detect the direct regulation mechanisms among these molecules.

Results

We first identified a novel transcription factor related to neural development.ISL2was overexpressed in glioma and correlated with poor patient survival.ISL2transcriptionally regulatedVEGFAexpression in GSCs and promoted the proliferation, invasion, and angiogenesis of hBMECs viaVEGFA-mediatedERKsignaling. Regarding its mechanism of action, cARF1 upregulatedISL2expression in GSCs via miR-342–3p sponging. Furthermore,U2AF2bound to and promoted the stability and expression of cARF1, whileISL2induced the expression ofU2AF2, which formed a feedback loop in GSCs. We also showed that bothU2AF2and cARF1 had an oncogenic effect, were overexpressed in glioma, and correlated with poor patient survival.

Conclusions

Our study identified a novel feedback loop amongU2AF2, cARF1, miR-342–3p, andISL2in GSCs. This feedback loop promoted glioma angiogenesis, and could provide an effective biomarker for glioma diagnosis and prognostic evaluation, as well as possibly being used for targeted therapy.
Maternal factors associated with low birth weight in public hospitals of Mekelle city, Ethiopia: a case-control study
Authors: Desta Sielu Alemayehu , Damte Ashenafi , Hailu Tsehay
Published: September 2020

Background

Mothers in low socio-economic conditions frequently have low birth weight infants. Inaddition Physically demanding work during pregnancy also contributes to poor fetal growth. During gestation a woman needs balanced nutrition for a healthy outcome. Women with inadequate nutritional status at conception are at greater risk of aquiring disease; their health usually depends on the availability and consumption of balanced diet, and therefore they are unlikely to be able to resist with their high nutrient needs during pregnancy. Therefore, the main purpose of this study was to assess the maternal risk factors associated low birth weight in public hospitals of Mekelle city, Tigray North Ethiopia, 2017/2018.

Methods

Un-matched case-control study design was conducted among women who delivered in public hospitals of Mekelle city. Data was collected using a structured questionnaire through interview, direct physical assessment and medical record review of mothers. Sample size was calculated by Epi-info version 7.0 to get a final sample size of 381(cases = 127 and controls = 254). SPSS version 20 was used for analysis. Bivariate and multivariate logistic regression analysis was used to determine the effect of the independent variables on birth weight. Presence of significant association was determined using OR with its 95%CI. A P value of less than 0.05 was considered to declare statistical significance. Table, graphs and texts were used to present the data.

Result

Most of the mothers (70.1% cases and 43.7% controls) were housewives. This study showed that maternal age ≤ 20 years (AOR = 6.42(95% CI = (1.93–21.42)), ANC follow up (AOR = 3.73(95%CI (1.5–9.24)), History of medical illness (AOR = 14.56(95% CI (3.69–57.45), Iron folate intake (AOR = 21.56(95%CI (6.54–71.14)), Maternal height less than 150 cm (AOR = 9.27(95%CI 3.45–24.89)) and Pregnancy weight gain (AOR = 4.93(95%CI = 1.8–13.48) were significant predictors of low birth weight.

Conclusion

The study suggests that inadequate ANC follow-up, preterm birth and history of chronic medical illness, maternal height, pregnancy weight gain, and Iron intake were. Were significant predictors of low birth weight. Health professionals should screen and consulate pregnant mothers who are at risk of having infants with LBW and ensure that women have access to essential health information on the causes of low birth weight.
Drivers of molecular and morphometric variation in Triatoma brasiliensis (Hemiptera: Triatominae): the resolution of geometric morphometrics for populational structuring on a microgeographical scale
Authors: Kamimura Edgard H. , Viana Maria Carolina , Lilioso Maurício , Fontes Fernanda H. M. , Pires-Silva Dayane , Valença-Barbosa Carolina , Carbajal-de-la-Fuente Ana L. , Folly-Ramos Elaine , Solferin Vera N. , Thyssen Patricia J. , Costa Jane , Almeida Carlos E.
Published: September 2020

Background

The protozoan Trypanosoma cruzi circulates in semiarid areas of northeastern Brazil in distinct ecotopes (sylvatic, peridomestic and domestic) where Triatoma brasiliensis Neiva, 1911 is the most important Chagas disease vector. In this study, we analyzed microevolutionary and demographic aspects of T. brasiliensis populations at the ecotypic, micro and macro-geographic scales by combining morphometrics and molecular results. Additionally, we aimed to address the resolution of both markers for delimiting populations in distinct scales.

Methods

We sampled populations of T. brasiliensis from distinct ecotypic and geographic sites in the states Rio Grande do Norte (RN) and Paraíba (PB). The geometric morphometry was carried out with 13 landmarks on the right wings (n = 698) and the genetic structure was assessed by sequencing a region of cytochrome b mitochondrial gene (n = 221). Mahalanobis distance (MD) and coefficient of molecular differentiation (ΦST) were calculated among all pairs of populations. The results of comparisons generated MD and ΦST dendrograms, and graphics of canonical variate analysis (CVA).

Results

Little structure was observed for both markers for macro-geographic scales. Mantel tests comparing geographic, morphometric and genetic matrices showed low correlation (all R2 < 0.35). The factorial graphics built with the CVA evidenced population delimitation for the morphometric data at micro-geographic scales.

Conclusions

We believe that T. brasiliensis carries in its genotype a source of information to allow the phenotypical plasticity across its whole distribution for shaping populations, which may have caused a lack of population delimitation for CVAs in morphometric analysis for macro-geographic scale analysis. On the other hand, the pattern of morphometric results in micro-geographic scales showed well-defined groups, highlighting the potential of this tool to inferences on the source for infestation.
An assessment of serial co-cultivation approach for generating novel Zymomonas mobilis strains
Authors: Fuchino Katsuya , Bruheim Per
Published: September 2020

Objective

The alphaproteobacterium Zymomonas mobilis is an efficient ethanol producer, and Z. mobilis-based biorefinery shows great potential for biofuel production. Serial co-cultivation is an emerging approach that promotes inter-species interactions which can improve or rewire the metabolic features in industrially useful microorganisms by inducing frequent mutations. We applied this method to assess if it improves or rewires the desirable physiological features of Z. mobilis, especially ethanol production.

Results

We performed serial co-culture of Z. mobilis with the baker’s yeast, Saccharomyces cerevisiae. We observed filamentation of Z. mobilis cells in the co-culture, indicating that the Z. mobilis cells were exposed to stress due to the presence of a competitor. After 50 times of serial transfers, we characterized the generated Z. mobilis strains, showing that long term co-culture did not drive significant changes in either the growth or profile of excreted metabolites in the generated strains. In line with this, whole genome sequencing of the generated Z. mobilis strains revealed only minor genetic variations from the parental strain. 50 generations of Z. mobilis monoculture did not induce morphological changes or any significant genetic variations. The result indicates that the method needs to be carefully optimized for Z. mobilis strain improvement.
Ultrasound imaging of carotid web with atherosclerosis plaque: a case report
Authors: Ning Bin , Zhang Dong , Sui Binbin , He Wen
Published: September 2020

Background

To the best of our knowledge, no previous studies on carotid webs with atherosclerosis plaque have been conducted. Thus, both radiologists and clinicians have insufficient knowledge of this disease, which could lead to misdiagnosis and missed diagnosis. An accurate diagnosis is beneficial to clinical management and prevention of stroke. Here, we present a case of a carotid web with an atherosclerotic plaque, which was confirmed by histopathology and was treated at the Department of Neurosurgery, Beijing Tiantan Hospital.

Case presentation

We report a rare case of a carotid web with an atherosclerotic plaque in a 61-year-old Han man. He presented to our hospital with history of intermittent dizziness and slurred speech for 1.5 years and numbness of both upper limbs for 4 months. A computed tomography angiography examination indicated severe stenosis at the beginning of the left internal carotid artery with plaque surface ulceration. Doppler ultrasound examination showed a carotid web with a thin isoechoic plaque and a membrane-like structure protruding into the lumen from the lateral posterior wall at the beginning of the left internal carotid artery. The thin isoechoic plaque could be seen at the base of the membrane-like structure. Carotid endarterectomy was performed to alleviate symptoms. A carotid web with atherosclerosis was diagnosed intraoperatively, and postoperative pathology confirmed extensive intima fibroid hyperplasia accompanied with myxoid degeneration. The base of the carotid web was attached to the thin atherosclerosis plaque, and between the web and the plaque, a cavity was observed. In this case report, we aim to discuss the diagnosis of carotid web with atherosclerosis, its physiopathology and management, and the possible reasons for missed diagnosis or misdiagnosis.

Conclusion

Carotid webs with atherosclerosis have no known etiological factors and are rarely reported. Thus, carotid webs could be easily confused with ulcerations on the surface of the atherosclerosis plaque. The diagnosis could be difficult and effective management remains indeterminate. Moreover, prompt recognition of this disease is key to correct treatment and management. Hence, this case report and the relevant data in the literature could contribute to the improvement of the diagnosis and treatment of this disease.
A barrier against reactive oxygen species: chitosan/acellular dermal matrix scaffold enhances stem cell retention and improves cutaneous wound healing
Authors: Lin Wei , Qi Xiaoyang , Guo Wenjing , Liang Danyang , Chen Heting , Lin Baoping , Deng Xiaoyuan
Published: September 2020

Background

Stem cell therapies have gained great attention for providing novel solutions for treatment of various injuries and diseases due to stem cells’ self-renewal, ability to differentiate into various cell types, and favorite paracrine function. Nevertheless, the low retention of transplanted stem cell still limits their clinical applications such as in wound healing in view of an induced harsh microenvironment rich in reactive oxygen species (ROS) during inflammatory reactions.

Methods

Herein, a novel chitosan/acellular dermal matrix (CHS/ADM) stem cell delivery system is developed, which is of great ROS scavenging activity and significantly attenuates inflammatory response.

Result

Under ROS microenvironment, this stem cell delivery system acts as a barrier, effectively scavenging an amount of ROS and protecting mesenchymal stem cells (MSCs) from the oxidative stress. It notably regulates intracellular ROS level in MSCs and reduces ROS-induced cellular death. Most importantly, such MSCs delivery system significantly enhances in vivo transplanted stem cell retention, promotes the vessel growth, and accelerates wound healing.

Conclusions

This novel delivery system, which overcomes the limitations of conventional plain collagen-based delivery system in lacking of ROS-environmental responsive mechanisms, demonstrates a great potential use in stem cell therapies in wound healing.
Effect of local anesthetics on viability and differentiation of various adult stem/progenitor cells
Authors: Kim Young Hoon , Park Ga Young , Rabinovitch Nechama , Tarafder Solaiman , Lee Chang H.
Published: September 2020

Background

Local anesthetics (LAs) are widely used to control pain during various clinical treatments. One of the side effects of LAs, cytotoxicity, has been investigated in various cells including stem/progenitor cells. However, our understanding of the effects of LAs on the differentiation capacity of stem/progenitor cells still remains limited. Therefore, a comparative study was conducted to investigate the effects of multiple LAs on viability and multi-lineage differentiation of stem/progenitor cells that originated from various adult tissues.

Method

Multiple types of stem/progenitor cells, including bone marrow mesenchymal stem/progenitor cells (MSCs), dental pulp stem/progenitor cells (DPSCs), periodontal ligament stem/progenitor cells (PDLSCs), and tendon-derived stem/progenitor cells, were either obtained from a commercial provider or isolated from adult human donors. Lidocaine (LD) and bupivacaine (BP) at various doses (1×, 0.75×, 0.5×, and 0.25× of each physiological dose) were applied to the different stem/progenitor cells for an hour, followed by induction of fibrogenic, chondrogenic, osteogenic, and adipogenic differentiation. Live/dead and MTT assays were performed at 24 h after the LD or BP treatment. At 2 weeks, qRT-PCR was conducted to evaluate the gene expressions associated with differentiation. After 4 weeks, multiple biochemical staining was performed to evaluate matrix deposition.

Results

At 24 h after LD or BP treatment, 1× and 0.75× physiological doses of LD and BP showed significant cytotoxicity in all the tested adult stem/progenitor cells. At 0.5×, BP resulted in higher viability than the same dose LD, with variance between cell types. Overall, the gene expressions associated with fibrogenic, chondrogenic, osteogenic, and adipogenic differentiation were attenuated in LD or BP pre-treated stem/progenitor cells, with notable dose-effect and dependence on types. In contrast, certain doses of LD and/or BP were found to increase specific gene expression, depending on the cell types.

Conclusion

Our data suggest that LAs such as LD and BP affect not only the viability but also the differentiation capacity of adult stem/progenitor cells from various anatomical sites. This study sheds light on stem cell applications for tissue regeneration in which isolation and transplantation of stem cells frequently involve LA administration.
Biological properties of bone marrow stem cells and adipose-derived stem cells derived from T2DM rats: a comparative study
Authors: Wang Lei , Shi Shaojie , Bai Ruiping , Wang Yue , Guo Zhao , Li Doudou
Published: September 2020

Background

Patients with type 2 diabetes mellitus (T2DM), especially those with poor glycemic control, are characterized by low bone mass and destruction of bone microstructure. Nowadays, autologous mesenchymal stem cells (auto-MSCs) have been used to repair defects and promote tissue regeneration due to handy source, low immunogenicity and self-renewing and multi-differentiating potential. However, T2DM changed the biological properties of auto-MSCs, and investigating the most suitable auto-MSCs for T2DM patients becomes a focus in tissue engineering.

Results

In this research, we compared the biological characteristics of adipose-derived stem cells (ASCs) and bone marrow stem cells (BMSCs) derived from T2DM rats. These results demonstrated that ASCs had a higher proliferation rate, colony-formation and cell-sheet forming ability, while BMSCs got better osteogenesis-related staining, expression of osteogenesis-related genes and proteins, and osteogenic capacity in vitro.

Conclusions

As it turned out, ASCs from T2DM had a higher proliferation, while BMSCs had significantly higher osteogenetic ability no matter in vitro and in vivo. Therefore, we should take into account the specific and dominated properties of MSC according to different needs to optimize the protocols and improve clinical outcomes for tissue regeneration of T2DM patients.
Shape-reserved stereo matching with segment-based cost aggregation and dual-path refinement
Authors: Huang Chih-Shuan , Huang Ya-Han , Chan Din-Yuen , Yang Jar-Ferr
Published: September 2020

Stereo matching is one of the most important topics in computer vision and aims at generating precise depth maps for various applications. The major challenge of stereo matching is to suppress inevitable errors occurring in smooth, occluded, and discontinuous regions. In this paper, the proposed stereo matching system uses segment-based superpixels and matching cost. After determination of edge and smooth regions and selection of matching cost, we suggest the segment-based adaptive support weights in cost aggregation instead of color similarity and spatial proximity only. The proposed dual-path depth refinements use the cross-based support region by referring texture features to correct the inaccurate disparities with iterative procedures to improve the depth maps for shape reserving. Specially for leftmost and rightmost regions, the segment-based refinement can greatly improve the mismatched disparity holes. The experimental results show that the proposed system can achieve higher accurate depth maps than the conventional methods.
Developmental stage-specific A-to-I editing pattern in the postnatal pineal gland of pigs (Sus scrofa)
Authors: Zhou Rong , Yao Wenye , Xie Chundi , Zhang Leixia , Pei Yangli , Li Hua , Feng Zheng , Yang Yalan , Li Kui
Published: September 2020

Background

RNA editing is a widespread post-transcriptional modification mechanism in mammalian genomes. Although many editing sites have been identified in domestic pigs (Sus scrofa), little is known about the characteristics and dynamic regulation of RNA editing in the pineal gland (PG), a small neuroendocrine gland that synthesizes and secretes melatonin, which is primarily responsible to modulate sleep patterns.

Results

This study analyzed the expression of adenosine-to-inosine (A-to-I) editing regulators and profiled the first dynamic A-to-I RNA editome during postnatal PG development. The results identified ADAR1 as the most abundantly expressed ADAR enzyme, which was down-regulated during postnatal PG development. Furthermore, 47,284 high-confidence RNA editing sites were identified, the majority of which (93.6%) were of the canonical A-to-I editing type, followed by C-to-T editing. Analysis of its characteristics showed that the A-to-I editing sites mostly localized in SINE retrotransposons PRE-1/Pre0_SS. Moreover, a strong deficiency and preference for guanine nucleotides at positions of one base upstream or downstream were found, respectively. The overall editing level at the puberty stage was higher than at both infancy and adulthood stages. Additionally, genome-wide RNA editing was found to exhibit a dynamic stage-specific fashion (postnatally). Genes that underwent developmental changes in RNA editing were associated with catabolic processes as well as protein localization and transport functions, implying that RNA editing might be responsible for the molecular machineries of the postnatal developing PG. Remarkably, RNA editing in 3′-UTRs might regulate gene expression by influencing miRNA binding during PG development.

Conclusions

This study profiles the first comprehensive developmental RNA editome in the pig PG, which contributes to the understanding of the importance of post-transcriptionally mediated regulation during mammalian postnatal PG development. Moreover, this study widely extends RNA editome resources in mammals.
Recent progress of prognostic biomarkers and risk scoring systems in chronic lymphocytic leukemia
Authors: Yun Xiaoya , Zhang Ya , Wang Xin
Published: September 2020

Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia with high heterogeneity in the western world. Thus, investigators identified a number of prognostic biomarkers and scoring systems to guide treatment decisions and validated them in the context of immunochemotherapy. A better understanding of prognostic biomarkers, including serum markers, flow cytometry outcomes, IGHV mutation status, microRNAs, chromosome aberrations and gene mutations, have contributed to prognosis in CLL. Del17p/ TP53 mutation, NOTCH1 mutation, CD49d, IGHV mutation status, complex karyotypes and microRNAs were reported to be of predictive values to guide clinical decisions. Based on the biomarkers above, classic prognostic models, such as the Rai and Binet staging systems, MDACC nomogram, GCLLSG model and CLL-IPI, were developed to improve risk stratification and tailor treatment intensity. Considering the presence of novel agents, many investigators validated the conventional prognostic biomarkers in the setting of novel agents and only TP53 mutation status/del 17p and CD49d expression were reported to be of prognostic value. Whether other prognostic indicators and models can be used in the context of novel agents, further studies are required.
The role of estrogen receptor beta in breast cancer
Authors: Zhou Yujing , Liu Xingdang
Published: September 2020

Breast cancer, a malignant tumor originating from mammary epithelial tissue, is the most common cancer among women worldwide. Challenges facing the diagnosis and treatment of breast cancer necessitate the search for new mechanisms and drugs to improve outcomes. Estrogen receptor (ER) is considered to be important for determining the diagnosis and treatment strategy. The discovery of the second estrogen receptor, ERβ, provides an opportunity to understand estrogen action. The emergence of ERβ can be traced back to 1996. Over the past 20 years, an increasing body of evidence has implicated the vital effect of ERβ in breast cancer. Although there is controversy among scholars, ERβ is generally thought to have antiproliferative effects in disease progression. This review summarizes available evidence regarding the involvement of ERβ in the clinical treatment and prognosis of breast cancer and describes signaling pathways associated with ERβ. We hope to highlight the potential of ERβ as a therapeutic target.
Qualitative research to explore the symptoms and impacts experienced by children with ulcerative colitis
Authors: Randall Jason A. , Guobyte Aiste , Delbecque Laure , Newton Louise , Symonds Tara , Hunter Theresa
Published: September 2020

Background

Ulcerative Colitis (UC) is a chronic gastrointestinal disease that often presents during one’s most productive years and is characterized by colon inflammation. Key symptoms and impacts in adults are well-known, however, experiences among pediatric populations have not been well documented. The purpose of this study was to understand the health-related quality of life and symptomatic experience of children (2–11 years) living with UC.

Methods

Qualitative, semi-structured face-to-face interviews were conducted. Children aged 5–11 years were interviewed, as well as their parents/caregivers in matched dyads. Parents/caregivers of children aged2–4 years were interviewed within a parent/caregiver-only cohort. All participants were recruited from the United States. Interviews were coded using thematic analysis.

Results

Key symptoms and impacts reflecting the lived experience of UC were identified following thematic analysis, generating a conceptual model. A total of 32 participants (20 parents/caregivers and 12 children) were interviewed. Results identified a substantial burden of UC in children. All children and parents/caregivers reported that they/their child experienced stomach/abdominal pain. Other symptoms discussed by over 75% were blood in stool, diarrhea/loose stools, stool urgency, incomplete evacuation, stool frequency, and feeling gassy/passing gas. The most frequently discussed impacts by over 75% of participants were on emotional and practical aspects, seriously affecting quality of life.

Conclusions

Qualitative analysis of the interviews identified a substantial burden of UC on children, with a profound impact on their lives. The symptomatic experience is reflective of adults and adolescents. A high level of agreement between parents/caregivers and children was demonstrated regarding the perception of the presence or absence of symptoms. Children aged 8–11 years showed higher levels of agreement with parents/caregivers than did younger children, indicating appropriateness of self-report of symptom data in the 8–11 years age group.
Hematological and demographic profile of Pakistani children with isolated ventricular septal defects (VSDs)
Authors: Sarwar Sumbal , Shabana  , Ehsan Farah , Tahir Amna , Jamil Mahrukh , Shahid Saleem Ullah , Hasnain Shahida , Khan Asim , Hyder Syed Najam
Published: September 2020

Background

Cardiac morphogenesis is a dynamic and complex process that involves a complex interaction of many genetic and environmental factors. Ventricular septal defects (VSDs) are the commonest congenital heart defects (CHDs), accounting for ~ 40% of all cardiac malformations. In Pakistan, the prevalence of VSD is increasing (4–6 in 1000 live births). In the current study, we aimed to determine the pattern of different hematological parameters and various risk factors in VSDs in local pediatric patients. We recruited the clinically diagnosed VSD children (n= 125) from various hospitals. The diagnosis was made based on echocardiography, size, number, and exact location of the defect. Hematological parameters, chemical pathological assays, and liver function analysis were performed. The blood group distribution and various risk factors were also assessed. The statistical analysis was done using the SPSS (IBM statistics version 22) software.

Results

The results showed that for RBCs, 20% of patients in category of 0 to 3 months are above normal range; for WBCs, 33.3% of patients are above normal range in category of 4–5 years and 12–14 years. For hemoglobin, highest percentage of patients was observed below normal range; 30% of patients in category of 0 to 3 months, 40% of patients in category 4–9 months, 35.2% of patients in category of 10 months–3 years, and 33.3% of patients in category of 12–14 years were below normal range. For platelet count, 5.66% patients were below normal range and 16.9% were above normal range. For prothrombin time (PT) and activated partial thromboplastin time (APTT) more than 90% patients were in normal range value. Elevated ALP level and significantly lower albumin levels were observed. In age range of 13–14 years, 50% patients were below range for both calcium and serum creatinine. The prevalence of cousin marriages was 62.3%, about 60% mothers used antibiotics during pregnancy, B + ve and O + ve had the highest frequencies, and most of the patients were seen in age group of 2–35 months.

Conclusion

All tested parameters show divergence from normal values their predictive capabilities of VSDs. To the best of our knowledge, the present study is the first to report data on hematological parameters and demographic risk factor associated with VSDs, in the Pakistani children. This data may have implication on the characterization and diagnosis of VSDs as well as on the assessment of related risk factors.
Diffusion-weighted MRI in staging of post hepatitis C fibrosis: does ADC value challenge liver biopsy?
Authors: Serag Dena , Ragab Eman
Published: September 2020

Background

There is obvious interest in finding a non-invasive diagnostic tool to detect the development of hepatic fibrosis and distinguish between its various stages. Chronic inflammation of the liver secondary to viral hepatitis, autoimmune conditions, sclerosing cholangitis, drug toxicity, chronic alcohol intake, different metabolic disorders, and steatosis lead to fibrosis and maybe cirrhosis. The current study aimed to assess the usefulness of diffusion-weighted magnetic resonance imaging (DW-MRI) in diagnosis of post hepatitis C fibrosis and detection of its stage.

Results

A prospective study had included 232 participants; 120 patients had chronic hepatitis C with/without HCC and 112 subjects had normal liver. There was no significant difference between the two groups regarding age or gender (p 0.192 and 0.227 respectively). DW-MRI was performed using 1.5 T machine. The mean liver ADC values and normalized liver ADC (liver ADC/spleen ADC) were measured at b value 800 s/mm2; both were significantly lower among cases than controls. Cutoff values of liver ADC were 1.531 × 10−3 mm2/s, 1.409 × 10−3 mm2/s, 1.192 × 10−3 mm2/s, and 1.093 × 10−3 mm2/s for METAVIR stages ≥ F1, ≥ F2, ≥ F3, and F4, respectively. Normalized liver ADC showed larger area under the curve (AUC) than mean liver ADC in all differentiation categories except for differentiating between F0 and all other fibrosis stages.

Conclusion

In line with the literature, DW-MR imaging using b value of 800 s/mm2 has proved to be a valuable diagnostic technique for detection and staging of post hepatitis C fibrosis/cirrhosis being noninvasive procedure with acceptable accuracy. DWI using liver/spleen ADC values raised the diagnostic performance with AUC more than 90% in all fibrosis stages on METAVIR score.
Clinical Characteristics and Long-term Follow-up of Patients with Diabetes Due To PTF1A Enhancer Mutations
Authors: Demirbilek Huseyin , Cayir Atilla , Flanagan Sarah E , Yıldırım Ruken , Kor Yılmaz , Gurbuz Fatih , Haliloğlu Belma , Yıldız Melek , Baran Rıza Taner , Akbas Emine Demet , Demiral Meliha , Ünal Edip , Arslan Gulcin , Vuralli Dogus , Buyukyilmaz Gonul , Al-Khawaga Sara , Saeed Amira , Al Maadheed Maryam , Khalifa Amel , Onal Hasan , Yuksel Bilgin , Ozbek Mehmet Nuri , Bereket Abdullah , Hattersley Andrew T , Hussain Khalid , De Franco Elisa
Published: September 2020

Context

Biallelic mutations in the PTF1A enhancer are the commonest cause of isolated pancreatic agenesis. These patients do not have severe neurological features associated with loss-of-function PTF1A mutations. Their clinical phenotype and disease progression have not been well characterized.

Objective

To evaluate phenotype and genotype characteristics and long-term follow-up of patients with PTF1A enhancer mutations.

Setting

Twelve tertiary pediatric endocrine referral centers.

Patients

Thirty patients with diabetes caused by PTF1A enhancer mutations. Median follow-up duration was 4 years.

Main Outcome Measures

Presenting and follow-up clinical (birthweight, gestational age, symptoms, auxology) and biochemical (pancreatic endocrine and exocrine functions, liver function, glycated hemoglobin) characteristics, pancreas imaging, and genetic analysis.

Results

Five different homozygous mutations affecting conserved nucleotides in the PTF1A distal enhancer were identified. The commonest was the Chr10:g.23508437A>G mutation (n = 18). Two patients were homozygous for the novel Chr10:g.23508336A>G mutation. Birthweight was often low (median SDS = –3.4). The majority of patients presented with diabetes soon after birth (median age of diagnosis: 5 days). Only 2/30 presented after 6 months of age. All patients had exocrine pancreatic insufficiency. Five had developmental delay (4 mild) on long-term follow-up. Previously undescribed common features in our cohort were transiently elevated ferritin level (n = 12/12 tested), anemia (19/25), and cholestasis (14/24). Postnatal growth was impaired (median height SDS: –2.35, median BMI SDS: –0.52 SDS) with 20/29 (69%) cases having growth retardation.

Conclusion

We report the largest series of patients with diabetes caused by PTF1A enhancer mutations. Our results expand the disease phenotype, identifying recurrent extrapancreatic features which likely reflect long-term intestinal malabsorption.
Integration of Islet/Beta-Cell Transplants with Host Tissue Using Biomaterial Platforms
Authors: Clough Daniel W , King Jessica L , Li Feiran , Shea Lonnie D
Published: September 2020

Cell-based therapies are emerging for type I diabetes mellitus (T1D), an autoimmune disease characterized by the destruction of insulin-producing pancreatic β-cells, as a means to provide long-term restoration of glycemic control. Biomaterial scaffolds provide an opportunity to enhance the manufacturing and transplantation of islets or stem cell–derived β-cells. In contrast to encapsulation strategies that prevent host contact with the graft, recent approaches aim to integrate the transplant with the host to facilitate glucose sensing and insulin distribution, while also needing to modulate the immune response. Scaffolds can provide a supportive niche for cells either during the manufacturing process or following transplantation at extrahepatic sites. Scaffolds are being functionalized to deliver oxygen, angiogenic, anti-inflammatory, or trophic factors, and may facilitate cotransplantation of cells that can enhance engraftment or modulate immune responses. This local engineering of the transplant environment can complement systemic approaches for maximizing β-cell function or modulating immune responses leading to rejection. This review discusses the various scaffold platforms and design parameters that have been identified for the manufacture of human pluripotent stem cell–derived β-cells, and the transplantation of islets/β-cells to maintain normal blood glucose levels.
Paraventricular Dynorphin A Neurons Mediate LH Pulse Suppression Induced by Hindbrain Glucoprivation in Female Rats
Authors: Tsuchida Hitomi , Mostari Parvin , Yamada Koki , Miyazaki Sae , Enomoto Yuki , Inoue Naoko , Uenoyama Yoshihisa , Tsukamura Hiroko
Published: September 2020

Malnutrition suppresses reproductive functions in mammals, which is considered to be mostly due to the inhibition of pulsatile gonadotropin-releasing hormone (GnRH)/gonadotropin secretion. Accumulating evidence suggests that kisspeptin neurons in the arcuate nucleus (ARC) play a critical role in the regulation of pulsatile GnRH/gonadotropin release. The present study aimed to examine if the hypothalamic dynorphin A (Dyn) neurons mediate the suppression of GnRH/luteinizing hormone (LH) pulses during malnutrition. Ovariectomized rats treated with a negative feedback level of estradiol-17β-treated (OVX+E2) were administered with intravenous (iv) or fourth cerebroventricle (4V) 2-deoxy-D-glucose (2DG), an inhibitor of glucose utilization, to serve as a malnutrition model. Central administration of a Dyn receptor antagonist blocked the iv- or 4V-2DG-induced suppression of LH pulses in OVX+E2 rats. The 4V 2DG administration significantly increased the number of Pdyn (Dyn gene)-positive cells co-expressing fos in the paraventricular nucleus (PVN), but not in the ARC and supraoptic nucleus (SON), and the iv 2DG treatment significantly increased the number of fos and Pdyn-co-expressing cells in the PVN and SON, but decreased it in the ARC. The E2 treatment significantly increased Pdyn expression in the PVN, but not in the ARC and SON. Double in situ hybridization for Kiss1 (kisspeptin gene) and Oprk1 (Dyn receptor gene) revealed that around 60% of ARC Kiss1-expressing cells co-expressed Oprk1. These results suggest that the PVN Dyn neurons, at least in part, mediate LH pulse suppression induced by the hindbrain or peripheral glucoprivation, and Dyn neurons may directly suppress the ARC kisspeptin neurons in female rats.
Differential Effects of Voclosporin and Tacrolimus on Insulin Secretion From Human Islets
Authors: Kolic Jelena , Beet Leanne , Overby Peter , Cen Haoning Howard , Panzhinskiy Evgeniy , Ure Daren R , Cross Jennifer L , Huizinga Robert B , Johnson James D
Published: September 2020

The incidence of new onset diabetes after transplant (NODAT) has increased over the past decade, likely due to calcineurin inhibitor–based immunosuppressants, including tacrolimus (TAC) and cyclosporin. Voclosporin (VCS), a next-generation calcineurin inhibitor, is reported to cause fewer incidences of NODAT but the reason is unclear. While calcineurin signaling plays important roles in pancreatic β-cell survival, proliferation, and function, its effects on human β-cells remain understudied. In particular, we do not understand why some calcineurin inhibitors have more profound effects on the incidence of NODAT. We compared the effects of TAC and VCS on the dynamics of insulin secretory function, programmed cell death rate, and the transcriptomic profile of human islets. We studied 2 clinically relevant doses of TAC (10 ng/mL, 30 ng/mL) and VCS (20 ng/mL, 60 ng/mL), meant to approximate the clinical trough and peak concentrations. TAC, but not VCS, caused a significant impairment of 15 mM glucose-stimulated and 30 mM KCl-stimulated insulin secretion. This points to molecular defects in the distal stages of exocytosis after voltage-gated Ca2+ entry. No significant effects on islet cell survival or total insulin content were identified. RNA sequencing showed that TAC significantly decreased the expression of 17 genes, including direct and indirect regulators of exocytosis (SYT16, TBC1D30, PCK1, SMOC1, SYT5, PDK4, and CREM), whereas VCS has less broad, and milder, effects on gene expression. Clinically relevant doses of TAC, but not VCS, directly inhibit insulin secretion from human islets, likely via transcriptional control of exocytosis machinery.
Myosin 1b flattens and prunes branched actin filaments
Authors: Pernier Julien , Morchain Antoine , Caorsi Valentina , Bertin Aurélie , Bousquet Hugo , Bassereau Patricia , Coudrier Evelyne
Published: September 2020

Motile and morphological cellular processes require a spatially and temporally coordinated branched actin network that is controlled by the activity of various regulatory proteins, including the Arp2/3 complex, profilin, cofilin and tropomyosin. We have previously reported that myosin 1b regulates the density of the actin network in the growth cone. Here, by performing in vitro F-actin gliding assays and total internal reflection fluorescence (TIRF) microscopy, we show that this molecular motor flattens (reduces the branch angle) in the Arp2/3-dependent actin branches, resulting in them breaking, and reduces the probability of new branches forming. This experiment reveals that myosin 1b can produce force sufficient enough to break up the Arp2/3-mediated actin junction. Together with the former in vivo studies, this work emphasizes the essential role played by myosins in the architecture and dynamics of actin networks in different cellular regions.

This article has an associated First Person interview with the first author of the paper.
Laryngeal and soft palate valving in the harbour seal (Phoca vitulina)
Authors: Adams Arlo , Vogl Wayne , Dawson Camilla , Raverty Stephen , Haulena Martin , Skoretz Stacey A.
Published: September 2020

Effective ‘valving’ in the upper aerodigestive tract (UAT) is essential to temporarily separate the digestive and respiratory pathways. Marine mammals are largely dedicated to feeding underwater, and in many cases swallowing prey whole. In seals, little work has been done to explore the anatomy and function of the upper aerodigestive tract in the context of valving mechanisms that function to separate food and air pathways. Here we use videofluoroscopy, gross dissection, histology and CT renderings to explore the anatomy of the larynx and soft palate in the harbour seal (Phoca vitulina), and generate models for how valving mechanisms in the head and neck may function during breathing, phonating, diving and swallowing. Harbour seals have an elevated larynx and the epiglottis may rise above the level of the soft palate, particularly in pups when sucking. In addition, the corniculate and arytenoid cartilages with associated muscles form most of the lateral margins of the laryngeal inlet and vestibule, and move independently to facilitate airway closure. The corniculate cartilages flex over the laryngeal inlet beneath the epiglottis to completely close the laryngeal vestibule and inlet. The vocal folds are thick and muscular and the medial margin of the folds contains a small vocal ligament. The soft palate has well-defined levator veli palatini muscles that likely function to elevate the palate and close the pharyngeal isthmus during feeding. Our results support the conclusion that harbour seals have evolved UAT valving mechanisms as adaptations to a marine environment that are not seen in terrestrial carnivores.
Gills versus kidney for ionoregulation in the obligate air-breathingArapaima gigas, a fish with a kidney in its air-breathing organ
Authors: Wood Chris M. , Pelster Bernd , Braz-Mota Susana , Val Adalberto L.
Published: September 2020

In Arapaima gigas, an obligate air-breather endemic to ion-poor Amazonian waters, a large complex kidney runs through the air-breathing organ (ABO). Previous indirect evidence suggested the kidney, relative to the small gills, may be exceptionally important in ionoregulation and N-waste excretion, with support of kidney function by direct O2 supply from the air-space. We tested these ideas by continuous urine collection and gill flux measurements in ∼700g fish. ATPase activities were many-fold greater in kidney than gills. In normoxia, gill Na+ influx and efflux were in balance, with net losses of Cl− and K+. Urine flow rate (UFR, ∼11 ml kg−1 h−1) and urinary ions (< 0.2 mmol L−1) were exceptional, with [urine]/[plasma]ratios of 0.02-0.002 for K+, Na+, and Cl−, indicating strong reabsorption with negligible urinary ion losses. Urinary [ammonia] was very high (10 mmol L−1, [urine]/[plasma] ∼20) indicating strong secretion. The kidney accounted for 21 – 24% of N-excretion, with ammonia dominating (95%) over urea-N through both routes. High urinary [ammonia] was coupled to high urinary [HCO3−]. Aerial hypoxia (15.3 kPa) and aerial hyperoxia (>40.9 kPa) had no effects on UFR, but both inhibited branchial Na+ influx, revealing novel aspects of the osmo-respiratory compromise. Aquatic hypoxia (4.1 kPa), but not aquatic hyperoxia (>40.9 kPa), inhibited gill Na+ influx, UFR and branchial and urinary ammonia excretion. We conclude that the kidney is more important than gills in ionoregulation, and is significant in N-excretion. While not definitive, our results do not indicate direct O2 supply from the ABO for kidney function.
Ecology, distribution and expansion of a Mediterranean native invader, the fireworm Hermodice carunculata (Annelida)
Authors: RIGHI SARA , PREVEDELLI DANIELA , SIMONINI ROBERTO
Published: September 2020

Global change and the overall raise of seawater temperature are causing a poleward shift in species distribution, increasing the occurrence of warm-water biota in many ecosystems worldwide. In the Mediterranean, the ongoing sea warming is promoting native subtropical species to invader status. The bearded fireworm Hermodice carunculata (Amphinomida) is a thermophilic generalist predator spreading in the Central Mediterranean Sea. Although it is a typical inhabitant of Ionian coasts, several sightings have occurred at more northerly localities along the Tyrrhenian and Adriatic Seas, suggesting that density increases and range expansion are underway. These distributional records are in contrast with historical literature and museum collections, which provide poor sporadic information.The present study aimed at investigating the spatiotemporal changes that have occurred in H. carunculata abundances and distribution in the Mediterranean basins surrounding the Italian peninsula so far. We examined an exhaustive collection of existing information. A total of 857 reports of H. carunculata were collected from 368 localities. These data significantly expand knowledge on the life and feeding habit of H. carunculata. The integration of different data sources allowed the reconstruction of the shifts that have happened over the last 50 years, which are coherent with the consistent warming trend of Mediterranean Sea surface temperatures. Recent colonization events have occurred both along the Adriatic and Western Mediterranean coasts. The present findings provide unique insights into the expansion of H. carunculata, supporting future spreading throughout the Northern and Western Mediterranean. Tracking these changes is critical to assess potential impacts on coastal rocky-benthic communities, public health and commercial fisheries.