bluuebunny/crossref_metadata_2025 huggingface dataset:
Overstimulation of the ergoreflex—A possible mechanism to explain symptoms in long COVID
Authors: Sze Shirley , Pan Daniel , Moss Alastair J. , Ong Cheng Ken , Pareek Manish , Squire Iain B. , Clark Andrew L.
Published: July 2022

Long COVID refers to a multitude of symptoms that persist long after SARS-CoV-2 infection. Fatigue and breathlessness are the most common symptoms of long COVID across a range of studies. They are also cardinal symptoms of chronic heart failure (CHF). In this review, we propose that fatigue and breathlessness in patients with long COVID may be explained by skeletal muscle abnormalities, in a manner similar to patients with CHF. The ergoreflex is a cardiorespiratory reflex activated by exercise, which couples ventilation and cardiovascular function to exercise intensity. At least part of the symptomatology of CHF is related to abnormal skeletal muscle and an enhanced ergoreflex, resulting in heightened sympathetic, vasoconstrictor and ventilator drives. Similarly, SARS-CoV-2 infection results in a hyperinflammatory and hypercatabolic state. This leads to reduction in skeletal muscle mass and altered function. We postulate that the ergoreflex is chronically overstimulated, resulting in fatigue and breathlessness. Exercise training preserves muscle mass and function as well as reduces ergoreflex activation; therefore may have a role in improving symptoms associated with long COVID. Should the ergoreflex be proven to be an important pathophysiological mechanism of long COVID, tailored exercise interventions should be trialed with the aim of improving both symptoms and perhaps outcomes in patients with long COVID.
A pioneer surgical technique for isolated periodontal defects by “closed” retraction of the papilla: A feasibility study
Authors: Apatzidou Danae Anastasia
Published: July 2022

Aim

A pioneer periodontal surgical approach employing the closed surgical technique (CST) in combination with the tissue-engineered biocomplex aimed to gain access to the osseous defect and improve soft tissue architecture.

Methods

The CST was applied in four systemically healthy periodontitis patients/defects who were followed for 12 months. It avoids papilla dissection and retraction of flaps in an open manner; thus, suturing is not required. It is designed for the reconstruction of residual isolated periodontal defects and is best indicated in the aesthetic region. It can be applied as a sole treatment approach to facilitate deep instrumentation of the defect, or it could be combined with subgingival application of regenerative materials. Hereby, the biocomplex was applied containing autologous alveolar bone marrow mesenchymal stem cells, seeded into collagen scaffolds, enriched with autologous fibrin/platelet lysate.

Results

The CST minimized postoperative discomfort and led to improved treatment outcomes with probing pocket depth reduction [average (SD)] of 24.4% (18.5), gain in clinical attachment levels of 25.8% (20.1), and evidence of remineralisation of the alveolar crest.

Conclusion

The CST is a tissue-friendly operation and facilitates subgingival application of biological agents via tunneling the soft tissues. However, surgical experience is required for nontraumatic manipulation of the gingival tissues during “closed” retraction of the flaps.

Clinical trial registration

Registered with Clinicaltrials.gov; ClinicalTrials.gov ID: NCT02449005.
Effectiveness and Tolerability of Once-Weekly GLP-1 Receptor Agonists in Clinical Practice: A Focus on Switching Between Once-Weekly Molecules in Type 2 Diabetes
Authors: Di Dalmazi Giulia , Coluzzi Sara , Baldassarre Maria Pompea Antonia , Ghit Amr , Graziano Giusi , Rossi Maria Chiara , Ciappini Beatrice , Milo Marica , Carrieri Federica , Nicolucci Antonio , Consoli Agostino , Formoso Gloria
Published: July 2022

Aims

This study aims to evaluate the effectiveness and tolerability of once-weekly glucagon-like peptide receptor agonists (OW GLP-1RAs) and to assess the clinical benefits of switching from one GLP-1RA to another (switchers) in a routine clinical setting.

Materials and Methods

This is a retrospective, real-world cohort study, based on electronic medical records utilized in one Italian diabetes clinic. Estimated mean changes in HbA1c and body weight after 6 and 12 months from the first prescription of a long-acting GLP1-RA were evaluated using longitudinal linear mixed models for repeated measures. The effectiveness of the three long-acting GLP1-RAs was compared separately in the GLP1-RA naive and switchers cohorts, after propensity score adjustment.

Results

Initiating a long-acting GLP1-RA was associated with statistically significant improvements in HbA1c (−1%) and body weight (−2.6 kg) after 6 months, and benefits were maintained after 12 months. In GLP1-RA naive cohort, semaglutide showed the largest effect on HbA1c (−1.55%; 95%CI, −1.77;−1.34) and body weight (−3.76 kg; 95%CI, −5.05;−2.47) at 6 months, maintained at 12 months (−1.55%; 95%CI, −1.82;−1.28 and −6.29 kg; 95%CI, −7.94;−4.63). In the switchers’ cohort, statistically significant reductions at 6 months in HbA1c and body weight were documented with semaglutide and dulaglutide only, with semaglutide associated with the most marked reduction (−0.84%; 95%CI, −1.03;−0.65 and −3.43 kg; 95%, −4.67;−2.19). Dropout rates were 9.2%, 28.5%, and 41.7% in semaglutide, dulaglutide, and exenatide groups, respectively.

Conclusions

The effectiveness and tolerability of the OW GLP-1RAs in the real world were documented. Semaglutide was associated with the highest response without impact on safety. Clinical improvements were obtained even in switchers, especially in those switching to semaglutide.
Children With Short Stature Display Reduced ACE2 Expression in Peripheral Blood Mononuclear Cells
Authors: Tonon Federica , Tornese Gianluca , Giudici Fabiola , Nicolardi Francesca , Toffoli Barbara , Barbi Egidio , Fabris Bruno , Bernardi Stella
Published: July 2022

Background

The cause of short stature remains often unknown. The renin-angiotensin system contributes to growth regulation. Several groups reported that angiotensin-converting enzyme 2 (ACE2)-knockout mice weighed less than controls. Our case-control study aimed to investigate if children with short stature had reduced ACE2 expression as compared to controls, and its significance.

Materials and Methods

children aged between 2 and 14 years were consecutively recruited in a University Hospital pediatric tertiary care center. Cases were children with short stature defined as height SD ≤ −2 diagnosed with growth hormone deficiency (GHD) or idiopathic short stature (ISS), before any treatment. Exclusion criteria were: acute diseases, kidney disease, endocrine or autoimmune disorders, precocious puberty, genetic syndromes, SGA history. ACE and ACE2 expression were measured in peripheral blood mononuclear cells, angiotensins were measured by ELISA.

Results

Children with short stature displayed significantly lower ACE2 expression, being 0.40 fold induction (0.01-2.27) as compared to controls, and higher ACE/ACE2, with no differences between GHD and ISS. ACE2 expression was significantly and inversely associated with the risk of short stature, OR 0.26 (0.07-0.82), and it had a moderate accuracy to predict it, with an AUC of 0.73 (0.61-0.84). The cutoff of 0.45 fold induction of ACE2 expression was the value best predicting short stature, identifying correctly 70% of the children.

Conclusions

Our study confirms the association between the reduction of ACE2 expression and growth retardation. Further studies are needed to determine its diagnostic implications.
Circulating Fibroblast Growth Factor 21 and Total Testosterone in Type 2 Diabetes Mellitus Men With Coronary Heart Disease
Authors: Mei Yufeng , Lyu Yongnan , Zhao Zhiming , Li Yan
Published: July 2022

Background

Fibroblast growth factor 21 increased in population with type 2 diabetes mellitus (T2DM), while serum total testosterone often decreased in men with T2DM. This study aimed to investigate the relationship between the prevalence of coronary artery disease (CAD) and circulating FGF21 concentrations and serum testosterone in T2DM men.

Methods

490 men with T2DM from January 2021 to December 2021 were recruited from the Renmin Hospital of Wuhan University, and they were divided into CAD group (n=248) and control group (n=242). FGF21 were determined based on ELISA principle and serum total testosterone was measured in a liquid chromatography mass spectrometer LC/MS-8050 (Shimadzu, Japan). Logistic and restricted cubic spline analyses were performed to examine the association between the prevalence of CAD and circulating FGF21 concentrations and serum testosterone in T2DM men. The receiver operating curve (ROC) analysis was used to explore the predictive performance.

Results

Circulating FGF21 levels were higher in T2DM men with CAD compared with those without CAD [214.63 (121.82, 348.64) pg/ml vs 166.55 (94.81,254.48) pg/ml, p<0.001], while serum total testosterone was lower [3.08 ± 0.07 ng/ml vs 3.76 ± 0.09 ng/ml, p<0.001]. The fully adjusted odds ratio (OR) and 95% confidence intervals (95%CI) was 2.956(1.409,6.201) for those in quartile 4 of FGF21 versus quartile 1 and the fully adjusted OR (95%CI) was 0.346(0.174,0.686) for those in quartile 4 of testosterone versus quartile 1. The receiver operating curve (ROC) analysis showed that the area under the curve (AUC) of combination of FGF21 and testosterone for predicting the occurrence of CAD in men with T2DM was 0.702 (95% CI: 0.667-0.741).

Conclusion

Circulating FGF21 levels were positively associated with CAD in men with T2DM, whereas serum total testosterone levels showed an inverse correlation with CAD in diabetic men.
Case Report: A novel WRN mutation in Werner syndrome patient with diabetic foot disease and myelodysplastic syndrome
Authors: Peng Huifang , Wang Jie , Liu Yanyun , Yang Haiping , Li Liping , Ma Yujin , Zhuo Huiqin , Jiang Hongwei
Published: July 2022

Werner syndrome is an autosomal recessive rare disease caused by a WRN gene mutation, which is rarely reported in the Chinese population. We report the clinical and genetic data of a Chinese patient with Werner syndrome. The proband was a 40-year-old male patient who presented with diabetic foot ulcers, accompanied by short stature, cataracts, hypogonadism, and hair thinning, and myelodysplastic syndrome (MDS) occurred after 18 months. Genetic sequencing showed there were compound heterozygous mutations as c.3384-1G>C and c.3744dupA in the WRN gene. The c.3744dupA mutation is a novel pathogenic variation for Werner syndrome.
Nomogram model based on preoperative serum thyroglobulin and clinical characteristics of papillary thyroid carcinoma to predict cervical lymph node metastasis
Authors: Chang Qungang , Zhang Jieming , Wang Yaqian , Li Hongqiang , Du Xin , Zuo Daohong , Yin Detao
Published: July 2022

Objective

Preoperative evaluation of cervical lymph node metastasis (LNM) in papillary thyroid carcinoma (PTC) has been one of the serious clinical challenges. The present study aims at understanding the relationship between preoperative serum thyroglobulin (PS-Tg) and LNM and intends to establish nomogram models to predict cervical LNM.

Methods

The data of 1,324 PTC patients were retrospectively collected and randomly divided into training cohort (n = 993) and validation cohort (n = 331). Univariate and multivariate logistic regression analyses were performed to determine the risk factors of central lymph node metastasis (CLNM) and lateral lymph node metastasis (LLNM). The nomogram models were constructed and further evaluated by 1,000 resampling bootstrap analyses. The receiver operating characteristic curve (ROC curve), calibration curve, and decision curve analysis (DCA) of the nomogram models were carried out for the training, validation, and external validation cohorts.

Results

Analyses revealed that age, male, maximum tumor size >1 cm, PS-Tg ≥31.650 ng/ml, extrathyroidal extension (ETE), and multifocality were the significant risk factors for CLNM in PTC patients. Similarly, such factors as maximum tumor size >1 cm, PS-Tg ≥30.175 ng/ml, CLNM positive, ETE, and multifocality were significantly related to LLNM. Two nomogram models predicting the risk of CLNM and LLNM were established with a favorable C-index of 0.801 and 0.911, respectively. Both nomogram models demonstrated good calibration and clinical benefits in the training and validation cohorts.

Conclusion

PS-Tg level is an independent risk factor for both CLNM and LLNM. The nomogram based on PS-Tg and other clinical characteristics are effective for predicting cervical LNM in PTC patients.
Brief Report - Monoclonal Antibodies Illustrate the Difficulties in Measuring Blocking TSH Receptor Antibodies
Authors: Davies Terry F. , Morshed Syed A. , Mezei Mihaly , Latif Rauf
Published: July 2022

TSH receptor (TSHR) antibodies are the cause of Graves’ disease and may also be found in patients with Hashimoto’s thyroiditis. They come in at least three varieties: thyroid stimulating, thyroid blocking and neutral. The measurement of TSH receptor antibodies in Graves’ disease and Hashimoto’s thyroiditis is a common clinical activity and can be useful in diagnosis and prognosis. We show that it is not possible to detect the blocking variety of TSHR antibody in patients with Graves’ disease because the stimulating antibody may overwhelm the measurement of blocking in the bioassays available for their measurement and may blind the valid interpretation of the results. To help explain this in more detail we show a series of studies with monoclonal TSHR antibodies which support this conclusion.
Development of DC Microgrid Integrated Electric Vehicle Charging Station With Fuzzy Logic Controller
Authors: Hadero Mathewos , Khan Baseem
Published: July 2022

The utilization of the electric vehicles increasing day by day. Further, energy grid infrastructure is not modernized enough to supply the growing demand of electric vehicles. Therefore, it is difficult to fully depend on the energy obtained from grid. As a result, integration of renewable energy (solar), grid supply and energy storage is critical. Therefore, the need of renewable energy powered charging facility with adequate controlling is the present day requirement. This paper proposed the development of a direct current (DC) microgrid for electric vehicle charging stations. This work employs a fuzzy logic controller to optimally integrate a DC microgrid. The maximum operating voltage of this DC microgrid charging station is 500 V. Power flow management using a fuzzy logic controller keeps voltage within the expected range with standard voltage deviation. Further, it improves the response time (1.645 ms). Moreover, the operating costs per year of the proposed system are also being investigated.
Rehabilitating Valley Floors to a Stage 0 Condition: A Synthesis of Opening Outcomes
Authors: Flitcroft Rebecca L. , Brignon William R. , Staab Brian , Bellmore J. Ryan , Burnett Jonathan , Burns Paul , Cluer Brian , Giannico Guillermo , Helstab Joseph M. , Jennings Jeremy , Mayes Christopher , Mazzacano Celeste , Mork Lauren , Meyer Kate , Munyon Jay , Penaluna Brooke E. , Powers Paul , Scott Daniel N. , Wondzell Steven M.
Published: July 2022

Degraded floodplains and valley floors are restored with the goal of enhancing habitat for native fish and aquatic-riparian biota and the protection or improvement of water quality. Recent years have seen a shift toward “process-based restoration” that is intended to reestablish compromised ecogeomorphic processes resulting from site- or watershed-scale degradation. One form of process-based restoration has developed in the Pacific Northwest, United States, that is intended to reconnect rivers to their floodplains by slowing down flows of sediment, water, and nutrients to encourage lateral and vertical connectivity at base flows, facilitating development of dynamic, self-forming, and self-sustaining river-wetland corridors. Synergies between applied practices and the theoretical work of Cluer and Thorne in 2014 have led this form of restoration to be referred to regionally as restoration to a Stage 0 condition. This approach to rehabilitation is valley scale, rendering traditional monitoring strategies that target single-thread channels inadequate to capture pre- and post-project site conditions, thus motivating the development of novel monitoring approaches. We present a specific definition of this new type of rehabilitation that was developed in collaborative workshops with practitioners of the approach. Further, we present an initial synthesis of results from monitoring activities that provide a foundation for understanding the effects of this approach of river rehabilitation on substrate composition, depth to groundwater, water temperature, macroinvertebrate richness and abundance, secondary macroinvertebrate production, vegetation conditions, wood loading and configuration, water inundation, flow velocity, modeled juvenile salmonid habitat, and aquatic biodiversity.
Spatiotemporal Variations of Ecosystem Service Indicators and the Driving Factors Under Climate Change in the Qinghai–Tibet Highway Corridor
Authors: Yang Siqi , Zhu Gaoru , Zhang Lixiao , Xu Honglei , Cheng Jinxiang
Published: July 2022

In recent decades, the influence of climate change and human activities on the ecosystem services (ES) in the Qinghai–Tibet Plateau (QTP) has been extensively investigated. However, few studies focus on linear traffic corridor area, which is heavily affected by human activities. Taking the Golmud–Lhasa national highway corridor as a case, this study investigated the land-use and land-cover change (LUCC) and spatiotemporal variations of ES indicators using ecosystem indices of fractional vegetation cover (FVC), leaf area index (LAI), evapotranspiration (ET), and net primary productivity (NPP) from 2000 to 2020. The results indicated that LUCC was faster in the last decade, mostly characterized by the conversion from grassland to unused land. In buffer within 3000 m, the proportions of productive areas represented the increased trends with distance. In terms of ES variations, the improved areas outweighed the degraded areas in terms of FVC, LAI, and NPP from 2000 to 2020, mostly positioned in the Qinghai Province. In addition, FVC, LAI, and NPP peaked at approximately 6000 m over time. With regard to influencing factors, precipitation (20.54%) and temperature (14.19%) both positively influenced the spatiotemporal variation of FVC. Nearly 60% of the area exhibited an increased NPP over time, especially in the Qinghai Province, which could be attributed to the temperature increase over the last two decades. In addition, the distance effects of climatic factors on ES indicators exhibited that the coincident effects almost showed an opposite trend, while the reverse effects showed a similar trend. The findings of this study could provide a reference for the ecological recovery of traffic corridors in alpine fragile areas.
Variations in the Yamuna River Water Quality During the COVID-19 Lockdowns
Authors: Singh Bhupendra Pratap , Rana Pallvi , Mittal Nishtha , Kumar Sumit , Athar Mohammad , Abduljaleel Zainularifeen , Rahman Shakilur
Published: July 2022

The COVID-19 pandemic that emerged in Wuhan city of China in December 2019 has adversely impacted the health and the economy, society, and other significant spheres of the human environment. The pandemic has severely impacted economic activities, especially the industrial production, transportation, tourism, and hoteling industries. The present study analyses the impact of varying severity of lockdowns of economic activities during various phases of the pandemic on the water quality of the Yamuna river on parameters like pH values, biological oxygen demand, chemical oxygen demand, dissolved oxygen, total suspended solids, and electrical conductivity. The study has found a significant improvement in water quality parameters with closing economic activities during lockdowns. The average levels of concentration of these parameters of water quality were quite low during the lockdown period at 7.26 (pH value), 31.32, 136.07, 7.93, 30.33 mg/L, and 1500.24 μS/cm compared to pre lockdown periods levels at 7.53 (pH), 39.62, 116.52, 6.1, 57.2 mg/L and 1743.01 μS/cm for biological oxygen demand, chemical oxygen demand, dissolved oxygen, total suspended solids, and electrical conductivity, respectively. In addition, the study has found a strong significant positive correlation between COD with BOD and TSS during the lockdown period. The major findings from the present study could be instrumental in making environmentally sustainable policies for the country’s economic development. There is also a huge scope of scaling up of the study at the national level to analyze the health of the rivers in the backdrop of lockdowns.
SYK Is Associated With Malignant Phenotype and Immune Checkpoints in Diffuse Glioma
Authors: Zhou Quanwei , Wei Min , Shen Wenyue , Huang Sheng , Fan Jianfeng , Huang He
Published: July 2022

Background: Diffuse glioma, the most common intracranial malignant tumor, is characterized by immunosuppression. The prognostic significance and potential therapeutic value of SYK remain obscure. Here, we explored the performance of SYK in predicting patient outcomes and as a therapeutic target.

Methods: The mRNA expression and clinical data for pancancer and normal tissues and more than 2,000 glioma samples were collected from public databases. The expression level of SYK was evaluated by qPCR and IHC. The prognostic value of SYK was assessed using the Kaplan–Meier curves and univariate and multivariate Cox regression analyses. A sequence of immune and stromal infiltration analyses was calculated based on the ESTIMATE algorithm, ssGSEA algorithm, TIMER, and single-cell analysis. The SYK-related subtypes were identified via a Consensus Cluster Plus analysis.

Results: SYK was significantly differentially expressed in multiple tumors and normal tissues. Importantly, high-expression SYK was enriched in malignant phenotypes of diffuse gliomas, which was further validated by qPCR and IHC. Survival analysis uncovered that SYK was an independently unfavorable prognostic marker in diffuse glioma. Functional enrichment analysis and immune and stromal infiltration analyses showed that SYK was involved in shaping the immunosuppressive microenvironment of diffuse glioma. Additionally, SYK expression was closely associated with some immune checkpoint molecules and M2 macrophage infiltration, which was validated by IHC and single-cell analysis. Diffuse glioma with Sub1 exhibited a worse prognosis, immunosuppressive microenvironment, and higher expression of immune checkpoint genes.

Conclusion: SYK is involved in shaping the immunosuppressive microenvironment and served as a promising prognosis biomarker and immunotherapeutic target for diffuse glioma.
Global, Regional, and National Burden and Trends of Down Syndrome From 1990 to 2019
Authors: Chen Liyuan , Wang Lifei , Wang Yi , Hu Haishan , Zhan Yuan , Zeng Zhilin , Liu Lidan
Published: July 2022

Introduction: Down syndrome (DS) is the leading cause of genetically defined intellectual disability and congenital birth defects worldwide. A large population of people diagnosed with DS globally is posing an enormous socioeconomic burden. However, the global burden and trends of DS have not been reported.

Methods: Based on the data from the Global Burden of Disease database in 2019, we analyzed the incidence, prevalence, disability-adjusted life years (DALYs), and death of DS from 1990 to 2019 according to sex, age, regions, and social-demographic index (SDI). Then, age-standardized rates (ASRs) and estimated annual percentage change (EAPC) of these aforementioned indexes were calculated to evaluate the temporal trend of DS. Finally, the association of SDI with DS epidemiological parameters was assessed.

Results: In the past 30 years, the incident cases, age-standardized incident rate (ASIR), and age-standardized prevalent rate (ASPR) of DS first decreased slightly and subsequently increased globally. The number of prevalent cases increased steadily, while the number and age-standardized rate (ASRs) of DALYs and deaths decreased gradually from 1990 to 2019. In the meantime, disease burdens were different across various SDI regions. The prevalent cases and ASPR for both sexes were increasing in all SDI regions except for the high-middle SDI region. At the national level, Brunei Darussalam, Ireland, and Haiti were the top three countries with the highest ASIR in 2019. Georgia was in the top three with the highest increase in ASRs of four parameters, while Serbia was consistently ranked in the top three with fastest declining. Furthermore, we found that ASIR and ASPR were positively correlated with SDI, yet the age-standardized DALYs and age-standardized death rate (ASDR) were negatively correlated with SDI.

Conclusion: In the past 30 years, the burden and trends of DS were heterogeneous across different regions and countries with different sociodemographic characteristics. Great improvements had been achieved in reducing DALYs and deaths globally. However, the increased number and ASRs of incident and prevalent cases in some regions, especially in low SDI regions, were contributing to numerous challenges to public health. The findings may provide valuable information to the development or implementation of more effective measures.
Case Report: A Novel Homozygous Missense Variant of FBN3 Supporting It Is a New Candidate Gene Causative of a Bardet–Biedl Syndrome–Like Phenotype
Authors: Genovesi Maria Luce , Torres Barbara , Goldoni Marina , Salvo Eliana , Cesario Claudia , Majolo Massimo , Mazza Tommaso , Piscopo Carmelo , Bernardini Laura
Published: July 2022

Fibrillin proteins are extracellular matrix glycoproteins assembling into microfibrils. FBN1, FBN2, and FBN3 encode the human fibrillins and mutations in FBN1 and FBN2 cause connective tissue disorders called fibrillinopathies, affecting cardiovascular, dermal, skeletal, and ocular tissues. Recently, mutations of the less characterized fibrillin family member, FBN3, have been associated in a single family with Bardet–Biedl syndrome (BBS). Here, we report on a patient born from two first cousins and affected by developmental delay, cognitive impairment, obesity, dental and genital anomalies, and brachydactyly/syndactyly. His phenotype was very similar to that reported in the previous FBN3-mutated family and fulfilled BBS clinical diagnostic criteria, although lacking polydactyly, the most recurrent clinical feature, as the previous siblings described. A familial SNP-array and proband’s WES were performed prioritizing candidate variants on the sole patient’s runs of homozygosity. This analysis disclosed a novel homozygous missense variant in FBN3 (NM_032447:c.5434A>G; NP_115823:p.Ile1812Val; rs115948457), inherited from the heterozygous parents. This study further supports that FBN3 is a candidate gene for a BBS-like syndrome characterized by developmental delay, cognitive impairment, obesity, dental, genital, and skeletal anomalies. Anyway, additional studies are necessary to investigate the exact role of the gene and possible interactions between FBN3 and BBS proteins.
Genome-Wide Association and Genomic Prediction of Growth Traits in the European Flat Oyster (Ostrea edulis)
Authors: Peñaloza Carolina , Barria Agustin , Papadopoulou Athina , Hooper Chantelle , Preston Joanne , Green Matthew , Helmer Luke , Kean-Hammerson Jacob , Nascimento-Schulze Jennifer C. , Minardi Diana , Gundappa Manu Kumar , Macqueen Daniel J. , Hamilton John , Houston Ross D. , Bean Tim P.
Published: July 2022

The European flat oyster (Ostrea edulis) is a bivalve mollusc that was once widely distributed across Europe and represented an important food resource for humans for centuries. Populations of O. edulis experienced a severe decline across their biogeographic range mainly due to overexploitation and disease outbreaks. To restore the economic and ecological benefits of European flat oyster populations, extensive protection and restoration efforts are in place within Europe. In line with the increasing interest in supporting restoration and oyster farming through the breeding of stocks with enhanced performance, the present study aimed to evaluate the potential of genomic selection for improving growth traits in a European flat oyster population obtained from successive mass-spawning events. Four growth-related traits were evaluated: total weight (TW), shell height (SH), shell width (SW) and shell length (SL). The heritability of the growth traits was in the low-moderate range, with estimates of 0.45, 0.37, 0.22, and 0.32 for TW, SH, SW and SL, respectively. A genome-wide association analysis revealed a largely polygenic architecture for the four growth traits, with two distinct QTLs detected on chromosome 4. To investigate whether genomic selection can be implemented in flat oyster breeding at a reduced cost, the utility of low-density SNP panels was assessed. Genomic prediction accuracies using the full density panel were high (> 0.83 for all traits). The evaluation of the effect of reducing the number of markers used to predict genomic breeding values revealed that similar selection accuracies could be achieved for all traits with 2K SNPs as for a full panel containing 4,577 SNPs. Only slight reductions in accuracies were observed at the lowest SNP density tested (i.e., 100 SNPs), likely due to a high relatedness between individuals being included in the training and validation sets during cross-validation. Overall, our results suggest that the genetic improvement of growth traits in oysters is feasible. Nevertheless, and although low-density SNP panels appear as a promising strategy for applying GS at a reduced cost, additional populations with different degrees of genetic relatedness should be assessed to derive estimates of prediction accuracies to be expected in practical breeding programmes.
The Prevalence and Genetic Spectrum of Familial Hypercholesterolemia in Qatar Based on Whole Genome Sequencing of 14,000 Subjects
Authors: Diboun Ilhame , Al-Sarraj Yasser , Toor Salman M. , Mohammed Shaban , Qureshi Nadeem , Al Hail Moza S. H. , Jayyousi Amin , Al Suwaidi Jassim , Albagha Omar M. E.
Published: July 2022

Familial hypercholesterolemia (FH) is an inherited disease characterized by reduced efficiency of low-density lipoprotein-cholesterol (LDL-C) removal from the blood and, consequently, an increased risk of life-threatening early cardiovascular complications. In Qatar, the prevalence of FH has not been determined and the disease, as in many countries, is largely underdiagnosed. In this study, we combined whole-genome sequencing data from the Qatar Genome Program with deep phenotype data from Qatar Biobank for 14,056 subjects to determine the genetic spectrum and estimate the prevalence of FH in Qatar. We used the Dutch Lipid Clinic Network (DLCN) as a diagnostic tool and scrutinized 11 FH-related genes for known pathogenic and possibly pathogenic mutations. Results revealed an estimated prevalence of 0.8% (1:125) for definite/probable cases of FH in the Qatari population. We detected 16 known pathogenic/likely pathogenic mutations in LDLR and one in PCSK9; all in a heterozygous state with high penetrance. The most common mutation was rs1064793799 (c.313+3A >C) followed by rs771019366 (p.Asp90Gly); both in LDLR. In addition, we identified 18 highly penetrant possibly pathogenic variants, of which 5 were Qatari-specific, in LDLR, APOB, PCSK9 and APOE, which are predicted to be among the top 1% most deleterious mutations in the human genome but further validations are required to confirm their pathogenicity. We did not detect any homozygous FH or autosomal recessive mutations in our study cohort. This pioneering study provides a reliable estimate of FH prevalence in Qatar based on a significantly large population-based cohort, whilst uncovering the spectrum of genetic variants associated with FH.
Metagenomic and metabolomic analyses reveal synergistic effects of fecal microbiota transplantation and anti-PD-1 therapy on treating colorectal cancer
Authors: Huang Jiayuan , Zheng Xing , Kang Wanying , Hao Huaijie , Mao Yudan , Zhang Hua , Chen Yuan , Tan Yan , He Yulong , Zhao Wenjing , Yin Yiming
Published: July 2022

Anti-PD-1 immunotherapy has saved numerous lives of cancer patients; however, it only exerts efficacy in 10-15% of patients with colorectal cancer. Fecal microbiota transplantation (FMT) is a potential approach to improving the efficacy of anti-PD-1 therapy, whereas the detailed mechanisms and the applicability of this combination therapy remain unclear. In this study, we evaluated the synergistic effect of FMT with anti-PD-1 in curing colorectal tumor-bearing mice using a multi-omics approach. Mice treated with the combination therapy showed superior survival rate and tumor control, compared to the mice received anti-PD-1 therapy or FMT alone. Metagenomic analysis showed that composition of gut microbiota in tumor-bearing mice treated with anti-PD-1 therapy was remarkably altered through receiving FMT. Particularly, Bacteroides genus, including FMT-increased B. thetaiotaomicron, B. fragilis, and FMT-decreased B. ovatus might contribute to the enhanced efficacy of anti-PD-1 therapy. Furthermore, metabolomic analysis upon mouse plasma revealed several potential metabolites that upregulated after FMT, including punicic acid and aspirin, might promote the response to anti-PD-1 therapy via their immunomodulatory functions. This work broadens our understanding of the mechanism by which FMT improves the efficacy of anti-PD-1 therapy, which may contribute to the development of novel microbiota-based anti-cancer therapies.
RNA-seq Based Transcriptome Analysis Reveals The Cross-Talk of Macrophage and Adipocyte of Chicken Subcutaneous Adipose Tissue during The Embryonic and Post-Hatch Period
Authors: Zhao Haidong , Wu Mingli , Tang Xiaoqin , Li Qi , Yi Xiaohua , Zhao Wanxia , Sun Xiuzhu
Published: July 2022

With high fecundity and short production cycle, poultry is one of the important sources of meat. During the embryonic and post-hatch period, the higher death rate caused huge economic losses in poultry production. Our previous study showed that chick subcutaneous adipose tissue is an important energy supply tissue besides yolk. Therefore, the metabolic mechanism of subcutaneous adipose tissue in chicks could provide a new perspective of brooding. The objectives of the current study were to evaluate the differences between chick subcutaneous adipose tissue and abdominal adipose tissue before and after hatching and reveal the cross-talk of different cells within the chick subcutaneous adipose tissue. The results of RNA-seq and weighted gene co-expression network analysis (WGCNA) of chick subcutaneous and abdominal adipose tissues showed that the function of chick subcutaneous tissue was related to immunoreaction, and macrophage could be the major immune infiltration cell type in chicken subcutaneous adipose tissue, which were also verified by qPCR, HE stain, and IHC. The results of free fatty acids (FFAs)-induced the cross-talk between macrophages and adipocytes showed that FFAs-Ccl2 (chicken CCL26) axis could have an important role in lipid transportation in adipose tissue. The results of Oil Red O and Nile red stain demonstrated that macrophages have the ability to absorb FFAs quickly. Interestingly, according to the genomic organization of CCL family with representative vertebrate species, we found that chicken CCL26 could be the major chemokine in chicken adipocyte as the status of CCL2 in mammal adipocyte. In conclusion, we demonstrate that FFA-induced Ccl2 (chicken CCL26) secretion is crucial in determining fat depot-selective adipose tissue macrophage (ATM) infiltration, which could be an important medium of lipid transportation in chicken subcutaneous adipose tissue. These findings may have multiple important implications for understanding macrophage biology with chick subcutaneous adipose tissue and provide theoretical basis for lipid metabolism in poultry brooding.
Chromosome instability and aneuploidy as context-dependent activators or inhibitors of antitumor immunity
Authors: Kuang Xiaohong , Li Jian
Published: July 2022

Chromosome instability (CIN) and its major consequence, aneuploidy, are hallmarks of human cancers. In addition to imposing fitness costs on tumor cells through several cell-intrinsic mechanisms, CIN/aneuploidy also provokes an antitumor immune response. However, as the major contributor to genomic instability, intratumor heterogeneity generated by CIN/aneuploidy helps tumor cells to evolve methods to overcome the antitumor role of the immune system or even convert the immune system to be tumor-promoting. Although the interplay between CIN/aneuploidy and the immune system is complex and context-dependent, understanding this interplay is essential for the success of immunotherapy in tumors exhibiting CIN/aneuploidy, regardless of whether the efficacy of immunotherapy is increased by combination with strategies to promote CIN/aneuploidy or by designing immunotherapies to target CIN/aneuploidy directly.
Role of Caveolin-1 in Sepsis – A Mini-Review
Authors: Lannes-Costa Pamella Silva , Pimentel Bruna Alves da Silva , Nagao Prescilla Emy
Published: July 2022

Sepsis is a generalized disease characterized by an extreme response to a severe infection. Moreover, challenges remain in the diagnosis, treatment and management of septic patients. In this mini-review we demonstrate developments on cellular pathogenesis and the role of Caveolin-1 (Cav-1) in sepsis. Studies have shown that Cav-1 has a significant role in sepsis through the regulation of membrane traffic and intracellular signaling pathways. In addition, activation of apoptosis/autophagy is considered relevant for the progression and development of sepsis. However, how Cav-1 is involved in sepsis remains unclear, and the precise mechanisms need to be further investigated. Finally, the role of Cav-1 in altering cell permeability during inflammation, in sepsis caused by microorganisms, apoptosis/autophagy activation and new therapies under study are discussed in this mini-review.
Insulin-Like Growth Factor 1 Attenuates the Pro-Inflammatory Phenotype of Neutrophils in Myocardial Infarction
Authors: Nederlof Rianne , Reidel Sophia , Spychala André , Gödecke Stefanie , Heinen André , Lautwein Tobias , Petzsch Patrick , Köhrer Karl , Gödecke Axel
Published: July 2022

Acute myocardial infarction (MI) induces an extensive sterile inflammation, which is dominated in the early phase by invading neutrophils and monocytes/macrophages. The inflammatory response after MI critically affects infarct healing and cardiac remodeling. Therefore, modulation of cardiac inflammation may improve outcome post MI. Insulin-like growth factor 1 (IGF1) treatment reduces infarct size and improves cardiac function after MIviaIGF1 receptor mediated signaling in myeloid cells. Our study aimed to investigate the effect of IGF1 on neutrophil phenotype bothin vitroandin vivoafter MI. We show that IGF1 induces an anti-inflammatory phenotype in bone marrow derived neutrophils. On the molecular and functional level IGF1 treated neutrophils were indistinguishable from those induced by IL4. Surprisingly, insulin, even though it is highly similar to IGF1 did not create anti-inflammatory neutrophils. Notably, the IGF1 effect was independent of the canonical Ras/Raf/ERK or PI3K/AKT pathway, but depended on activation of the JAK2/STAT6 pathway, which was not activated by insulin treatment. Single cell sequencing analysis 3 days after MI also showed that 3 day IGF1 treatment caused a downregulation of pro-inflammatory genes and upstream regulators in most neutrophil and many macrophage cell clusters whereas anti-inflammatory genes and upstream regulators were upregulated. Thus, IGF1 acts like an anti-inflammatory cytokine on myeloid cellsin vitroand attenuates the pro-inflammatory phenotype of neutrophils and macrophagesin vivoafter MI. IGF1 treatment might therefore represent an effective immune modulatory therapy to improve the outcome after MI.
Heterologous saRNA Prime, DNA Dual-Antigen Boost SARS-CoV-2 Vaccination Elicits Robust Cellular Immunogenicity and Cross-Variant Neutralizing Antibodies
Authors: Rice Adrian , Verma Mohit , Voigt Emily , Battisti Peter , Beaver Sam , Reed Sierra , Dinkins Kyle , Mody Shivani , Zakin Lise , Tanaka Shiho , Morimoto Brett , Olson C. Anders , Gabitzsch Elizabeth , Safrit Jeffrey T. , Spilman Patricia , Casper Corey , Soon-Shiong Patrick
Published: July 2022

We assessed if immune responses are enhanced in CD-1 mice by heterologous vaccination with two different nucleic acid-based COVID-19 vaccines: a next-generation human adenovirus serotype 5 (hAd5)-vectored dual-antigen spike (S) and nucleocapsid (N) vaccine (AdS+N) and a self-amplifying and -adjuvanted S RNA vaccine (AAHI-SC2) delivered by a nanostructured lipid carrier. The AdS+N vaccine encodes S modified with a fusion motif to increase cell-surface expression and an N antigen modified with an Enhanced T-cell Stimulation Domain (N-ETSD) to direct N to the endosomal/lysosomal compartment and increase MHC class I and II stimulation potential. The S sequence in the AAHI-SC2 vaccine comprises the D614G mutation, two prolines to stabilize S in the prefusion conformation, and 3 glutamines in the furin cleavage region to confer protease resistance. CD-1 mice received vaccination by homologous and heterologous prime > boost combinations. Humoral responses to S were the highest with any regimen that included the AAHI-SC2 vaccine, and IgG bound to wild type and Delta (B.1.617.2) variant S1 at similar levels. An AAHI-SC2 prime followed by an AdS+N boost particularly enhanced CD4+ and CD8+ T-cell responses to both wild type and Delta S peptides relative to all other vaccine regimens. Sera from mice receiving AAHI-SC2 homologous or heterologous vaccination were found to be highly neutralizing for all pseudovirus strains tested: Wuhan, Beta, Delta, and Omicron strains. The findings here, taken in consideration with the availability of both vaccines in thermostable formulations, support the testing of heterologous vaccination by an AAHI-SC2 > AdS+N regimen in animal models of SARS-CoV-2 infection to assess its potential to provide increased protection against emerging SARS-CoV-2 variants particularly in regions of the world where the need for cold-chain storage has limited the distribution of other vaccines.
NOTCH1 mutation associates with impaired immune response and decreased relapse-free survival in patients with resected T1-2N0 laryngeal cancer
Authors: Gong Xiao-yang , Chen Hai-bin , Zhang Li-qing , Chen Dong-sheng , Li Wang , Chen Dong-hui , Xu Jin , Zhou Han , Zhao Le-le , Song Yun-jie , Xiao Ming-zhe , Deng Wang-long , Qi Chuang , Wang Xue-rong , Chen Xi
Published: July 2022

Background

Patients with early-stage laryngeal cancer, even stage T1-2N0, are at considerable risk of recurrence and death. The genetic and immunologic characteristics of recurrent laryngeal cancer remain unclear.

Methods

A total of 52 T1-2N0 laryngeal cancer patients were enrolled. Of these, 42 tissue samples were performed by targeted DNA sequencing, and 21 cases were performed by NanoString immuno-oncology targeted RNA sequencing to identify the distinct molecular bases and immunologic features associated with relapse in patients with early laryngeal cancer, respectively.

Results

To the best to our knowledge, we present for the first time an overview of the genomic mutation spectrum of early-stage laryngeal cancers. A total of 469 genomic alterations were detected in 211 distinct cancer-relevant genes, and the genes found to be mutated in more than five patients (>10%) included tumor protein p53 (TP53, 78.5%), FAT atypical cadherin 1 (FAT1, 26%), LDL receptor related protein 1B (LRP1B, 19%), cyclin dependent kinase inhibitor 2A (CDKN2A, 17%), tet methylcytosine dioxygenase 2 (TET2, 17%), notch receptor 1 (NOTCH1, 12%) and neuregulin 1 (NRG1, 12%). Recurrent laryngeal cancer demonstrated a higher tumor mutation burden (TMB), as well as higher LRP1B mutation and NOTCH1 mutation rates. Univariate and multivariate analyses revealed that high TMB (TMB-H) and NOTCH1 mutation are independent genetic factors that are significantly associated with shorter relapse-free survival (RFS). Simultaneously, the results of the transcriptome analysis presented recurrent tumors with NOTCH1 mutation displayed upregulation of the cell cycle pathway, along with decreased B cells score, T cells score, immune signature score and tumor-infiltrating lymphocytes (TILs) score. The Cancer Genome Atlas (TCGA)-laryngeal cancer dataset also revealed weakened immune response and impaired adhesion functions in NOTCH1-mutant patients.

Conclusions

Genomic instability and impaired immune response are key features of the immunosurveillance escape and recurrence of early laryngeal cancer after surgery. These findings revealed immunophenotypic attenuation in recurrent tumors and provided valuable information for improving the management of these high-risk patients. Due to the small number of patients in this study, these differences need to be further validated in a larger cohort.
Anti-Phospholipid Antibodies and Coronavirus Disease 2019: Vaccination Does Not Trigger Early Autoantibody Production in Healthcare Workers
Authors: Borghi Maria Orietta , Bombaci Mauro , Bodio Caterina , Lonati Paola Adele , Gobbini Andrea , Lorenzo Mariangela , Torresani Erminio , Dubini Antonella , Bulgarelli Ilaria , Solari Francesca , Pregnolato Francesca , Bandera Alessandra , Gori Andrea , Parati Gianfranco , Abrignani Sergio , Grifantini Renata , Meroni Pier Luigi
Published: July 2022

A molecular mimicry between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and human proteins supports the possibility that autoimmunity takes place during coronavirus disease 2019 (COVID-19) contributing to tissue damage. For example, anti-phospholipid antibodies (aPL) have been reported in COVID-19 as a result of such mimicry and thought to contribute to the immunothrombosis characteristic of the disease. Consistently, active immunization with the virus spike protein may elicit the production of cross-reactive autoantibodies, including aPL. We prospectively looked at the aPL production in healthcare workers vaccinated with RNA- (BNT162b2, n. 100) or adenovirus-based vaccines (ChAdOx1, n. 50). Anti-cardiolipin, anti-beta2 glycoprotein I, anti-phosphatidylserine/prothrombin immunoglobulin G (IgG), IgA, and IgM before and after vaccination were investigated. Anti-platelet factor 4 immunoglobulins were also investigated as autoantibodies associated with COVID-19 vaccination. Additional organ (anti-thyroid) and non-organ (anti-nuclear) autoantibodies and IgG against human proteome were tested as further post-vaccination autoimmunity markers. The antibodies were tested one or three months after the first injection of ChAdOx1 and BNT162b2, respectively; a 12-month clinical follow-up was also performed. Vaccination occasionally induced low titers of aPL and other autoantibodies but did not affect the titer of pre-existing autoantibodies. No significant reactivities against a microarray of approximately 20,000 human proteins were found in a subgroup of ChAdOx1-vaccinees. Consistently, we did not record any clinical manifestation theoretically associated with an underlying autoimmune disorder. The data obtained after the vaccination (two doses for the RNA-based and one dose for the adenovirus-based vaccines), and the clinical follow-up are not supporting the occurrence of an early autoimmune response in this cohort of healthcare workers.