bluuebunny/crossref_metadata_2025 huggingface dataset:
Aeromedical Decision Making for Military Aircrew with Graves’ Disease
Authors: Loh Edwin Hong-Teck , Soh Feng Wei , See Brian , Tan Benjamin Boon Chuan
Published: January 2022

BACKGROUND: Graves’ Disease (GD) is a common cause of hyperthyroidism. Although definitive treatment with radioactive iodine (RAI) is preferred for military aircrew, there are cultural and individual differences in receptivity toward RAI, and clinical guidelines that recommend
antithyroid drugs (ATD) as the first line therapy. We examined a case series of Republic of Singapore Air Force (RSAF) aviators with GD treated with ATD and the impact of their condition on aeromedical disposition.CASE SERIES: All RSAF aircrew diagnosed with GD and treated with
ATD over a 15-yr period were retrospectively identified and analyzed to determine the impact on their fitness for flying duties. The mean age of the 13 aircrew was 33 ± 7.1 yr (range, 25–47 yr), with 11 (84.6%) being males. There were 10 (76.9%) who had ATD as the only treatment
while 3 (23.1%) were initially treated with ATD but subsequently underwent RAI or surgery. Of the 10 treated with only ATD, 3 (30.0%) were returned to restricted flying, 6 (60.0%) were returned to unrestricted flying, and 1 (10.0%) is still undergoing ATD titration. There were 10 (76.9%) aircrew
who were returned to some form of flying duties while on low doses of ATD.DISCUSSION: This case series suggests that ATD is a viable treatment modality in the aeromedical management of military aviators with GD and it is possible to return military aircrew on a stable maintenance
dose of ATD to flying duties. A framework is proposed to support the aeromedical decision-making process for military aircrew in the treatment of GD.Loh EH-T, Soh FW, See B, Tan BBC. Aeromedical decision making for military aircrew with Graves’ disease. Aerosp Med Hum Perform.
2021; 92(12):980–986.
Oculometric Feature Changes During Acute Hypoxia in a Simulated High-Altitude Airdrop Scenario
Authors: Pradhan Gaurav N. , Ottestad William , Meland Anders , Kåsin Jan Ivar , Høiseth Lars Øivind , Cevette Michael J. , Stepanek Jan
Published: January 2022

BACKGROUND: Severe acute hypoxia results in a rapid deterioration of cognitive functioning and thus poses a risk for human operations in high altitude environments. This study aimed at investigating the effects of oxygen system failure during a high-altitude high-opening (HAHO)
parachute jump scenario from 30,000 ft (9144 m) on human physiology and cognitive performance using a noncontact eye-tracking task.METHODS: Nine healthy male volunteers (ages 27–48) were recruited from the Norwegian Special Operations Commandos. Eye-tracking data were collected
to derive information on cognitive performance in the context of rapid dynamic changes in pressure altitude while performing a modified King-Devick test. The baseline data was collected at 8000 ft (2438 m) while breathing 100% oxygen during decompression. For every test, the corresponding
arterial blood gas analysis was performed.RESULTS: The study subjects endured severe hypoxia, which resulted in significant prolongations of fixation time (range: 284.1–245.6 ms) until 23,397 ft (131 m) and fixation size (range: 34.6–32.4 mm) until 25,389 ft (7739 m)
as compared to the baseline (217.6 ± 17.8 ms and 27.2 ± 4.5 mm, respectively). The increase in the saccadic movement and decrease in the saccadic velocity was observed until 28,998 ft and 27,360 ft (8839 and 8339 m), respectively.DISCUSSION: This is the first study
to investigate cognitive performance from measured oculometric variables during severe hypobaric hypoxia in a simulated high-altitude airdrop mission scenario. The measurement of altered oculometric variables under hypoxic conditions represents a potential avenue to study altered cognitive
performance using noncontact sensors that can derive information and serve to provide the individual with a warning from impending incapacitation.Pradhan GN, Ottestad W, Meland A, Kåsin JI, Høiseth LØ, Cevette MJ, Stepanek J. Oculometric feature changes during
acute hypoxia in a simulated high-altitude airdrop scenario. Aerosp Med Hum Perform. 2021; 92(12):928–936.
PERJUANGAN LA ODE NGKADIRI DI KERAJAAN MUNA DALAM MELAWAN BELANDA : 1626-1667
Authors: Wa Sema Wa Sema , Aswati Aswati , Hamuni Hamuni
Published: January 2022

Tujuan penelitian ini adalah untuk (1)  Menjelaskan latar belakang masuknya Belanda di Kerajaan Muna tahun 1613, (2) Menjelaskan alasan perjuangan La Ode Ngkadiri melawan Belanda, (3) Menjelaskan strategi perjuangan La Ode Ngkadiri melawan Belanda, (4) Menjelaskan dampak perjuangan La Ode Ngkadiri dalam melawan Belanda bagi masyarakat Muna. Penelitian ini menggunakan metode sejarah dengan lima tahapan kerja antara lain (1) Pemilihan Topik (2) Heuristik (3) Verifikasi Sumber (4) Interpretasi Sumber (5) Historiografi. Hasil penelitian menunjukkan bahwa (1) Latar belakang kedatangan bangsa Belanda di Kerajaan Muna adalah untuk mengatasi ekonomi di negarannya. Hal tersebut didukung oleh potensi alam wilayah kerajaan Muna yang kaya kayu jati, kapuk, jagung dan komoditas lainnya. Belanda juga berniat ingin menerapkan sistem monopoli perdagangan di Kerajaan Muna. (2) Perlawanan La Ode Ngkadiri terhadap Belanda  disebabkan ketidaksukaannya akan sikap Belanda yang selalu memecah belah  rakyat Muna demi menanamkan pengaruh kekuasaannya. (3) Strategi La Ode Ngkadiri dalam menentang Belanda yaitu  bertindak secara non kooperatif atau tidak mau bekerja sama. La Ode Ngkadiri menghadapi Belanda dengan melakukan penolakan yakni tidak bersedia menerima pemerintahan Belanda untuk memasuki kerajaan Muna. La Ode Ngkdiri membangun strategi dengan mengadakan penjagaan ketat di wilayah kerajaan terutama pelabuhan-pelabuhan yang sering disinggahi kapal-kapal dagang Belanda. (4) Dampak perjuangan La Ode Ngkadiri melawan Belanda bagi masyarakat Muna yakni berbagai aktivitas pemerintahan dan ekonomi masyarakat tidak dapat dilaksanakan dengan baik. Hal ini disebabkan karena perhatian utama masyarakat Muna pada saat itu tertuju pada upaya mendukung perjuangan La Ode Ngkadiri dalam mempertahankan  keutuhan wilayah Muna.
CARACTERIZACIÓN CLINICOEPIDEMIOLÓGICA DE PACIENTES CON ENFERMEDAD RENAL CRÓNICA, RIOBAMBA, 2021
Authors:   Hospital Provincial General Docente Riobamba, Robalino Rivadeneira María Elena , Robalino Gualoto Raquel Sorayda ,   Hospital Provincial General Docente Riobamba, Cobos Castillo Marlon Ismael ,   Universidad Estatal de Bolívar,   Hospital Provincial General Docente Riobamba, Andrade Zuña Karla Estefanía ,   Universidad Estatal de Bolívar,   Hospital Provincial General Docente Riobamba, Chanaguano Tixelema Cecilia Consuelo ,   Universidad Estatal de Bolívar,   Hospital Provincial General Docente Riobamba, Urdaneta Carruyo Geritza Margarita ,   Universidad del Zulia-Facultad de Medicina, Zulia, Venezuela
Published: January 2022

La enfermedad renal crónica es uno de los grandes retos para los profesionales de la salud; constituye un problema de salud que genera discapacidad funcional, disminución de calidad de vida y elevados costos a los sistemas de salud. El objetivo de la presente investigación fue caracterizar clinicoepidemiológicamente a los pacientes con diagnóstico de enfermedad renal crónica atendidos en el Hospital Provincial General Docente de Riobamba. Para esto se desarrolló una investigación básica, descriptiva y de corte transversal. El universo estuvo constituido por 96 pacientes con diagnóstico de enfermedad renal crónica y la muestra quedó conformada por un total de 78 pacientes. Se aplicó un cuestionario que permitió identificar las características clínicas y epidemiológicas de los pacientes incluidos en el estudio. Los principales resultados incluyen un promedio de edad de 54,68 años. Predominaron las pacientes femeninas (60,26%). El 98,72% de ellos presento al menos una comorbilidad asociada, donde la hipertensión arterial (92,21%) y la diabetes mellitus (35,06%) fueron las más representadas. El 42,31% de los pacientes presentó trastornos nutricionales por exceso. Se concluye que el patrón clínico epidemiológico de los pacientes con enfermedad renal crónica coincide con los elementos reportados en la literatura. Sin embargo, existen elementos como la presencia de la enfermedad en menores de 40 años y el elevado porcentaje de trastornos nutricionales por exceso, que constituyen señales de alarma para los directivos de salud y para los profesionales en torno a la promoción de salud y prevención de enfermedades.
BIMBINGAN TEKNIS PERENCANAAN TANDON AIR BAWAH TANAH DI SMP NEGERI 22 KOTA MADYA MALANG
Authors: Novianto Dandung , Naibaho Armin , Subagio Udi , Appono Gerard , Burhamtoro Burhamtoro
Published: January 2022

With the vision of "Realizing Students Who Are Excellent in Achievement, Skilled, Praised in Character and Cultured in an Environment Based on Faith and Faith" SMP Negeri 22 Malang is located in the eastern area of Malang City, bordering the Malang Regency area, precisely in the hilly area of Villa Gunung Buring, Kelurahan Cemoro, the enclosure of Kedungkandang District, Malang City. This school was founded on October 20, 1999, with a land area of 5,597 m2 with a total area of 2,160 m2 consisting of 36 rooms, the number of study groups is 20 classes, each 6-7 study groups, the total number of students is 610 people and is supported by 35 educators. person. As we know above, with a large enough number of teachers, employees and students, it needs quite a lot of clean water. Whereas the water source at the school is obtained from the distribution of water from the housing whose discharge is very small, so it requires a water reservoir to accommodate water, currently the school only has a water reservoir above with a small volume capacity with a small pressure so that the water is unable to meet even though it has been assisted by a pump due to small water discharge.For this reason, the school has a plan to make an underground water reservoir with the aim of storing water which is then raised to the upper reservoir with the help of a pump, that the water reservoir planning is carried by the ground.
A Novel Ferroptosis-Based Molecular Signature Associated with Biochemical Recurrence-Free Survival and Tumor Immune Microenvironment of Prostate Cancer
Authors: Ke Zhi-Bin , You Qi , Sun Jiang-Bo , Zhu Jun-Ming , Li Xiao-Dong , Chen Dong-Ning , Su Li , Zheng Qing-Shui , Wei Yong , Xue Xue-Yi , Xu Ning
Published: January 2022

Objective: To identify ferroptosis-related molecular clusters, and to develop and validate a ferroptosis-based molecular signature for predicting biochemical recurrence-free survival (BCRFS) and tumor immune microenvironment of prostate cancer (PCa).

Materials and Methods: The clinical data and transcriptome data of PCa were downloaded from TCGA and GEO database. Ferroptosis-related genes (FRGs) were obtained from FerrDb database. We performed consensus clustering analysis to identify ferroptosis-related molecular subtypes for PCa. Univariate and multivariate Cox regression analysis were used to establish a ferroptosis-based signature for predicting BCRFS. Internal verification, external verification and subgroup survival analysis were then successfully performed.

Results: There was a total of 40 differentially expressed FRGs in PCa. We then identified three ferroptosis-related molecular clusters of PCa, which have significantly different immune infiltrating cells, tumor immune microenvironment and PD-L1 expression level. More importantly, a novel ferroptosis-based signature for predicting BCRFS of PCa based on four FRGs (including ASNS, GPT2, NFE2L2, RRM2) was developed. Internal and external verifications were then successfully performed. Patients with high-risk score were associated with significant poor BCRFS compared with those with low-risk score in training cohort, testing cohort and validating cohort, respectively. The area under time-dependent Receiver Operating Characteristic (ROC) curve were 0.755, 0.705 and 0.726 in training cohort, testing cohort and validating cohort, respectively, indicating the great performance of this signature. Independent prognostic analysis indicated that this signature was an independent predictor for BCRFS of PCa. Subgroup analysis revealed that this signature was particularly suitable for younger or stage T III-IV or stage N0 or cluster 1-2 PCa patients. Patients with high-risk score have significantly different tumor immune microenvironment in comparison with those with low-risk score. The results of qRT-PCR successfully verified the mRNA expression levels of ASNS, GPT2, RRM2 and NFE2L2 in DU-145 and RWPE-1 cells while the results of IHC staining exactly verified the relative protein expression levels of ASNS, GPT2, RRM2 and NFE2L2 between PCa and BPH tissues.

Conclusions: This study successfully identified three ferroptosis-related molecular clusters. Besides, we developed and validated a novel ferroptosis-based molecular signature, which performed well in predicting BCRFS and tumor immune microenvironment of PCa.
Extrachromosomal Circular DNA (eccDNA): From Chaos to Function
Authors: Zuo Shanru , Yi Yihu , Wang Chen , Li Xueguang , Zhou Mingqing , Peng Qiyao , Zhou Junhua , Yang Yide , He Quanyuan
Published: January 2022

Extrachromosomal circular DNA (eccDNA) is a type of double-stranded circular DNA that is derived and free from chromosomes. It has a strong heterogeneity in sequence, length, and origin and has been identified in both normal and cancer cells. Although many studies suggested its potential roles in various physiological and pathological procedures including aging, telomere and rDNA maintenance, drug resistance, and tumorigenesis, the functional relevance of eccDNA remains to be elucidated. Recently, due to technological advancements, accumulated evidence highlighted that eccDNA plays an important role in cancers by regulating the expression of oncogenes, chromosome accessibility, genome replication, immune response, and cellular communications. Here, we review the features, biogenesis, physiological functions, potential functions in cancer, and research methods of eccDNAs with a focus on some open problems in the field and provide a perspective on how eccDNAs evolve specific functions out of the chaos in cells.
Lyz2-Cre-Mediated Genetic Deletion of Septin7 Reveals a Role of Septins in Macrophage Cytokinesis and Kras-Driven Tumorigenesis
Authors: Menon Manoj B. , Yakovleva Tatiana , Ronkina Natalia , Suwandi Abdulhadi , Odak Ivan , Dhamija Sonam , Sandrock Inga , Hansmann Florian , Baumgärtner Wolfgang , Förster Reinhold , Kotlyarov Alexey , Gaestel Matthias
Published: January 2022

By crossing septin7-floxed mice with Lyz2-Cre mice carrying the Cre recombinase inserted in the Lysozyme-M (Lyz2) gene locus we aimed the specific deletion of septin7 in myeloid cells, such as monocytes, macrophages and granulocytes. Septin7flox/flox:Lyz2-Cre mice show no alterations in the myeloid compartment. Septin7-deleted macrophages (BMDMs) were isolated and analyzed. The lack of Septin7 expression was confirmed and a constitutive double-nucleation was detected in Septin7-deficient BMDMs indicating a defect in macrophage cytokinesis. However, phagocytic function of macrophages as judged by uptake of labelled E. coli particles and LPS-stimulated macrophage activation as judged by induction of TNF mRNA expression and TNF secretion were not compromised. In addition to myeloid cells, Lyz2-Cre is also active in type II pneumocytes (AT2 cells). We monitored lung adenocarcinoma formation in these mice by crossing them with the conditional knock-in Kras-LSL-G12D allele. Interestingly, we found that control mice without septin7 depletion die after 3–5 weeks, while the Septin7-deficient animals survived 11 weeks or even longer. Control mice sacrificed in the age of 4 weeks display a bronchiolo-alveolar hyperplasia with multiple adenomas, whereas the Septin7-deficient animals of the same age are normal or show only a weak multifocal brochiolo-alveolar hyperplasia. Our findings indicate an essential role of Septin7 in macrophage cytokinesis but not in macrophage function. Furthermore, septin7 seems absolutely essential for oncogenic Kras-driven lung tumorigenesis making it a potential target for anti-tumor interventions.
Genetic Regulatory Networks of Apolipoproteins and Associated Medical Risks
Authors: Basavaraju Preethi , Balasubramani Rubadevi , Kathiresan Divya Sri , Devaraj Ilakkiyapavai , Babu Kavipriya , Alagarsamy Vasanthakumar , Puthamohan Vinayaga Moorthi
Published: January 2022

Apolipoproteins (APO proteins) are the lipoprotein family proteins that play key roles in transporting lipoproteins all over the body. There are nearly more than twenty members reported in the APO protein family, among which the A, B, C, E, and L play major roles in contributing genetic risks to several disorders. Among these genetic risks, the single nucleotide polymorphisms (SNPs), involving the variation of single nucleotide base pairs, and their contributing polymorphisms play crucial roles in the apolipoprotein family and its concordant disease heterogeneity that have predominantly recurred through the years. In this review, we have contributed a handful of information on such genetic polymorphisms that include APOE, ApoA1/B ratio, and A1/C3/A4/A5 gene cluster-based population genetic studies carried throughout the world, to elaborately discuss the effects of various genetic polymorphisms in imparting various medical conditions, such as obesity, cardiovascular, stroke, Alzheimer's disease, diabetes, vascular complications, and other associated risks.
Layer-By-Layer Fabrication of Thicker and Larger Human Cardiac Muscle Patches for Cardiac Repair in Mice
Authors: Wang Lu , Zhang Jianyi
Published: January 2022

The engineered myocardial tissues produced via most manufacturing techniques are typically just a few dozen micrometers thick, which is too thin for therapeutic applications in patients. Here, we used a modified layer-by-layer (LBL) fabrication protocol to generate thick human cardiac muscle patches (hCMPs) with thicknesses of ~3.75 mm. The LBL-hCMPs were composed of a layer of endothelial cells (ECs) sandwiched between two layers of cardiomyocytes (CMs): both cell populations were differentiated from the same human induced pluripotent stem cell line (hiPSCs) and suspended in a fibrin matrix, and the individual layers were sutured together, leaving channels that allowed the culture medium to access the internal cell layer. The LBL-hCMPs were cultured on a dynamic culture platform with electrical stimulation, and when compared to Control-hCMPs consisting of the same total number of hiPSC-ECs and -CMs suspended in a single layer of fibrin, hiPSC-CMs in the LBL-hCMPs were qualitatively more mature with significantly longer sarcomeres and expressed significantly higher levels of mRNA transcripts for proteins that participate in cardiomyocyte contractile activity and calcium handing. Apoptotic cells were also less common in LBL- than in Control-hCMPs. The thickness of fabricated LBL-hCMP gradually decreased to 0.8 mm by day 28 in dynamic culture. When the hCMP constructs were compared in a mouse model of myocardial infarction, the LBL-hCMPs were associated with significantly better measurements of engraftment, cardiac function, infarct size, hypertrophy, and vascularity. Collectively these observations indicate that our modified LBL fabrication protocol produced thicker hCMPs with no decline in cell viability, and that LBL-hCMPs were more potent than Control-hCMPs for promoting myocardial repair in mice.
Interplay Between Thyroid Hormone Status and Pulmonary Hypertension in Graves’ Disease: Relevance of the Assessment in Thyrotoxic and Euthyroid Patients
Authors: Araruna Larisse Vieira Mendes , Oliveira Daniela Camargo de , Pereira Mônica Corso , Moura Neto Arnaldo , Tambascia Marcos Antonio , Zantut-Wittmann Denise Engelbrecht
Published: January 2022

Background

Graves’ disease (GD) is the most common cause of hyperthyroidism and can cause cardiac changes, such as pulmonary hypertension.

Methods

This is a prospective study in which we obtained demographic, clinical, laboratory data and characteristics of the GD, in addition to investigating cardiorespiratory function, focusing on the detection of pulmonary hypertension. Patients were separated into two groups: thyrotoxicosis and euthyroidism. Ninety patients with GD of both sexes, over 18 years of age, were included. The cardiorespiratory assessment included an echocardiographic evaluation, a questionnaire of specific symptoms, spirometry and a six-minute walk test.

Results

The hyperthyroid group included 42 patients (47.73%) and the euthyroid group 46 patients (52.27%); 78 were women (86.67%). The prevalence of pulmonary hypertension between the hyperthyroidism (48.57%) and the euthyroidism (29.41%) groups was not different. Free thyroxine levels (FT4) (OR 1.266), higher left atrium volume (OR 1.113) and right ventricle diameter were associated with pulmonary hypertension. A direct correlation between FT4 with forced vital capacity (FVC) and forced expiratory volume in the first second (FEV1), as also an inverse correlation between initial oxygen saturation (SpO2) with diagnostic time and drop SpO2 with the ratio between the diastolic velocity E of the mitral flow and the diastolic velocity of the mitral ring (E/e’) were observed in the euthyroid group. An inverse correlation between FT4 levels with walked distance as % of predicted value, and a direct correlation between E/e’ ratio and walked distance as % of predicted value were observed in the hyperthyroid group.

Conclusion

We emphasize the importance of a cardiorespiratory reassessment in GD, even after a long-term control of the thyrotoxic state, as we demonstrate that about 30% of these patients remain with PH and are subject to specific treatment.
A Nomogram for Predicting Intraoperative Hemodynamic Instability in Patients With Pheochromocytoma
Authors: Zhang Zhiqiang , Ye Yunlin , Yu Jiajie , Liao Shufen , Pan Weibin , Guo Yan , Jiang Shuangjian , Luo Cheng , Zheng Fufu
Published: January 2022

Purpose

Surgical removal of pheochromocytoma (PCC), including open, laparoscopic, and robot-assisted adrenalectomy, is the cornerstone of therapy, which is associated with high risk of intraoperative and postoperative life-threatening complications due to intraoperative hemodynamic instability (IHD). This study aims to develop and validate a nomogram based on clinical characteristics as well as computed tomography (CT) features for the prediction of IHD in pheochromocytoma surgery.

Methods

The data from 112 patients with pheochromocytoma were collected at a single center between January 1, 2010, and December 31, 2019. Clinical and radiological features were selected with the least absolute shrinkage and selection operator regression analysis to predict IHD then constitute a nomogram. The performance of the nomogram was assessed in terms of discrimination, calibration, and clinical utility.

Results

Age, tumor shape, Mayo Adhesive Probability score, laterality, necrosis, body mass index, and surgical technique were identified as risk predictors of the presence of IHD. The nomogram was then developed using these seven variables. The model showed good discrimination with a C-index of 0.773 (95% CI, 0.683–0.862) and an area under the receiver operating characteristic curve (AUC) of 0.739 (95% CI, 0.642–0.837). The calibration plot suggested good agreement between predicted and actual probabilities. Besides, calibration was tested with the Hosmer–Lemeshow test (P = 0.961). The decision curve showed the clinical effectiveness of the nomogram.

Conclusions

Our nomogram based on clinical and CT parameters could facilitate the treatment strategy according to assessment of the risk of IHD in patients with pheochromocytoma.
Too Hot to Nest? In a Hot Summer the Tortoise Chersina angulata Can Switch From Nesting to Facultative Viviparity
Authors: Kuchling Gerald , Hofmeyr Margaretha D.
Published: January 2022

In a captive colony of Chersina angulata in Cape Town, South Africa, we observed in 2015/16 retention of the last egg clutch inside the female until the hatching stage was reached, conforming to the generally accepted definition of viviparity. Retrospective climatic analysis indicates egg retention until the hatching stage co-occurred with unusually hot summer weather: the average air temperatures in December 2015 and January and February 2016 were higher than during the preceding five and the following 5 years when facultative viviparity could not be observed. Late December and January appears to be the critical period for females to either deposit their last clutch of the nesting season into a nest, or to retain the last clutch for embryonic development inside the female. Over the 28 December to 24 January period the minimum, average and maximum air temperatures in 2015–16 were about 3°C higher than in the five following years. This association of facultative viviparity with unusual summer heat suggests that hot ambient temperatures at the end of the nesting season may cue females to switch from oviposition to facultative viviparity. Compared to incubation in a nest this phenotypic plasticity of the reproductive mode—to retain during hot summers the season’s last clutch inside the female—may buffer the developing embryos from excessive heat exposure: females can thermo-regulate by moving among microhabitats whereas sun exposed shallow nests cannot escape high ground temperatures. This novel reproductive strategy has the potential to enhance the resilience of species to global warming.
Bioinformatics Analysis Identifies Potential Ferroptosis Key Genes in the Pathogenesis of Pulmonary Fibrosis
Authors: He Jie , Li Xiaoyan , Yu Mi
Published: January 2022

Objective: Ferroptosis has an important role in developing pulmonary fibrosis. The present project aimed to identify and validate the potential ferroptosis-related genes in pulmonary fibrosis by bioinformatics analyses and experiments.

Methods: First, the pulmonary fibrosis tissue sequencing data were obtained from Gene Expression Omnibus (GEO) and FerrDb databases. Bioinformatics methods were used to analyze the differentially expressed genes (DEGs) between the normal control group and the pulmonary fibrosis group and extract ferroptosis-related DEGs. Hub genes were screened by enrichment analysis, protein-protein interaction (PPI) analysis, and random forest algorithm. Finally, mouse pulmonary fibrosis model was made for performing an exercise intervention and the hub genes’ expression was verified through qRT-PCR.

Results: 13 up-regulated genes and 7 down-regulated genes were identified as ferroptosis-related DEGs by comparing 103 lung tissues with idiopathic pulmonary fibrosis (IPF) and 103 normal lung tissues. PPI results indicated the interactions among these ferroptosis-related genes. Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway enrichment and Genome-Ontology (GO) enrichment analyses showed that these ferroptosis-related genes involved in the organic anion transport, response to hypoxia, response to decrease oxygen level, HIF-1 signaling pathway, renal cell carcinoma, and arachidonic acid metabolism signaling pathway. The confirmed genes using PPI analysis and random forest algorithm included CAV1, NOS2, GDF15, HNF4A, and CDKN2A. qRT-PCR of the fibrotic lung tissues from the mouse model showed that the mRNA levels of NOS2 and GDF15 were up-regulated, while CAV1 and CDKN2A were down-regulated. Also, treadmill training led to an increased expression of CAV1 and CDKN2A and a decrease in the expression of NOS2 and GDF15.

Conclusion: Using bioinformatics analysis, 20 potential genes were identified to be associated with ferroptosis in pulmonary fibrosis. CAV1, NOS2, GDF15, and CDKN2A were demonstrated to be influencing the development of pulmonary fibrosis by regulating ferroptosis. These findings suggested that, as an aerobic exercise treatment, treadmill training reduced ferroptosis in the pulmonary fibrosis tissues, and thus, reduces inflammation in the lungs. Aerobic exercise training initiate concomitantly with induction of pulmonary fibrosis reduces ferroptosis in lung. These results may develop our knowledge about pulmonary fibrosis and may contribute to its treatment.
Characteristics of the Immune Cell Infiltration Landscape in Gastric Cancer to Assistant Immunotherapy
Authors: Li Chenlu , Pan Jingjing , Jiang Yinyan , Yu Yan , Jin Zhenlin , Chen Xupeng
Published: January 2022

Background: Gastric cancer (GC) was usually associated with poor prognosis and invalid therapeutical response to immunotherapy due to biological heterogeneity. It is urgent to screen reliable indices especially immunotherapy-associated parameters that can predict the therapeutic responses to immunotherapy of GC patients.

Methods: Gene expression profile of 854 GC patients were collected from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets (GSE84433) with their corresponding clinical and somatic mutation data. Based on immune cell infiltration (ICI) levels, molecular clustering classification was performed to identify subtypes and ICI scores in GC patients. After functional enrichment analysis of subtypes, we further explored the correlation between ICI scores and Tumor Mutation Burden (TMB) and the significance in clinical immunotherapy response.

Results: Three subtypes were identified based on ICI scores with distinct immunological and prognostic characteristics. The ICI-cluster C, associated with better outcomes, was characterized by significantly higher stromal and immune scores, T lymphocytes infiltration and up-regulation of PD-L1. ICI scores were identified through using principal component analysis (PCA) and the low ICI scores were consistent with the increased TMB and the immune-activating signaling pathways. Contrarily, the high-ICI score cluster was involved in the immunosuppressive pathways, such as TGF-beta, MAPK and WNT signaling pathways, which might be responsible for poor prognosis of GC. External immunotherapy and chemotherapy cohorts validated the patients with lower ICI scores exhibited significant therapeutic responses and clinical benefits.

Conclusion: This study elucidated that ICI score could sever as an effective prognostic and predictive indicator for immunotherapy in GC. These findings indicated that the systematic assessment of tumor ICI landscapes and identification of ICI scores have crucial clinical implications and facilitate tailoring optimal immunotherapeutic strategies.
Pan-Cancer DNA Methylation Analysis and Tumor Origin Identification of Carcinoma of Unknown Primary Site Based on Multi-Omics
Authors: Liu Pengfei
Published: January 2022

The metastatic cancer of unknown primary (CUP) sites remains a leading cause of cancer death with few therapeutic options. The aberrant DNA methylation (DNAm) is the most important risk factor for cancer, which has certain tissue specificity. However, how DNAm alterations in tumors differ among the regulatory network of multi-omics remains largely unexplored. Therefore, there is room for improvement in our accuracy in the prediction of tumor origin sites and a need for better understanding of the underlying mechanisms. In our study, an integrative analysis based on multi-omics data and molecular regulatory network uncovered genome-wide methylation mechanism and identified 23 epi-driver genes. Apart from the promoter region, we also found that the aberrant methylation within the gene body or intergenic region was significantly associated with gene expression. Significant enrichment analysis of the epi-driver genes indicated that these genes were highly related to cellular mechanisms of tumorigenesis, including T-cell differentiation, cell proliferation, and signal transduction. Based on the ensemble algorithm, six CpG sites located in five epi-driver genes were selected to construct a tissue-specific classifier with a better accuracy (>95%) using TCGA datasets. In the independent datasets and the metastatic cancer datasets from GEO, the accuracy of distinguishing tumor subtypes or original sites was more than 90%, showing better robustness and stability. In summary, the integration analysis of large-scale omics data revealed complex regulation of DNAm across various cancer types and identified the epi-driver genes participating in tumorigenesis. Based on the aberrant methylation status located in epi-driver genes, a classifier that provided the highest accuracy in tracing back to the primary sites of metastatic cancer was established. Our study provides a comprehensive and multi-omics view of DNAm-associated changes across cancer types and has potential for clinical application.
Mitochondrial DNA Footprints from Western Eurasia in Modern Mongolia
Authors: Cardinali Irene , Bodner Martin , Capodiferro Marco Rosario , Amory Christina , Rambaldi Migliore Nicola , Gomez Edgar J. , Myagmar Erdene , Dashzeveg Tumen , Carano Francesco , Woodward Scott R. , Parson Walther , Perego Ugo A. , Lancioni Hovirag , Achilli Alessandro
Published: January 2022

Mongolia is located in a strategic position at the eastern edge of the Eurasian Steppe. Nomadic populations moved across this wide area for millennia before developing more sedentary communities, extended empires, and complex trading networks, which connected western Eurasia and eastern Asia until the late Medieval period. We provided a fine-grained portrait of the mitochondrial DNA (mtDNA) variation observed in present-day Mongolians and capable of revealing gene flows and other demographic processes that took place in Inner Asia, as well as in western Eurasia. The analyses of a novel dataset (N = 2,420) of mtDNAs highlighted a clear matrilineal differentiation within the country due to a mixture of haplotypes with eastern Asian (EAs) and western Eurasian (WEu) origins, which were differentially lost and preserved. In a wider genetic context, the prevalent EAs contribution, larger in eastern and central Mongolian regions, revealed continuous connections with neighboring Asian populations until recent times, as attested by the geographically restricted haplotype-sharing likely facilitated by the Genghis Khan’s so-calledPax Mongolica. The genetic history beyond the WEu haplogroups, notably detectable on both sides of Mongolia, was more difficult to explain. For this reason, we moved to the analysis of entire mitogenomes (N = 147). Although it was not completely possible to identify specific lineages that evolvedin situ, two major changes in the effective (female) population size were reconstructed. The more recent one, which began during the late Pleistocene glacial period and became steeper in the early Holocene, was probably the outcome of demographic events connected to western Eurasia. The Neolithic growth could be easily explained by the diffusion of dairy pastoralism, as already proposed, while the late glacial increase indicates, for the first time, a genetic connection with western Eurasian refuges, as supported by the unusual high frequency and internal sub-structure in Mongolia of haplogroup H1, a well-known post-glacial marker in Europe. Bronze Age events, without a significant demographic impact, might explain the age of some mtDNA haplogroups. Finally, a diachronic comparison with available ancient mtDNAs made it possible to link six mitochondrial lineages of present-day Mongolians to the timeframe and geographic path of the Silk Route.
Microbiota-Meditated Immunity Abnormalities Facilitate Hepatitis B Virus Co-Infection in People Living With HIV: A Review
Authors: Ouyang Jing , Zaongo Silvere D. , Zhang Xue , Qi Miaomiao , Hu Aizhen , Wu Hao , Chen Yaokai
Published: January 2022

Hepatitis B virus (HBV) co-infection is fairly common in people living with HIV (PLWH) and affects millions of people worldwide. Identical transmission routes and HIV-induced immune suppression have been assumed to be the main factors contributing to this phenomenon. Moreover, convergent evidence has shown that people co-infected with HIV and HBV are more likely to have long-term serious medical problems, suffer more from liver-related diseases, and have higher mortality rates, compared to individuals infected exclusively by either HIV or HBV. However, the precise mechanisms underlying the comorbid infection of HIV and HBV have not been fully elucidated. In recent times, the human gastrointestinal microbiome is progressively being recognized as playing a pivotal role in modulating immune function, and is likely to also contribute significantly to critical processes involving systemic inflammation. Both antiretroviral therapy (ART)-naïve HIV-infected subjects and ART-treated individuals are now known to be characterized by having gut microbiomic dysbiosis, which is associated with a damaged intestinal barrier, impaired mucosal immunological functioning, increased microbial translocation, and long-term immune activation. Altered microbiota-related products in PLWH, such as lipopolysaccharide (LPS) and short-chain fatty acids (SCFA), have been associated with the development of leaky gut syndrome, favoring microbial translocation, which in turn has been associated with a chronically activated underlying host immune response and hence the facilitated pathogenesis of HBV infection. Herein, we critically review the interplay among gut microbiota, immunity, and HIV and HBV infection, thus laying down the groundwork with respect to the future development of effective strategies to efficiently restore normally diversified gut microbiota in PLWH with a dysregulated gut microbiome, and thus potentially reduce the prevalence of HBV infection in this population.
NFATc1/αA and Blimp-1 Support the Follicular and Effector Phenotype of Tregs
Authors: Koenig Anika , Vaeth Martin , Xiao Yin , Chiarolla Cristina M. , Erapaneedi Raghu , Klein Matthias , Dietz Lena , Hundhausen Nadine , Majumder Snigdha , Schuessler Felix , Bopp Tobias , Klein-Hessling Stefan , Rosenwald Andreas , Berberich Ingolf , Berberich-Siebelt Friederike
Published: January 2022

CD4+CXCR5+Foxp3+ T-follicular regulatory (TFR) cells control the germinal center responses. Like T-follicular helper cells, they express high levels of Nuclear Factor of Activated T-cells c1, predominantly its short isoform NFATc1/αA. Ablation of NFATc1 in Tregs prevents upregulation of CXCR5 and migration of TFR cells into B-cell follicles. By contrast, constitutive active NFATc1/αA defines the surface density of CXCR5, whose level determines how deep a TFR migrates into the GC and how effectively it controls antibody production. As one type of effector Treg, TFR cells express B lymphocyte-induced maturation protein-1 (Blimp-1). Blimp-1 can directly repress Cxcr5 and NFATc1/αA is necessary to overcome this Blimp-1-mediated repression. Interestingly, Blimp-1 even reinforces the recruitment of NFATc1 to Cxcr5 by protein-protein interaction and by those means cooperates with NFATc1 for Cxcr5 transactivation. On the contrary, Blimp-1 is necessary to counterbalance NFATc1/αA and preserve the Treg identity. This is because although NFATc1/αA strengthens the follicular development of Tregs, it bears the inherent risk of causing an ex-Treg phenotype.
Comprehensive Flow Cytometry Profiling of the Immune System in COVID-19 Convalescent Individuals
Authors: Gil-Manso Sergio , Miguens Blanco Iria , López-Esteban Rocío , Carbonell Diego , López-Fernández Luis Andrés , West Lori , Correa-Rocha Rafael , Pion Marjorie
Published: January 2022

SARS-CoV-2 has infected more than 200 million people worldwide, with more than 4 million associated deaths. Although more than 80% of infected people develop asymptomatic or mild COVID-19, SARS-CoV-2 can induce a profound dysregulation of the immune system. Therefore, it is important to investigate whether clinically recovered individuals present immune sequelae. The potential presence of a long-term dysregulation of the immune system could constitute a risk factor for re-infection and the development of other pathologies. Here, we performed a deep analysis of the immune system in 35 COVID-19 recovered individuals previously infected with SARS-CoV-2 compared to 16 healthy donors, by flow cytometry. Samples from COVID-19 individuals were analysed from 12 days to 305 days post-infection. We observed that, 10 months post-infection, recovered COVID-19 patients presented alterations in the values of some T-cell, B-cell, and innate cell subsets compared to healthy controls. Moreover, we found in recovered COVID-19 individuals increased levels of circulating follicular helper type 1 (cTfh1), plasmablast/plasma cells, and follicular dendritic cells (foDC), which could indicate that the Tfh-B-foDC axis might be functional to produce specific immunoglobulins 10 months post-infection. The presence of this axis and the immune system alterations could constitute prognosis markers and could play an important role in potential re-infection or the presence of long-term symptoms in some individuals.
The Impact of Systemic Inflammation on Alzheimer’s Disease Pathology
Authors: Xie Junhua , Van Hoecke Lien , Vandenbroucke Roosmarijn E.
Published: January 2022

Alzheimer’s disease (AD) is a devastating age-related neurodegenerative disorder with an alarming increasing prevalence. Except for the recently FDA-approved Aducanumab of which the therapeutic effect is not yet conclusively proven, only symptomatic medication that is effective for some AD patients is available. In order to be able to design more rational and effective treatments, our understanding of the mechanisms behind the pathogenesis and progression of AD urgently needs to be improved. Over the last years, it became increasingly clear that peripheral inflammation is one of the detrimental factors that can contribute to the disease. Here, we discuss the current understanding of how systemic and intestinal (referred to as the gut-brain axis) inflammatory processes may affect brain pathology, with a specific focus on AD. Moreover, we give a comprehensive overview of the different preclinical as well as clinical studies that link peripheral Inflammation to AD initiation and progression. Altogether, this review broadens our understanding of the mechanisms behind AD pathology and may help in the rational design of further research aiming to identify novel therapeutic targets.
Uncrewed Surface Vessel Technological Diffusion Depends on Cross-Sectoral Investment in Open-Ocean Archetypes: A Systematic Review of USV Applications and Drivers
Authors: Patterson Ruth G. , Lawson Emily , Udyawer Vinay , Brassington Gary B. , Groom Rachel A. , Campbell Hamish A.
Published: January 2022

Accessing the world's oceans is essential for monitoring and sustainable management of the maritime domain. Difficulty in reaching remote locations has resulted in sparse coverage, undermining our capacity to deter illegal activities and gather data for physical and biological processes. Uncrewed Surface Vessels (USVs) have existed for over two decades and offer the potential to overcome difficulties associated with monitoring and surveillance in remote regions. However, they are not yet an integral component of maritime infrastructure. We analyse 15 years of non-autonomous and semi-autonomous USV-related literature to determine the factors limiting technological diffusion into everyday maritime operations. We systematically categorised over 1,000 USV-related publications to determine how government, academia and industry sectors use USVs and what drives their uptake. We found a striking overlap between these sectors for 11 applications and nine drivers. Low cost was a consistent and central driver for USV uptake across the three sectors. Product ‘compatibility' and lack of ‘complexity' appear to be major factors limiting USV technological diffusion amongst early adopters. We found that the majority (21 of 27) of commercially available USVs lacked the complexity required for multiple applications in beyond the horizon operations. We argue that the best value for money to advance USV uptake is for designs that offer cross-disciplinary applications and the ability to operate in an unsheltered open ocean without an escort or mothership. The benefits from this technological advancement can excel under existing collaborative governance frameworks and are most significant for remote and developing maritime nations.
DNA Barcoding of Scavenging Amphipod Communities at Active and Inactive Hydrothermal Vents in the Indian Ocean
Authors: Kniesz Katharina , Jażdżewska Anna Maria , Martínez Arbizu Pedro , Kihara Terue Cristina
Published: January 2022

Hydrothermal vent areas have drawn increasing interest since they were discovered in 1977. Because of chemoautotrophic bacteria, they possess high abundances of vent endemic species as well as many non-vent species around the fields. During the survey conducted by the Bundesanstalt für Geowissenschaften und Rohstoffe (Federal Institute for Geosciences and Natural Resources, BGR) to identify inactive polymetallic sulfide deposits along Central and Southeast Indian Ridges, the INDEX project studied the scavenging amphipod community at three newly discovered hydrothermal fields. A sample consisting of 463 representatives of Amphipoda (Malacostraca: Crustacea) was collected by means of baited traps in active and inactive vents of three different sites and subsequently studied by both morphological and genetic methods. Molecular methods included the analysis of two mitochondrial (cytochrome c oxidase subunit I [COI] and 16S rRNA) and one nuclear (18S rRNA) genes. By six delimitation methods, 22 molecular operational taxonomic units (MOTUs) belonging to 12 genera and 10 families were defined. The existence of potential species complexes was noted for the representatives of the genus Paralicella. The inactive site, where 19 species were found, showed higher species richness than did the active one, where only 10 taxa were recorded. Seven genera, Ambasiopsis, Cleonardo, Eurythenes, Parandania, Pseudonesimus, Tectovalopsis, and Valettiopsis, were observed only at inactive sites, whereas Haptocallisoma, was collected exclusively at active ones. The species Abyssorchomene distinctus (Birstein and Vinogradov, 1960), Hirondellea brevicaudata Chevreux, 1910, and Hirondellea guyoti Barnard and Ingram, 1990, have been previously reported from vent sites in the Atlantic or Pacific oceans. The present study provides the first report of Eurythenes magellanicus (H. Milne Edwards, 1848) and five other already described species in the Indian Ocean. The addition of 356 sequences strongly increases the number of amphipod barcodes in reference databases and provides for the first time COI barcodes for Cleonardo neuvillei Chevreux, 1908, Haptocallisoma abyssi (Oldevig, 1959), Hirondellea guyoti, Tectovalopsis fusilus Barnard and Ingram, 1990, and the genera Haptocallisoma, Pseudonesimus, and Valettiopsis.