bluuebunny/crossref_metadata_2025 huggingface dataset:
Increased Levels of Plasma Extracellular Heat-Shock Proteins 60 and 70 kDa Characterized Early-Onset Neonatal Sepsis
Authors: Canul-Euan Arturo Alejandro , Zúñiga-González Gibran , Palacios-Luna Janelly Estefania , Maida-Claros Rolando , Díaz Néstor Fabián , Saltigeral-Tigeral Patricia , Karina García-May Perla , Díaz-Ruiz Oscar , Flores-Herrera Héctor
Published: December 2021

Background: Extracellular heat-shock proteins (eHsp) are highly conserved molecules that play an important role in inflammatory diseases and have been quantified in plasma from patients with infectious diseases, including sepsis. There is a constant search for dependable biochemical markers that, in combination with conventional methods, could deliver a prompt and reliable diagnosis of early-onset neonatal sepsis.

Objective: We sought to assess the level of eHsp-27, eHsp-60, eHsp-70, and tumor necrosis factor-alpha (TNFα) in plasma of healthy neonates at term and infants with early-onset neonatal sepsis.

Methods: This study included 34 newborns that were classified as healthy neonates at term (blood samples from the umbilical cord, n = 23) or infants with early-onset neonatal sepsis (blood samples obtained from umbilical artery by standard sterile procedures before starting a systemic antibiotic intervention, n = 11). All blood samples were centrifuged, and the plasma recovered to determine eHsp-27, eHsp-60, eHsp-70, and TNFα levels by ELISA.

Results: Our results indicate that the level of eHsp-27 in healthy neonates at term was 0.045 ± 0.024 pg/ml. This value decreased 2.5-fold in infants with early-onset neonate sepsis (0.019 ± 0.006 pg/ml, p = 0.004). In contrast, the levels of eHsp-60 and eHsp-70 in healthy neonates at term were 13.69 ± 5.3 and 4.03 ± 2.6 pg/ml, respectively. These protein levels increased significantly 1.8- and 1.9-fold in the plasma of infants with early-onset neonatal sepsis (p ≤ 0.001). The level of TNFα in healthy neonates at term was 2.94 ± 0.46 pg/ml, with a 3.0-fold increase in infants with early-onset neonatal sepsis (8.96 ± 0.72 pm/ml, p ≤ 0.001). The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of eHsp compared with that of C-reactive protein were 73.3, 60.0, 47.8, and 33.3%, respectively.

Conclusion: This study demonstrated a consistent increase of eHsp-60 and eHsp-70 in the plasma of infants diagnosed with early-onset neonatal sepsis. These proteins showed higher sensitivity and specificity than C-reactive protein and blood culture test.
Colchicine Effectiveness and Safety in Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis
Authors: Welzel Tatjana , Ellinghaus Maren , Wildermuth Anna L. , Deschner Norbert , Benseler Susanne M. , Kuemmerle-Deschner Jasmin B.
Published: December 2021

Introduction: Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) is the most common fever syndrome in childhood. High disease activity (DA) dramatically impacts the health-related quality of life. Thus, effective and safe treatment is crucial. Colchicine might be effective, but data are still lacking. Study aimed to assess colchicine safety and effectiveness in PFAPA.

Methods: This single center study was conducted between 03/2012 and 05/2021 in PFAPA patients without variants in genetic panel testing aged ≤ 18 years fulfilling Marshall criteria and classification criteria of Gattorno et al. Exclusion criteria were elevated liver enzymes, impaired kidney function, celiac disease, lactose intolerance, previous/ongoing biologics, known colchicine-intolerance. Demographics, clinical characteristics, treatment, DA, colchicine effectiveness and safety were recorded at baseline, first and last visit. Colchicine was started at 0.5–1.0 mg/day. DA was captured by physician (PGA) and patient/parent (PPGA) global assessment on a 10 cm visual analog scale, categorized as mild (<2), moderate (2–4), and high (≥5). Adverse event (AE) monitoring included gastrointestinal symptoms, liver enzyme/creatinine elevation, leukopenia, neutropenia. Primary outcome included response (R; composite of PPGA + PGA decrease ≥2) at last follow-up. Secondary outcomes were partial response (PR; PGA decrease = 1 + PPGA decrease ≥1), no response (NR; unchanged/worsened PGA/PPGA), colchicine safety, flare characteristics.

Results: Twenty-seven PFAPA patients were included, 52% were female, median age was 5.8 years (1–10.75), median follow-up time was 13 months. At baseline, median PPGA was high; median PGA moderate. All patients had febrile flares. Median flare frequency was every 4–5 weeks; median duration 5–6 days. Nine patients were pre-treated with corticosteroids, increasing flare frequency in 8/9. Primary Outcome: 17 patients (63%) were responders. Secondary outcomes: PR was achieved in 15%; NR in 22% at last follow-up. DA decreased significantly (p <0.0001). At last follow-up, 52% reported no flares, median flare duration decreased to 1–2 days. At first follow-up, 22% reported mild abdominal pain/diarrhea. Moderate abdominal pain/diarrhea occurred with ≥1 mg/day. Mild asymptomatic liver enzyme elevation or leucopenia were rare; no severe AE or colchicine discontinuation were observed.

Conclusion: Colchicine seems to be safe, well-tolerated, and effective in PFAPA patients. It can be considered in children with moderate/high DA even those without corticosteroid-benefit.
Early Vascular Aging in Children With Tuberous Sclerosis Complex
Authors: Skrzypczyk Piotr , Wabik Anna Maria , Szyszka Michał , Józwiak Sergiusz , Bombiński Przemysław , Jakimów-Kostrzewa Aleksandra , Brzewski Michał , Pańczyk-Tomaszewska Małgorzata
Published: December 2021

Objectives: Experimental data indicate that activating mutations in the mTOR (mammalian target of rapamycin) pathway may lead to abnormal arterial wall structure. Vascular anomalies like arterial stenoses are reported in pediatric patients with tuberous sclerosis complex (TSC). In addition, large renal lesions (angiomyolipoma—AML and cysts) are risk factors for arterial hypertension in adult patients with TSC. This study aimed to assess blood pressure, including central blood pressure and arterial damage (early vascular aging—EVA) in children with TSC.

Materials and Methods: In a group of 33 pediatric patients with TSC (11.13 ± 4.03 years, 15 boys, 18 girls), we evaluated peripheral and central office blood pressure, 24-h ambulatory blood pressure, and arterial damage: aortic pulse wave velocity (aPWV) [m/s], [Z-score], augmentation index (AIx75HR [%]), common carotid artery intima-media thickness (cIMT) [mm], [Z-score], stiffness of common carotid artery (E-tracking), renal lesions in magnetic resonance and ultrasonography, and selected biochemical parameters. The control group consisted of 33 healthy children (11.23 ± 3.28 years, 15 boys, 18 girls).

Results: In TSC group 7 (21.2%) children had arterial hypertension, 27 (81.8%) children had renal angiomyolipomas, 26 (78.8%)—renal cysts, and 4 (12.1%) patients were treated with mTOR inhibitors (2 patients with everolimus and 2 patients with sirolimus) at the moment of evaluation. Children with TSC had higher central systolic blood pressure (AoSBP) (98.63 ± 9.65 vs. 90.45 ± 6.87 [mm Hg], p < 0.001), cIMT (0.42 ± 0.05 vs. 0.39 ± 0.03 [mm], p = 0.011), cIMT Z-score (0.81 ± 1.21 vs. 0.16 ± 0.57, p = 0.007), aPWV (4.78 ± 0.81 vs. 4.25 ± 0.56 [m/s], p = 0.003) and aPWV Z-score (−0.14 ± 1.15 vs. −0.96 ± 0.87, p = 0.002) compared to healthy children, without differences in AIx75HR (8.71 ± 15.90 vs. 5.24 ± 11.12 [%], p = 0.319) and stiffness of common carotid artery. In children with TSC AoSBP correlated positively with serum cystatin C concentration (r = 0.377, p = 0.030) and with maximum diameter of renal cyst (R = 0.419, p = 0.033); mean arterial pressure (MAP) 24 h Z-score correlated with serum cystatin C concentration (R = 0.433, p = 0.013); and aPWV Z-score with daily urinary albumin loss [mg/24 h] (R = 0.412, p = 0.029).

Conclusions: Children with tuberous sclerosis complex are at risk of elevated central blood pressure and early vascular aging. In children with TSC, blood pressure and arterial stiffness are related to renal involvement.
Morphological Analysis of Nose in Patients of Tessier No. 0 Cleft With a Bifid Nose in China
Authors: Wang Xin , Wang Huan , You Jianjun , Zheng Ruobing , Xu Yihao , Zhang Xulong , Guo Junsheng , Fan Fei
Published: December 2021

Objective: Facial cleft involves complex malformations. No study assessed the facial deformity of Tessier No. 0 cleft with a bifid nose. Thus, we used anthropometric measurements to access the nose in patients.

Methods: A total of 24 bifid nose deformities underwent surgery at our institution between 2010 and 2019. Standardized photographs were taken preoperatively and postoperatively. Landmarks were identified on these images; measurements for nasal analysis were performed and compared with the established Chinese norms. Surgical method differences were also analyzed.

Results: The median follow-up time was 2.51 years. Postoperatively, there is a significant difference in comparison with preoperative in the nasal index, medial canthus and nose width index, nasolabial angle, nasofacial angle, ala length and nasal bridge length index, nasal tip protrusion and nasal width index, and nasal width and ala length index. Furthermore, the medial canthus and nose width index, and nasal width and ala length index were significantly larger in ordinary people, while ala length and nasal bridge length index and nasal tip protrusion and nasal width index were smaller. After surgery, most angles and index were standard except the nasolabial angle in the females, and ala length and nasal bridge length index in the males. Moreover, as for the group of costal cartilage transplantation, most index and angles have improved after surgery including nasolabial angle, nasofacial angle, ala length and nasal bridge length index, nasal tip protrusion and nasal width index, and nasal width and ala length index. However, only nasal tip protrusion and nasal width index, columella length and nasal tip protrusion index, and nasal width and ala length index in the silicone prosthesis group implantation has significance. Costal cartilage transplantation can also better improve ala length and nasal bridge length index than the silicone prosthesis implantation.

Conclusion: Most defects can be repaired with surgery, but the outcome has a lack of evaluation. Thus, anthropometric assessment can serve as a material for nasal and reconstructive surgery.
Vasoactive-Inotropic Score and Vasoactive-Ventilation-Renal Score as Outcome Predictors for Children on Extracorporeal Membrane Oxygenation
Authors: Shukla Ira , Hanson Sheila J. , Yan Ke , Zhang Jian
Published: December 2021

We aimed to determine the association of vasoactive-inotropic score (VIS) and vasoactive-ventilation-renal (VVR) score with in-hospital mortality and functional outcomes at discharge of children who receive ECMO. A sub-analysis of the multicenter, prospectively collected data by the Collaborative Pediatric Critical Care Research Network (CPCCRN) for Bleeding and Thrombosis on ECMO (BATE database) was conducted. Of the 514 patients who received ECMO across eight centers from December 2012 to February 2016, 421 were included in the analysis. Patients > 18 years of age, patients placed on ECMO directly from cardiopulmonary bypass or as an exit procedure, or patients with an invalid or missing VIS score were excluded. Higher VIS (OR = 1.008, 95% CI: 1.002–1.014, p = 0.011) and VVR (OR: 1.006, 95% CI: 1.001–1.012, p = 0.023) were associated with increased mortality. VIS was associated with worse Pediatric Cerebral Performance Category (PCPC) (OR = 1.027, 95% CI: 1.010–1.044, p = 0.002) and Pediatric Overall Performance Category (POPC) score (OR = 1.023, 95% CI: 1.009–1.038, p = 0.002) at discharge. No association was found between VIS or VVR and Functional Status Score (FSS) at discharge. Using multivariable analyses, controlling for ECMO mode, ECMO location, ECMO indication, primary diagnosis, and chronic diagnosis, extremely high VIS and VVR were still associated with increased mortality.
Case Report and Review of the Literature: Congenital Diaphragmatic Hernia and Craniosynostosis, a Coincidence or Common Cause?
Authors: Gaillard Linda , Goverde Anne , van den Bosch Quincy C. C. , Jehee Fernanda S. , Brosens Erwin , Veenma Danielle , Magielsen Frank , de Klein Annelies , Mathijssen Irene M. J. , van Dooren Marieke F.
Published: December 2021

Congenital diaphragmatic hernia (CDH) is a life-threatening birth defect that presents as either an isolated diaphragm defect or as part of a complex disorder with a wide array of anomalies (complex CDH). Some patients with complex CDH display distinct craniofacial anomalies such as craniofrontonasal dysplasia or craniosynostosis, defined by the premature closure of cranial sutures. Using clinical whole exome sequencing (WES), we found a BCL11B missense variant in a patient with a left-sided congenital diaphragmatic hernia as well as sagittal suture craniosynostosis. We applied targeted sequencing of BCL11B in patients with craniosynostosis or with a combination of craniosynostosis and CDH. This resulted in three additional BCL11B missense mutations in patients with craniosynostosis. The phenotype of the patient with both CDH as well as craniosynostosis was similar to the phenotype of previously reported patients with BCL11B missense mutations. Although these findings imply that both craniosynostosis as well as CDH may be associated with BCL11B mutations, further studies are required to establish whether BCL11B variants are causative mutations for both conditions or if our finding was coincidental.
Case Report: Emphysematous Pyelonephritis With a Congenital Giant Ureterocele
Authors: Kitano Hiroyuki , Hieda Keisuke , Kitagawa Hiroki , Nakaoka Yusuke , Koba Yumiko , Ota Kohei , Shigemoto Norifumi , Hayashi Tetsutaro , Kashiyama Seiya , Teishima Jun , Shime Nobuaki , Ohge Hiroki , Hinata Nobuyuki
Published: December 2021

A 14-year-old girl noticed malodorous urine and experienced left flank pain. The patient was presented to our hospital with gradually increasing pain. She had no underlying disease but had a history of pain on micturition for several days. Hematologic examination indicated low white blood cell and platelet counts and a high serum lactate level. Computed tomography showed that a part of the parenchyma of the left kidney had poor contrast and was deteriorated, with fluid and gas retention from the perirenal region to the retroperitoneal cavity. A left hydroureter and large ureterocele were observed in the bladder. She was diagnosed with emphysematous pyelonephritis (EPN) with a giant congenital ureterocele. Vasopressors and blood transfusion failed to maintain normal circulatory dynamics, and an open left nephrectomy and transurethral ureterocele fenestration were performed. The excised outer portion of the left kidney was dissolved by the infection and replaced with blood clots and necrotic tissue. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry identified the inflammatory, gas-producing bacteria Actinotignum schaalii, Peptoniphilus asaccharolyticus, and Actinomyces odontolyticus. Meropenem was administered for 4 days postoperatively and then de-escalated to sulbactam/ampicillin for another 10 days. The patient was discharged on day 17 of hospitalization, and the postoperative course remained favorable. EPN is extremely rare in pediatric patients, and it is believed that nephrectomy is sometimes necessary if the patient does not have normal circulatory dynamics despite the use of catecholamines.
A Case Report and Literature Review of a Novel Mutation in the MAGED2 Gene of a Patient With Severe Transient Polyhydramnios
Authors: Wu Xiaoxia , Huang Le , Luo Caiqun , Liu Yang , Niu Jianmin
Published: December 2021

Background: Polyhydramnios occurs frequently during pregnancy. Mutations in the MAGED2 gene can cause X-linked acute early-onset polyhydramnios with a severe but transient form of antenatal Bartter's syndrome.

Case Presentation: Here, we report a new novel frameshift mutation c.733_734delCT (p. Leu245GlufsTer4) in the MAGED2 gene (NM_177433.1) that caused prenatal polyhydramnios, but did not cause polyuria after birth. Follow-up was conducted for 2 months, and the baby's growth and development were normal, without polyuria and renal impairment. In addition, we identified all individuals with MAGED2 mutations reported in the literature before March 2021.

Conclusion: We report a new case with a novel variant of the MAGED2 gene that caused severe hydramnios but with a good result and summary clinical characteristics in a newborn with antenatal Bartter's syndrome caused by an MAGED2 mutation. Good prenatal diagnosis and genetic consultation can improve pregnancy monitoring and newborn management.
Effects of a 12-Weeks Yoga Intervention on Motor and Cognitive Abilities of Preschool Children
Authors: Aleksić Veljković Aleksandra , Katanić Borko , Masanovic Bojan
Published: December 2021

Since early childhood is regarded as an important period of motor and cognitive development, understanding the effects of physical activity on motor abilites and cognitive development in preschool children has major public health implications. This study investigates the effects of a 12 weeks' yoga intervention program on motor and cognitive abilities in preschool children. Preschool children (n = 45; age 5–6 years) attending regular preschool programs were non-randomly assigned to yoga intervention (n = 23; 30 min sessions three times per week) or a control group (n = 22; no additional organized physical activity program). Exercise training for the intervention group included yoga program. Motor abilities (BOT-2 subtests: fine motor integration, manual dexterity, balance and bilateral coordination), and cognitive abilities (School Maturity Test subtests: visual memory, stacking cubes and codes) were assessed before and after the intervention period in both groups. Data were analyzed using repeated-measures ANOVA. Participants in the intervention group improved fine motor integration (p = 0.022), fine motor skills in general (0.029), bilateral coordination (0.000), balance (0.000), and body coordination (0.000). Preschool children's participation in the preschool yoga intervention significantly improved their motor abilities, but not their cognitive abilities.
Growth Hormone Secretagogue Receptor 1A Antagonist JMV2959 Effectively Prevents Morphine Memory Reconsolidation and Relapse
Authors: Zhao Jing , Du Xinyu , Chen Mingzhu , Zhu Shimin
Published: December 2021

Relapse to drug seeking after prolonged abstinence is a major problem in the clinical treatment of drug addiction. The use of pharmacological interventions to disrupt established drug reward memories is a promising strategy for the treatment of drug addiction. A growth hormone secretagogue receptor 1 A antagonist, JMV2959, has been shown to reduce morphine-induced conditioned place preference (CPP) in rats within hours of intervention; thus, JMV2959 is a potential candidate for drug addiction treatment. However, the effect of JMV2959 on reconsolidation to disrupt drug seeking remains unknown. In this study, we assessed the effect of JMV2959 on morphine induced memory reconsolidation to inhibit drug seeking after drug withdrawal. Our results showed that the administration of JMV2959 (6 mg/kg) significantly reduced environmental cue induced CPP, which suggested a preventive effect of JMV2959 on morphine induced memory reconsolidation. Additionally, JMV2959 administration significantly altered the locomotor activity and food and water intake but did not significantly alter the natural reward preference. We concluded that JMV2959 may be an effective candidate to treat drug addiction.
Predicting Blood Concentration of Tacrolimus in Patients With Autoimmune Diseases Using Machine Learning Techniques Based on Real-World Evidence
Authors: Zheng Ping , Yu Ze , Li Liren , Liu Shiting , Lou Yan , Hao Xin , Yu Peng , Lei Ming , Qi Qiaona , Wang Zeyuan , Gao Fei , Zhang Yuqing , Li Yilei
Published: December 2021

Tacrolimus is a widely used immunosuppressive drug in patients with autoimmune diseases. It has a narrow therapeutic window, thus requiring therapeutic drug monitoring (TDM) to guide the clinical regimen. This study included 193 cases of tacrolimus TDM data in patients with autoimmune diseases at Southern Medical University Nanfang Hospital from June 7, 2018, to December 31, 2020. The study identified nine important variables for tacrolimus concentration using sequential forward selection, including height, tacrolimus daily dose, other immunosuppressants, low-density lipoprotein cholesterol, mean corpuscular volume, mean corpuscular hemoglobin, white blood cell count, direct bilirubin, and hematocrit. The prediction abilities of 14 models based on regression analysis or machine learning algorithms were compared. Ultimately, a prediction model of tacrolimus concentration was established through eXtreme Gradient Boosting (XGBoost) algorithm with the best predictive ability (R2 = 0.54, mean absolute error = 0.25, and root mean square error = 0.33). Then, SHapley Additive exPlanations was used to visually interpret the variable’s impacts on tacrolimus concentration. In conclusion, the XGBoost model for predicting blood concentration of tacrolimus on the basis of real-world evidence has good predictive performance, providing guidance for the adjustment of regimen in clinical practice.
Update on Poly ADP-Ribose Polymerase Inhibitors in Ovarian Cancer With Non-BRCA Mutations
Authors: Xu Qin , Li Zhengyu
Published: December 2021

Poly ADP-ribose polymerase inhibitor (PARPi) has become an important maintenance therapy for ovarian cancer after surgery and cytotoxic chemotherapy, which has changed the disease management model of ovarian cancer, greatly decreased the risk of recurrence, and made the prognosis of ovarian cancer better to certain extent. The three PARPis currently approved by the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of ovarian cancer are Olaparib, Niraparib and Rucaparib. With the incremental results from new clinical trials, the applicable population of PARPi for ovarian cancer have expanded to population with non-BRCA mutations. Although BRCA mutated population are still the main beneficiaries of PARPi, recent clinical trials indicated PARPis’ therapeutic potential in non-BRCA mutated population, especially in homologous recombination repair deficiency (HRD) positive population. However, lack of unified HRD status detection method poses a challenge for the accurate selection of PARPi beneficiaries. The reversal of homologous recombination (HR) function during the treatment will not only cause resistance to PARPis, but also reduce the accuracy of the current method to determine HRD status. Therefore, the development of reliable HRD status detection methods to determine the beneficiary population, as well as rational combination treatment are warranted. This review mainly summarizes the latest clinical trial results and combination treatment of PARPis in ovarian cancer with non-BRCA mutations, and discusses the application prospects, including optimizing combination therapy against drug resistance, developing unified and accurate HRD status detection methods for patient selection and stratification. This review further poses an interesting topic: the efficacy and safety in patients retreated with PARPis after previous PARPi treatment---“PARPi after PARPi”.
Mmp12 Is Upregulated by in utero Second-Hand Smoke Exposures and Is a Key Factor Contributing to Aggravated Lung Responses in Adult Emphysema, Asthma, and Lung Cancer Mouse Models
Authors: Noël Alexandra , Perveen Zakia , Xiao Rui , Hammond Harriet , Le Donne Viviana , Legendre Kelsey , Gartia Manas Ranjan , Sahu Sushant , Paulsen Daniel B. , Penn Arthur L.
Published: December 2021

Matrix metalloproteinase-12 (Mmp12) is upregulated by cigarette smoke (CS) and plays a critical role in extracellular matrix remodeling, a key mechanism involved in physiological repair processes, and in the pathogenesis of emphysema, asthma, and lung cancer. While cigarette smoking is associated with the development of chronic obstructive pulmonary diseases (COPD) and lung cancer,in uteroexposures to CS and second-hand smoke (SHS) are associated with asthma development in the offspring. SHS is an indoor air pollutant that causes known adverse health effects; however, the mechanisms by whichin uteroSHS exposures predispose to adult lung diseases, including COPD, asthma, and lung cancer, are poorly understood. In this study, we tested the hypothesis thatin uteroSHS exposure aggravates adult-induced emphysema, asthma, and lung cancer.

Methods:Pregnant BALB/c mice were exposed from gestational days 6–19 to either 3 or 10mg/m3of SHS or filtered air. At 10, 11, 16, or 17weeks of age, female offspring were treated with either saline for controls, elastase to induce emphysema, house-dust mite (HDM) to initiate asthma, or urethane to promote lung cancer. At sacrifice, specific disease-related lung responses including lung function, inflammation, gene, and protein expression were assessed.

Results:In the elastase-induced emphysema model,in uteroSHS-exposed mice had significantly enlarged airspaces and up-regulated expression ofMmp12(10.3-fold compared to air-elastase controls). In the HDM-induced asthma model,in uteroexposures to SHS produced eosinophilic lung inflammation and potentiatedMmp12gene expression (5.7-fold compared to air-HDM controls). In the lung cancer model,in uteroexposures to SHS significantly increased the number of intrapulmonary metastases at 58weeks of age and up-regulatedMmp12(9.3-fold compared to air-urethane controls). In all lung disease models,Mmp12upregulation was supported at the protein level.

Conclusion:Our findings revealed thatin uteroSHS exposures exacerbate lung responses to adult-induced emphysema, asthma, and lung cancer. Our data show that MMP12 is up-regulated at the gene and protein levels in three distinct adult lung disease models followingin uteroSHS exposures, suggesting that MMP12 is central toin uteroSHS-aggravated lung responses.
Beneficial Effects on Brain Micro-Environment by Caloric Restriction in Alleviating Neurodegenerative Diseases and Brain Aging
Authors: Zhang Li , Xu Huachong , Ding Ning , Li Xue , Chen Xiaoyin , Chen Zhuangfei
Published: December 2021

Aging and neurodegenerative diseases are frequently associated with the disruption of the extracellular microenvironment, which includes mesenchyme and body fluid components. Caloric restriction (CR) has been recognized as a lifestyle intervention that can improve long-term health. In addition to preventing metabolic disorders, CR has been shown to improve brain health owing to its enhancing effect on cognitive functions or retarding effect on the progression of neurodegenerative diseases. This article summarizes current findings regarding the neuroprotective effects of CR, which include the modulation of metabolism, autophagy, oxidative stress, and neuroinflammation. This review may offer future perspectives for brain aging interventions.
High Density Surface Electromyography Activity of the Lumbar Erector Spinae Muscles and Comfort/Discomfort Assessment in Piano Players: Comparison of Two Chairs
Authors: Aranceta-Garza Alejandra , Russo Alessandro , D’Emanuele Samuel , Serafino Francesca , Merletti Roberto
Published: December 2021

Introduction:At a professional level, pianists have a high prevalence of playing-related musculoskeletal disorders. This exploratory crossover study was carried out to assess and compare quantitatively [using high density surface electromyography (HDsEMG)], and qualitatively (using musculoskeletal questionnaires) the activity of the lumbar erector spinae muscles (ESM) and the comfort/discomfort in 16 pianists sitting on a standard piano stool (SS) and on an alternative chair (A-chair) with lumbar support and a trunk-thigh angle between 105° and 135°.

Materials and Methods:The subjects played for 55 min and HDsEMG was recorded for 20 s every 5 min. For the quantitative assessment of the muscle activity, the spatial mean of the root mean square (RMSROA) and the centroid of the region of activity (ROA) of the ESM were compared between the two chairs. For the qualitative assessment, musculoskeletal questionnaire-based scales were used: General Comfort Rating (GCR); Helander and Zhang’s comfort (HZc) and discomfort (HZd); and Body Part Discomfort (BPD).

Results:When using the A-chair, 14 out of 16 pianists (87.5%) showed a significantly lower RMSROAon the left and right side (p< 0.05). The mixed effects model revealed that both chairs (F= 28.21,p< 0.001) and sides (F= 204.01,p< 0.001) contributed to the mean RMSROAvariation by subject (Z= 2.64,p= 0.004). GCR comfort indicated that participants found the A-Chair to be “quite comfortable,” and the SS to be “uncomfortable.” GCR discomfort indicated that the SS caused more numbness than the A-Chair (p= 0.05) and indicated the A-Chair to cause more feeling of cramps (p= 0.034). No difference was found on HZc (p= 0.091) or HZd (p= 0.31) between chairs. Female participants (n= 9) reported greater comfort when using the A-Chair than the SS (F= 7.09,p= 0.01) with respect to males. No differences between chairs were indicated by the BPD assessment.

Conclusion:It is concluded that using a chair with lumbar support, such as the A-chair, will provide greater comfort, less exertion of the ESM and less discomfort than the standard piano stool.
A Spatial Model of Hepatic Calcium Signaling and Glucose Metabolism Under Autonomic Control Reveals Functional Consequences of Varying Liver Innervation Patterns Across Species
Authors: Verma Aalap , Manchel Alexandra , Narayanan Rahul , Hoek Jan B. , Ogunnaike Babatunde A. , Vadigepalli Rajanikanth
Published: December 2021

Rapid breakdown of hepatic glycogen stores into glucose plays an important role during intense physical exercise to maintain systemic euglycemia. Hepatic glycogenolysis is governed by several different liver-intrinsic and systemic factors such as hepatic zonation, circulating catecholamines, hepatocellular calcium signaling, hepatic neuroanatomy, and the central nervous system (CNS). Of the factors regulating hepatic glycogenolysis, the extent of lobular innervation varies significantly between humans and rodents. While rodents display very few autonomic nerve terminals in the liver, nearly every hepatic layer in the human liver receives neural input. In the present study, we developed a multi-scale, multi-organ model of hepatic metabolism incorporating liver zonation, lobular scale calcium signaling, hepatic innervation, and direct and peripheral organ-mediated communication between the liver and the CNS. We evaluated the effect of each of these governing factors on the total hepatic glucose output and zonal glycogenolytic patterns within liver lobules during simulated physical exercise. Our simulations revealed that direct neuronal stimulation of the liver and an increase in circulating catecholamines increases hepatic glucose output mediated by mobilization of intracellular calcium stores and lobular scale calcium waves. Comparing simulated glycogenolysis between human-like and rodent-like hepatic innervation patterns (extensive vs. minimal) suggested that propagation of calcium transients across liver lobules acts as a compensatory mechanism to improve hepatic glucose output in sparsely innervated livers. Interestingly, our simulations suggested that catecholamine-driven glycogenolysis is reduced under portal hypertension. However, increased innervation coupled with strong intercellular communication can improve the total hepatic glucose output under portal hypertension. In summary, our modeling and simulation study reveals a complex interplay of intercellular and multi-organ interactions that can lead to differing calcium dynamics and spatial distributions of glycogenolysis at the lobular scale in the liver.
Serum MicroRNA Expression Patterns in Subjects After the 5-km Exercise Are Strongly Associated With Cardiovascular Adaptation
Authors: Li Dandan , Wang Pingping , Wei Wenyan , Wang Cheng , Zhong Yong , Lv Lei , Wang Junjun
Published: December 2021

Circulating microRNAs (miRNAs) have been reported dysregulated during exercise. However, the changes of specific serum miRNAs during the 5-km run test with intensity of 51–52% maximum oxygen uptake (V̇O2max) and their association with traditional cardiovascular-related indicators remain well-characterized. Levels of miR-1, miR-21, miR-146a, miR-155, miR-181, and miR-210 were detected in 120 young subjects before and after the exercise training by quantitative reverse-transcription PCR (RT-qPCR). Besides, the levels of cardiac troponin I (cTNI), myoglobin (Myo), creatine kinase (CK), creatine kinase-MB (CK-MB), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), ischemia-modified albumin (IMA), interleukin-6 (IL-6), and C-reactive protein (CRP) were measured and the correlation between levels of serum miRNAs and biochemical parameters was also analyzed. Compared with resting state, the serum levels of miR-1, miR-146a, miR-155, miR-181, and miR-210 were significantly increased after exercise training. Serum levels of miR-146a, miR-155, and miR-210 after exercise training were positively correlated with Myo, CK-MB, and LDH, respectively, while miR-1, miR-146a, miR-181, and miR-155 were positively correlated with the levels of IL-6. Additionally, all the five miRNAs were negatively correlated with IMA levels. The multivariate logistic regression analysis showed that high levels of miR-146a, AST, LDH, and IL-6 in serum were risk factors, while low IMA contents were a protective factor for cardiovascular adaptation during exercise. In conclusion, the dynamic changes of miRNAs under the condition of the 5-km continuous running contribute to the adaptive regulation of the cardiovascular function of the body.
Thrombus-Targeting Polymeric Nanocarriers and Their Biomedical Applications in Thrombolytic Therapy
Authors: Guan Qixiao , Dou Hongjing
Published: December 2021

Due to the high morbidity and mortality of cardiovascular diseases, there is an urgent need for research on antithrombotic strategies. In view of the short half-life, insufficient drug penetration, poor targeting capabilities, and hemorrhagic side-effects of traditional thrombus treatment methods, the combination of thrombolytic therapy and nanocarriers brought by the development of nanotechnology in recent years may provide effective solutions for these undesirable side-effects caused by insufficient targeting. Polymeric nanocarriers, based on macromolecules and various functional groups, can connect specific targeting molecules together through chemical modification to achieve the protection and targeted delivery of thrombolytic drugs. However, simple chemical molecular modifications may be easily affected by the physiological environment encountered in the circulatory system. Therefore, the modification of nanocarriers with cell membranes can provide camouflage to these platforms and help to extend their circulation time while also imparting them with the biological functions of cell membranes, thus providing them with precise targeting capabilities, among which the most important is the biological modification of platelet membranes. In addition, some nanoparticles with their own therapeutic functions have also been developed, such as polypyrrole, which can exhibit a photothermal effect to induce thrombolysis. Herein, combined with the mechanism of thrombosis and thrombolysis, we outline the recent advances achieved with thrombus-targeting nanocarriers with regard to thrombosis treatment. On this basis, the design considerations, advantages, and challenges of these thrombolytic therapies in clinical transformation are discussed.
Sensory Afferent Renal Nerve Activated Gαi2 Subunit Proteins Mediate the Natriuretic, Sympathoinhibitory and Normotensive Responses to Peripheral Sodium Challenges
Authors: Moreira Jesse D. , Nist Kayla M. , Carmichael Casey Y. , Kuwabara Jill T. , Wainford Richard D.
Published: December 2021

We have previously reported that brain Gαi2 subunit proteins are required to maintain sodium homeostasis and are endogenously upregulated in the hypothalamic paraventricular nucleus (PVN) in response to increased dietary salt intake to maintain a salt resistant phenotype in rats. However, the origin of the signal that drives the endogenous activation and up-regulation of PVN Gαi2 subunit protein signal transduction pathways is unknown. By central oligodeoxynucleotide (ODN) administration we show that the pressor responses to central acute administration and central infusion of sodium chloride occur independently of brain Gαi2 protein pathways. In response to an acute volume expansion, we demonstrate, via the use of selective afferent renal denervation (ADNX) and anteroventral third ventricle (AV3V) lesions, that the sensory afferent renal nerves, but not the sodium sensitive AV3V region, are mechanistically involved in Gαi2 protein mediated natriuresis to an acute volume expansion [peak natriuresis (μeq/min) sham AV3V: 43 ± 4 vs. AV3V 45 ± 4 vs. AV3V + Gαi2 ODN 25 ± 4, p < 0.05; sham ADNX: 43 ± 4 vs. ADNX 23 ± 6, AV3V + Gαi2 ODN 25 ± 3, p < 0.05]. Furthermore, in response to chronically elevated dietary sodium intake, endogenous up-regulation of PVN specific Gαi2 proteins does not involve the AV3V region and is mediated by the sensory afferent renal nerves to counter the development of the salt sensitivity of blood pressure (MAP [mmHg] 4% NaCl; Sham ADNX 124 ± 4 vs. ADNX 145 ± 4, p < 0.05; Sham AV3V 125 ± 4 vs. AV3V 121 ± 5). Additionally, the development of the salt sensitivity of blood pressure following central ODN-mediated Gαi2 protein down-regulation occurs independently of the actions of the brain angiotensin II type 1 receptor. Collectively, our data suggest that in response to alterations in whole body sodium the peripheral sensory afferent renal nerves, but not the central AV3V sodium sensitive region, evoke the up-regulation and activation of PVN Gαi2 protein gated pathways to maintain a salt resistant phenotype. As such, both the sensory afferent renal nerves and PVN Gαi2 protein gated pathways, represent potential targets for the treatment of the salt sensitivity of blood pressure.
Potential Benefits of a Minimal Dose Eccentric Resistance Training Paradigm to Combat Sarcopenia and Age-Related Muscle and Physical Function Deficits in Older Adults
Authors: Harper Sara A. , Thompson Brennan J.
Published: December 2021

The ability of older adults to perform activities of daily living is often limited by the ability to generate high mechanical outputs. Therefore, assessing and developing maximal neuromuscular capacity is essential for determining age-related risk for functional decline as well as the effectiveness of therapeutic interventions. Interventions designed to enhance neuromuscular capacities underpinning maximal mechanical outputs could positively impact functional performance in daily life. Unfortunately, < 10% of older adults meet the current resistance training guidelines. It has recently been proposed that a more “minimal dose” RT model may help engage a greater proportion of older adults, so that they may realize the benefits of RT. Eccentric exercise offers some promising qualities for such an approach due to its efficiency in overloading contractions that can induce substantial neuromuscular adaptations. When used in a minimal dose RT paradigm, eccentric-based RT may be a particularly promising approach for older adults that can efficiently improve muscle mass, strength, and functional performance. One approach that may lead to improved neuromuscular function capacities and overall health is through heightened exercise tolerance which would favor greater exercise participation in older adult populations. Therefore, our perspective article will discuss the implications of using a minimal dose, submaximal (i.e., low intensity) multi-joint eccentric resistance training paradigm as a potentially effective, and yet currently underutilized, means to efficiently improve neuromuscular capacities and function for older adults.
Translational Control in Liver Disease
Authors: Balvey Alexandra , Fernandez Mercedes
Published: December 2021

Chronic liver disease is one of the biggest threats to public health worldwide. Worryingly, the incidence of liver disease is dramatically rising due to the aging of the population and the global epidemics of obesity. Both are major risk factors for chronic liver disease and adverse prognostic factors, causing an increase in mortality rate. It is of great concern that 80–95% of obese people have non-alcoholic fatty liver disease, the major precursor for liver failure and a global health challenge. Currently, the only curative treatment for advanced chronic liver disease is liver transplantation, which is, however, hampered by high treatment costs and the scarcity of donor organs. New strategies are therefore urgently needed to prevent and reverse chronic liver disease. And for that it is essential to understand better the molecular mechanisms underlying human disease. This review focuses on the abnormalities in the regulation of translation by RNA-binding proteins during chronic liver disease and their pathological impact on portal hypertension, fibrosis, steatosis, neovascularization, and cancer development.
Spray-Induced Silencing of Pathogenicity Gene MoDES1 via Exogenous Double-Stranded RNA Can Confer Partial Resistance Against Fungal Blast in Rice
Authors: Sarkar Atrayee , Roy-Barman Subhankar
Published: December 2021

Over the past years, RNA interference (RNAi) has been used as a promising combat strategy against a wide range of pests and pathogens in ensuring global food security. It involves the induction of highly specific posttranscriptional regulation of target essential genes from an organism, via the application of precursor long, non-coding double-stranded RNA (dsRNA) molecules that share sequence-complementarity with the mRNAs of the targets. Fungal blast disease caused by Magnaporthe oryzae is one of the most deadly diseases of rice and wheat incurring huge losses in global crop yield. To date, the host-induced gene silencing (HIGS) and virus-induced gene silencing (VIGS) aspects of RNAi have been successfully exploited in developing resistance against M. oryzae in rice. Spray-induced gene silencing (SIGS) is a current, potential, non-transformative, and environment-friendly pest and pathogen management strategy, where naked or nanomaterial-bound dsRNA are sprayed on leaves to cause selective knockdown of pathogenicity genes. Although it relies on the ability of fungal pathogens to uptake sprayed RNA, its efficiency varies largely across phytopathogens and their genes, targeted for silencing. Here, we report a transient dsRNA supplementation system for the targeted knockdown of MoDES1, a host-defense suppressor pathogenicity gene from M. oryzae. We validate the feasibility of in vivo SIGS and post-uptake transfer of RNA signals to distal plant parts in rice-M. oryzae pathosystem through a GFP-based reporter system. A protocol for efficient silencing via direct foliar spray of naked dsRNA was optimized. As proof-of-concept, we demonstrate the phenotypic impacts of in vitro dsDES1 treatment on growth, conidiation, ROS-scavenging ability, and pathogenic potential of M. oryzae. Furthermore, our extrapolatory dsDES1 spray experiments on wounded leaves and whole rice plants indicate resultant silencing of MoDES1 that conferred significant resistance against the fungal blast disease. The evaluation of primary and secondary host defense responses provides evidence supporting the notion that spray of sequence-specific dsRNA on wounded leaf tissue can cause systemic and sustained silencing of a M. oryzae target gene. For the first time, we establish a transgene-free SIGS approach as a promising crop protection strategy against the notorious rice-blast fungus.
A Rice Ancestral Genetic Resource Conferring Ideal Plant Shapes for Vegetative Growth and Weed Suppression
Authors: Inagaki Noritoshi , Asami Hidenori , Hirabayashi Hideyuki , Uchino Akira , Imaizumi Toshiyuki , Ishimaru Ken
Published: December 2021

To maximize crop growth, crops need to capture sunlight efficiently. This property is primarily influenced by the shape of the crops such as the angle, area, and arrangement of leaves. We constructed a rice (Oryza sativa L.) inbred line that displayed an ideal transition of plant shapes in terms of sunlight receiving efficiency. During vegetative growth, this line exhibited tiller spreading with increased tiller number, which formed a parabolic antenna-like structure. The architecture probably improved light reception efficiency of individuals compared with the recurrent parent. The line achieved not only acceleration of the vegetative growth, but also significant suppression of weed growth under the canopy. The increased light reception efficiency of the line has consequently reduced the amount of incident light to the ground and supplied significant competitiveness against weeds. The spread tillers became erect from the entry of the reproductive growth phase, adaptively sustaining light reception efficiency in thicker stands. The line carries a small chromosomal segment from Oryza rufipogon Griff., a putative progenitor of Asian cultivated rice. The introduced chromosome segment had little effect on grain yield and quality. Our results shed light on potentials hidden in the wild rice chromosome segment to achieve the valuable traits.
Integrated Bioinformatics Analyses of PIN1, CKX, and Yield-Related Genes Reveals the Molecular Mechanisms for the Difference of Seed Number Per Pod Between Soybean and Cowpea
Authors: Liu Lü-Meng , Zhang Han-Qing , Cheng Kun , Zhang Yuan-Ming
Published: December 2021

There is limited advancement on seed number per pod (SNPP) in soybean breeding, resulting in low yield in China. To address this issue, we identified PIN1 and CKX gene families that regulate SNPP in Arabidopsis, analyzed the differences of auxin and cytokinin pathways, and constructed interaction networks on PIN1, CKX, and yield-related genes in soybean and cowpea. First, the relative expression level (REL) of PIN1 and the plasma membrane localization and phosphorylation levels of PIN1 protein were less in soybean than in cowpea, which make auxin transport efficiency lower in soybean, and its two interacted proteins might be involved in serine hydrolysis, so soybean has lower SNPP than cowpea. Then, the CKX gene family, along with its positive regulatory factor ROCK1, had higher REL and less miRNA regulation in soybean flowers than in cowpea ones. These lead to higher cytokinin degradation level, which further reduces the REL of PIN1 and decreases soybean SNPP. We found that VuACX4 had much higher REL than GmACX4, although the two genes essential in embryo development interact with the CKX gene family. Next, a tandem duplication experienced by legumes led to the differentiation of CKX3 into CKX3a and CKX3b, in which CKX3a is a key gene affecting ovule number. Finally, in the yield-related gene networks, three cowpea CBP genes had higher RELs than two soybean CBP genes, low RELs of three soybean-specific IPT genes might lead to a decrease in cytokinin synthesis, and some negative and positive SNPP regulation were found, respectively, in soybean and cowpea. These networks may explain the SNPP difference in the two crops. We deduced that ckx3a or ckx3a ckx6 ckx7 mutants, interfering CYP88A, and over-expressed DELLA increase SNPP in soybean. This study reveals the molecular mechanism for the SNPP difference in the two crops, and provides an important idea for increasing soybean yield.