bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparing the Nucleocapsid Proteins of Human Coronaviruses: Structure, Immunoregulation, Vaccine, and Targeted Drug
Authors: Zhang Bo , Tian Junjie , Zhang Qintao , Xie Yan , Wang Kejia , Qiu Shuyi , Lu Keyu , Liu Yang
Published: April 2022

The seven pathogenic human coronaviruses (HCoVs) include HCoV-229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU1, which usually cause mild upper respiratory tract diseases, and SARS-CoV, MERS-CoV, and SARS-CoV-2, which cause a severe acute respiratory syndrome. The nucleocapsid (N) protein, as the dominant structural protein from coronaviruses that bind to the genomic RNA, participates in various vital activities after virus invasion and will probably become a promising target of antiviral drug design. Therefore, a comprehensive literature review of human coronavirus’ pathogenic mechanism and therapeutic strategies is necessary for the control of the pandemic. Here, we give a systematic summary of the structures, immunoregulation, and potential vaccines and targeted drugs of the HCoVs N protein. First, we provide a general introduction to the fundamental structures and molecular function of N protein. Next, we outline the N protein mediated immune regulation and pathogenesis mechanism. Finally, we comprehensively summarize the development of potential N protein-targeted drugs and candidate vaccines to treat coronavirus disease 2019 (COVID-19). We believe this review provides insight into the virulence and transmission of SARS-CoV-2 as well as support for further study on epidemic control of COVID-19.
Intron-Encoded Domain of Herstatin, An Autoinhibitor of Human Epidermal Growth Factor Receptors, Is Intrinsically Disordered
Authors: Tashiro Daisuke , Suetaka Shunji , Sato Nao , Ooka Koji , Kunihara Tomoko , Kudo Hisashi , Inatomi Junichi , Hayashi Yuuki , Arai Munehito
Published: April 2022

Human epidermal growth factor receptors (HER/ERBB) form dimers that promote cell proliferation, migration, and differentiation, but overexpression of HER proteins results in cancer. Consequently, inhibitors of HER dimerization may function as effective antitumor drugs. An alternatively spliced variant of HER2, called herstatin, is an autoinhibitor of HER proteins, and the intron 8-encoded 79-residue domain of herstatin, called Int8, binds HER family receptors even in isolation. However, the structure of Int8 remains poorly understood. Here, we revealed by circular dichroism, NMR, small-angle X-ray scattering, and structure prediction that isolated Int8 is largely disordered but has a residual helical structure. The radius of gyration of Int8 was almost the same as that of fully unfolded states, although the conformational ensemble of Int8 was less flexible than random coils. These results demonstrate that Int8 is intrinsically disordered. Thus, Int8 is an interesting example of an intrinsically disordered region with tumor-suppressive activity encoded by an intron. Furthermore, we show that the R371I mutant of Int8, which is defective in binding to HER2, is prone to aggregation, providing a rationale for the loss of function.
Cotranslational Biogenesis of Membrane Proteins in Bacteria
Authors: Mercier Evan , Wang Xiaolin , Bögeholz Lena A. K. , Wintermeyer Wolfgang , Rodnina Marina V.
Published: April 2022

Nascent polypeptides emerging from the ribosome during translation are rapidly scanned and processed by ribosome-associated protein biogenesis factors (RPBs). RPBs cleave the N-terminal formyl and methionine groups, assist cotranslational protein folding, and sort the proteins according to their cellular destination. Ribosomes translating inner-membrane proteins are recognized and targeted to the translocon with the help of the signal recognition particle, SRP, and SRP receptor, FtsY. The growing nascent peptide is then inserted into the phospholipid bilayer at the translocon, an inner-membrane protein complex consisting of SecY, SecE, and SecG. Folding of membrane proteins requires that transmembrane helices (TMs) attain their correct topology, the soluble domains are inserted at the correct (cytoplasmic or periplasmic) side of the membrane, and – for polytopic membrane proteins – the TMs find their interaction partner TMs in the phospholipid bilayer. This review describes the recent progress in understanding how growing nascent peptides are processed and how inner-membrane proteins are targeted to the translocon and find their correct orientation at the membrane, with the focus on biophysical approaches revealing the dynamics of the process. We describe how spontaneous fluctuations of the translocon allow diffusion of TMs into the phospholipid bilayer and argue that the ribosome orchestrates cotranslational targeting not only by providing the binding platform for the RPBs or the translocon, but also by helping the nascent chains to find their correct orientation in the membrane. Finally, we present the auxiliary role of YidC as a chaperone for inner-membrane proteins. We show how biophysical approaches provide new insights into the dynamics of membrane protein biogenesis and raise new questions as to how translation modulates protein folding.
Plasma Phosphorylated-tau181 Is a Predictor of Post-stroke Cognitive Impairment: A Longitudinal Study
Authors: Huang Li-Kai , Chao Shu-Ping , Hu Chaur-Jong , Chien Li-Nien , Chiou Hung-Yi , Lo Yu-Chun , Hsieh Yi-Chen
Published: April 2022

Introduction

Post-stroke cognitive impairment (PSCI) cannot be neglected because it drastically influences the daily life of patients and their families. However, there are no studies exploring the association between preclinical blood biomarkers of neurodegeneration including plasma amyloid-β (Aβ), tau, and brain-derived neurotrophic factor (BDNF) together with the risk of PSCI. This longitudinal study was to investigate whether these blood biomarkers with imaging markers of cerebral small vessel disease can improve the prediction for PSCI. In addition, we also explored the association between blood biomarkers with the trajectories of PSCI.

Methods

Adult patients with first-ever acute ischemic stroke were recruited, and the cognitive and functional abilities of these patients were evaluated. Furthermore, blood biomarkers of neurodegeneration including plasma Aβ-40, Aβ-42, total tau, phosphorylated tau 181 (p-tau181), and BDNF levels and image markers of cerebral small vessel disease were measured. Each patient was followed up at 3 and 12 months at the outpatient department.

Results

Of 136 patients, 40 and 50 patients developed PSCI at 3 and 12 months after stroke, respectively. In functional trajectories, 27 patients did not have PSCI at 3 months but did at 12 months. By contrast, the PSCI status of 17 patients at 3 months was reversed at 12 months. Patients with high-acute plasma p-tau181 had a significantly lower PSCI risk at 3 months (odds ratio [OR] = 0.62, 95% CI = 0.40–0.94, p = 0.0243) and 12 months (OR = 0.69, 95% CI = 0.47–0.99, p = 0.0443) after adjustment for covariates and image biomarkers. Discrimination and reclassification statistics indicated that the p-tau181 level can improve discrimination ability for PSCI at 3 and 12 months, respectively. In addition, the plasma p-tau181 level was the highest in subjects without PSCI followed by those with delayed-onset PSCI and early-onset PSCI with reversal, whereas the lowest plasma p-tau181 level was found among those with persistent PSCI, showing a significant trend test (p = 0.0081).

Conclusion

Plasma p-tau181 is a potential biomarker for predicting early- and delayed-onset PSCI. Future studies should incorporate plasma p-tau181 as an indicator for timely cognitive intervention in the follow-up of patients with stroke.
Antiepileptic Effect and Safety Profile of Rapamycin in Pediatric Patients With Tuberous Sclerosis Complex
Authors: Sadowski Krzysztof , Sijko Kamil , Domańska-Pakieła Dorota , Borkowska Julita , Chmielewski Dariusz , Ulatowska Agata , Józwiak Sergiusz , Kotulska Katarzyna
Published: April 2022

Background

Epilepsy develops in 70–90% of children with Tuberous Sclerosis Complex (TSC) and is often resistant to medication. Treatment with mTOR pathway inhibitors is an important therapeutic option in drug-resistant epilepsy associated with TSC. Our study evaluated the antiepileptic effect of rapamycin in the pediatric population of patients diagnosed with TSC.

Methods

This single center, open-label study evaluated safety and anti-epileptic efficacy of 12 months of rapamycin treatment in 32 patients aged from 11 months to 14 years with drug-resistant TSC- associated epilepsy.

Results

After the first 6 months of treatment, the improvement in seizure frequency, defined as at least a 50% reduction in the number of seizures per week compared to baseline, was seen in 18 individuals (56.25%). We observed no change in 12 individuals (37.5%) and worsening, defined as increase in the number of seizures—in 2 patients (6.25%). The overall improvement defined as at least a 50% reduction in seizure frequency was found in 65.6% of all patients after 12 months with 28% of patients obtaining complete remission. Another five patients experienced at least an 80% reduction in the frequency of seizures. Concomitant treatment with vigabatrin, and to a much lesser extent topiramate and levetiracetam, was an additional favorable prognostic factor for the success of the therapy. A linear relationship between the cumulative dose of rapamycin and its therapeutic effect was observed. The safety profile of the drug was satisfactory. In none of the observed cases did the adverse events reach the level that required withdrawal of the rapamycin treatment. The reason for dropouts was insufficient drug efficacy in 3 cases.

Conclusions

Long-term use of rapamycin, especially in combination with vigabatrin, might be a beneficial therapeutic option in the treatment of drug-resistant epilepsy in children with TSC.
Clinical Characteristics and Risk Factors for Mortality in Cryptococcal Meningitis: Evidence From a Cohort Study
Authors: Wang Fengjuan , Wang Yu , He Jianqing , Cheng Zhe , Wu Shouquan , Wang Minggui , Niu Ting
Published: April 2022

Introduction

Despite advances in the diagnosis and management, cryptococcal meningitis (CM) is still associated with high mortality due to insufficient knowledge about clinical characteristics and risk factors for poor outcomes. The aim of the present study is to provide additional evidence for regarding clinical characteristics, diagnosis, and factors associated with increased risk of mortality in CM patients.

Methods

In this cohort study, we included eligible patients consecutively admitted to West China Hospital between January 2009 and December 2018. The clinical characteristics and diagnosis method of cerebrospinal fluid culture and India ink stain were analyzed. Independent risk factors were identified by a multivariable logistic regression.

Results

A total of 186 CM patients were included in the analysis. After a 1-year follow-up, 63 patients had died. Headache is the most common presenting symptom (97.3%), followed by vomiting (72%), fever (71.5%), altered consciousness (45.7%), abnormal vision (32.8%), and seizure (15.1%). Older age, altered consciousness or seizures, lower white blood cell count or total protein in cerebrospinal fluid (CSF), and unidentified CSF cryptococcal antigen (CrAg) are all factors associated with increasing risk of death (P < 0.05). We also found a dose-dependent trend between the number of symptoms and risk of death (trend p < 0.001). Multivariate logistic regression revealed that age (P = 0.004, OR = 1.042, 95% CI 1.013–1.071), seizure (P = 0.025, OR = 3.105, 95% CI 1.152–8.369), altered consciousness (P < 0.001, OR=6.858, 95% CI 3.063–15.38), and unidentified CSF CrAg are the independent prognostic factors. In addition, we observed that diagnosis of 28.5% and 22.5% CM could not be established by a single testing of CSF India ink stain or culture, respectively. Use of multiple testing methods or combination of the two assays increases the detection rate.

Conclusion

Our data show that older age, seizures, altered consciousness, and an inability to detect CSF CrAg are the independent risk factors of death within 1 year in CM patients. Moreover, we recommend use of multiple testing methods with CSF culture and India ink stain. Combined testing with both assays should be considered for initial CM diagnosis.
Low Contrast Visual Evoked Potentials for Early Detection of Optic Neuritis
Authors: Park Soo-Hyun , Park Choul-Yong , Shin Young Joo , Jeong Kyoung Sook , Kim Nam-Hee
Published: April 2022

Optic neuritis (ON) detection is important for the early diagnosis and management of multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD). However, the conventional high-contrast visual evoked potential (VEP) used for ON detection lacks sensitivity for identifying ON presenting as mild or unremarkable visual disturbance, which is common in first-episode ON. Therefore, this study aimed to investigate whether a change in contrast or check size improves the sensitivity of VEP to first-ever ON. In total, 60 patients with the demyelinating disease (29 MS and 31 idiopathic patients with ON) without ON or with first-ever ON at least 6 months prior and 32 healthy controls underwent neuro-ophthalmic evaluations. VEPs were induced using three pattern-reversal checkerboard stimuli having, respectively, 10% contrast with a check size of 32' (LC32 VEP), 100% contrast with a check size of 32' (HC32 VEP; conventional VEP), and 100% contrast with a check size of 16' (HC16 VEP). The receiver operating characteristic (ROC) curve analysis and area under the curve (AUC) were calculated to determine the most appropriate VEP method for detecting optic nerve involvement. The optimal cut-off point was determined using the Youden index (J-index). The McNemar test was used to determine whether dichotomous proportions were equivalent. In comparison with first-ever ON eyes (n = 39) and healthy eyes (n = 64), LC32 VEP showed the highest AUC for discriminating ON (0.750, p < 0.001; 0.730 for HC32 VEP, p < 0.001; 0.702 for HC16 VEP, p = 0.001). In the first-ever ON group, LC32 VEP and conventional HC32 VEP were abnormal in 76.9 and 43.6%, respectively (McNemar, p < 0.001), and combining these tests did not improve sensitivity. These indicate that LC32 VEP is the most sensitive method for detecting first-ever ON. Visual evoked potential with 10% contrast stimuli was superior to conventional VEP for detecting first-ever ON. Thus, adding these LC stimuli might be helpful in identifying optic nerve involvement in ON with mild or unremarkable visual impairment.
Fatigue in Multiple Sclerosis: A Review of the Exploratory and Therapeutic Potential of Non-Invasive Brain Stimulation
Authors: Ayache Samar S. , Serratrice Nicolas , Abi Lahoud Georges N. , Chalah Moussa A.
Published: April 2022

Fatigue is the most commonly reported symptom in patients with multiple sclerosis (MS). It is a worrisome, frequent, and debilitating manifestation that could occur at any time during the course of MS and in all its subtypes. It could engender professional, familial, and socioeconomic consequences and could severely compromise the patients' quality of life. Clinically, the symptom exhibits motor, cognitive, and psychosocial facets. It is also important to differentiate between perceived or subjective self-reported fatigue and fatigability which is an objective measure of decrement in the performance of cognitive or motor tasks. The pathophysiology of MS fatigue is complex, and its management remains a challenge, despite the existing body of literature on this matter. Hence, unraveling its neural mechanisms and developing treatment options that target the latter might constitute a promising field to explore. A PubMed/Medline/Scopus search was conducted to perform this review which aims (a) to reappraise the available electrophysiological studies that explored fatigue in patients with MS with a particular focus on corticospinal excitability measures obtained using transcranial magnetic stimulation and (b) to assess the potential utility of employing neuromodulation (i.e., non-invasive brain stimulation techniques) in this context. A special focus will be put on the role of transcranial direct current stimulation and transcranial magnetic stimulation. We have provided some suggestions that will help overcome the current limitations in upcoming research.
Vagus Nerve Stimulation as a Potential Therapy in Early Alzheimer’s Disease: A Review
Authors: Vargas-Caballero Mariana , Warming Hannah , Walker Robert , Holmes Clive , Cruickshank Garth , Patel Bipin
Published: April 2022

Cognitive dysfunction in Alzheimer’s disease (AD) is caused by disturbances in neuronal circuits of the brain underpinned by synapse loss, neuronal dysfunction and neuronal death. Amyloid beta and tau protein cause these pathological changes and enhance neuroinflammation, which in turn modifies disease progression and severity. Vagal nerve stimulation (VNS), via activation of the locus coeruleus (LC), results in the release of catecholamines in the hippocampus and neocortex, which can enhance synaptic plasticity and reduce inflammatory signalling. Vagal nerve stimulation has shown promise to enhance cognitive ability in animal models. Research in rodents has shown that VNS can have positive effects on basal synaptic function and synaptic plasticity, tune inflammatory signalling, and limit the accumulation of amyloid plaques. Research in humans with invasive and non-invasive VNS devices has shown promise for the modulation of cognition. However, the direct stimulation of the vagus nerve afforded with the invasive procedure carries surgical risks. In contrast, non-invasive VNS has the potential to be a broadly available therapy to manage cognitive symptoms in early AD, however, the magnitude and specificity of its effects remains to be elucidated, and the non-inferiority of the effects of non-invasive VNS as compared with invasive VNS still needs to be established. Ongoing clinical trials with healthy individuals and patients with early AD will provide valuable information to clarify the potential benefits of non-invasive VNS in cognition and AD. Whether invasive or non-invasive VNS can produce a significant improvement on memory function and whether its effects can modify the progression of AD will require further investigation.
Exploring Muscle Health Deterioration and Its Determinants Among Community-Dwelling Older Adults
Authors: Chao Yuan-Ping , Fang Wen-Hui , Chen Wei-Liang , Peng Tao-Chun , Yang Wei-Shiung , Kao Tung-Wei
Published: April 2022

Background

Age-related muscle mass and function decline are critical issues that have gained attention in clinical practice and research. Nevertheless, little is known regarding the time course of muscle health progression, and its determinants during this transition should be estimated.

Methods

We enrolled community-dwelling adults aged ≥65 years during their regular health checkup. The participants’ body composition and muscle function were measured annually from 2015 to 2021. Presarcopenia was characterized by the loss of muscle mass only; dynapenia was defined as low muscle function without changes in muscle mass; and sarcopenia was indicated as a decline in both muscle mass and muscle function. We observed the natural course of muscle health progression during aging. The relationship between muscle health decline and different determinants among old adults was examined.

Results

Among 568 participants, there was 18.49%, 3.52%, and 1.06% of healthy individuals transited to dynapenia, presarcopenia, and sarcopenia, respectively. Significant positive correlations between age, fat-to-muscle ratio (FMR) and the dynapenia transition were existed [hazard ratio (HR) = 1.08 and HR = 1.73, all p < 0.05]. Serum albumin level had negative correlation with the dynapenia transition risk (HR = 0.30, p = 0.004). Participants with these three risk factors had the highest HR of dynapenia transition compared to those without (HR = 8.67, p = 0.001). A dose-response effect existed between risk factors numbers and the risk of dynapenia transition (p for trend < 0.001). This positive association and dose-response relationship remains after multiple covariates adjustment (HR = 7.74, p = 0.002, p for trend < 0.001). Participants with two or more than two risk factors had a higher risk of dynapenia transition than those with low risk factors (p = 0.0027), and the HR was 1.96 after multiple covariate adjustment (p = 0.029).

Conclusion

Healthy community-dwelling old adults tended to transit to dynapenia during muscle health deterioration. Individuals with older age, higher FMR, lower albumin level had a higher risk of dynapenia transition; and a positive dose-response effect existed among this population as well.
Zebrafish as a Model to Unveil the Pro-Osteogenic Effects of Boron-Vitamin D3 Synergism
Authors: Sojan Jerry Maria , Gundappa Manu Kumar , Carletti Alessio , Gaspar Vasco , Gavaia Paulo , Maradonna Francesca , Carnevali Oliana
Published: April 2022

The micronutrient boron (B) plays a key role during the ossification process as suggested by various in vitro and in vivo studies. To deepen our understanding of the molecular mechanism involved in the osteogenicity of B and its possible interaction with vitamin D3 (VD), wild-type AB zebrafish (Danio rerio) were used for morphometric analysis and transcriptomic analysis in addition to taking advantage of the availability of specific zebrafish osteoblast reporter lines. First, osteoactive concentrations of B, VD, and their combinations were established by morphometric analysis of the opercular bone in alizarin red-stained zebrafish larvae exposed to two selected concentrations of B (10 and 100 ng/ml), one concentration of VD (10 pg/ml), and their respective combinations. Bone formation, as measured by opercular bone growth, was significantly increased in the two combination treatments than VD alone. Subsequently, a transcriptomic approach was adopted to unveil the molecular key regulators involved in the synergy. Clustering of differentially expressed genes revealed enrichment toward bone and skeletal functions in the groups co-treated with B and VD. Downstream analysis confirmed mitogen-activated protein kinase as the most regulated pathway by the synergy groups in addition to transforming growth factor-β signaling, focal adhesion, and calcium signaling. The best-performing synergistic treatment, B at 10 ng/ml and VD at 10 pg/ml, was applied to two zebrafish transgenic lines, Tg(sp7:mCherry) and Tg(bglap:EGFP), at multiple time points to further explore the results of the transcriptomic analysis. The synergistic treatment with B and VD induced enrichment of intermediate (sp7+) osteoblast at 6 and 9 days post fertilization (dpf) and of mature (bglap+) osteoblasts at 15 dpf. The results obtained validate the role of B in VD-dependent control over bone mineralization and can help to widen the spectrum of therapeutic approaches to alleviate pathological conditions caused by VD deficiency by using low concentrations of B as a nutritional additive.
Pre-sleep Protein Supplementation Affects Energy Metabolism and Appetite in Sedentary Healthy Adults
Authors: Hao Yingying , Li Xingchen , Zhu Zheng , Cao Zhen-Bo
Published: April 2022

Purpose

To assess the acute effect of pre-sleep protein supplementation combined with resistance exercise on energy metabolism (including 24-h total energy expenditure (TEE), sleep energy expenditure (SEE), basal energy expenditure (BEE), glycolipid oxidation, and appetite of sedentary adults.

Methods

A total of thirty-one sedentary participants completed this randomized, double-blind, crossover study. Participants completed the following 24-h experimental conditions in random order in the Human Calorimeter chamber: (1) 40-g protein supplementation with dinner before a nighttime resistance exercise, and followed by pre-sleep placebo intake (PRO-PLA); (2) placebo intake with dinner before a nighttime resistance exercise, and followed by pre-sleep 40-g protein supplementation (PLA-PRO); and (3) placebo supplementation both with dinner and pre-sleep combined with a nighttime resistance exercise (PLA). Subjective appetite score before breakfast the next day was evaluated using the visual analog scale.

Results

The SEE values were significantly higher by a mean of 21.7 kcal and 33.3 kcal in PRO-PLA (318.3 ± 44.3 kcal) and PLA-PRO (329.9 ± 45.2 kcal), respectively, than in PLA (296.6 ± 46.6 kcal). In addition, the SEE values for PLA-PRO was also significantly higher by 11.6 kcal than that for PRO-PLA. Further, the fullness the next morning was significantly higher by 30.8% in PLA-PRO (43.9 ± 23.5 mm) than in PLA (33.5 ± 26.6 mm). These effects remained after adjustment for 24-h energy intake.

Conclusion

Pre-sleep protein supplementation combined with resistance exercise can significantly increase the SEE and fullness in the next morning, indicating a possible strategy to improve sleep energy metabolism in the sedentary population.
Low-Intensity Focused Ultrasound Targeted Microbubble Destruction Enhanced Paclitaxel Sensitivity by Decreasing Autophagy in Paclitaxel-Resistant Ovarian Cancer
Authors: Fan Gonglin , Qin Jiale , Fu Xiaofeng , Si Xing , Li Liqiang , Yang Keji , Wang Beibei , Lou Haiya , Zhu Jiang
Published: April 2022

Ultrasound targeted microbubble destruction (UTMD) was introduced as a promising method to improve anti-tumor therapeutic efficacy, while minimizing side effects to healthy tissues. Nevertheless, the acoustical phenomenon behind the UTMD as well as the exact mechanisms of autophagy action involved in the increased anti-cancer response are still not fully understood. Therefore, we examined the drug resistance-reversing effects of low-intensity focused ultrasound with microbubble (LIFU+MB) in paclitaxel (PTX)-resistant ovarian cancer cells. Cell viability was evaluated using CCK8 (Cell Counting Kit-8), apoptosis was detected by flow cytometry, quantitative real-time PCR and Western blot were used to detect the expressions of mRNA and protein, and autophagy was observed by transmission electron microscopy (TEM). We revealed that the level of autophagy was increased (p < 0.05) in PTX-resistant ovarian cancer cells. Treatment of LIFU+MB combined with PTX can notably inhibit proliferation as well as increase apoptosis (p < 0.01) in drug-resistant cells. We proposed that LIFU+MB might affect the sensitivity of ovarian cancer cells to PTX by modulating autophagy. To verify the hypothesis, we analyzed the autophagy level of drug-resistant cells after the treatment of LIFU+MB and found that autophagy was significantly inhibited. Altogether, our findings demonstrated that LIFU+MB could reverse PTX resistance in ovarian cancer via inhibiting autophagy, which provides a novel strategy to improve chemosensitivity in ovarian cancer.
Preoperative Pectoralis Muscle Index Predicts Distant Metastasis-Free Survival in Breast Cancer Patients
Authors: Huang Wen-juan , Zhang Meng-lin , Wang Wen , Jia Qing-chun , Yuan Jia-rui , Zhang Xin , Fu Shuang , Liu Yu-xi , Miao Shi-di , Wang Rui-tao
Published: April 2022

Background

Breast cancer is one of the most commonly diagnosed cancers, and the fourth leading cause of cancer deaths in females worldwide. Sarcopenia is related to adverse clinical outcomes in patients with malignancies. Muscle index is a key parameter in evaluating sarcopenia. However, there is no data investigating the association between muscle index and distant metastasis in breast cancer. The aim of this study was to explore whether muscle index can effectively predict distant metastasis and death outcomes in breast cancer patients.

Study Design

The clinical data of 493 breast cancer patients at the Harbin Medical University Cancer Hospital between January 2014 and December 2015 were retrospectively analyzed. Quantitative measurements of pectoralis muscle area and skeletal muscle area were performed at the level of the fourth thoracic vertebra (T4) and the eleventh thoracic vertebra (T11) of the chest computed tomography image, respectively. The pectoralis muscle index (PMI) and skeletal muscle index (SMI) were assessed by the normalized muscle area (area/the square of height). Survival analysis was performed using the log-rank test and Cox proportional hazards regression analysis.

Result

The patients with metastases had lower PMI at T4 level (PMI/T4) and SMI at T11 level (SMI/T11) compared with the patients without metastases. Moreover, there were significant correlations between PMI/T4 and lymphovascular invasion, Ki67 expression, multifocal disease, and molecular subtype. In addition, multivariate analysis revealed that PMI/T4, not SMI/T11, was an independent prognostic factor for distant metastasis-free survival (DMFS) and overall survival (OS) in breast cancer patients.

Conclusions

Low PMI/T4 is associated with worse DMFS and OS in breast cancer patients. Future prospective studies are needed.
CDC25C as a Predictive Biomarker for Immune Checkpoint Inhibitors in Patients With Lung Adenocarcinoma
Authors: Zhang Wengang , Shang Xiaoling , Yang Fei , Han Wenfei , Xia Handai , Liu Ni , Liu Yanguo , Wang Xiuwen
Published: April 2022

The application of immune checkpoint inhibitors (ICIs) in non-small cell lung cancer has significantly improved patient survival. However, most patients fail to respond to ICIs or develop drug resistance during treatment. Therefore, novel biomarkers are needed to predict the efficacy of ICIs or provide clues on how to overcome drug resistance. Here, it was revealed that cell division cycle 25C (CDC25C) expression was upregulated in lung adenocarcinoma (LUAD) compared to that of normal lung tissue in multiple databases. This was further verified by q-PCR. Furthermore, higher CDC25C expression was associated with shorter overall survival and worse pathological stage. Most importantly, a higher CDC25C expression was associated with shorter progression-free survival in LUAD patients treated with nivolumab, suggesting the role of the cell cycle in immunotherapy. In addition, CDC25C expression was significantly associated with immune cell infiltration and immune-related signatures in the LUAD tumor microenvironment. Moreover, CDC25C was differentially expressed and correlated with overall survival in multiple tumors, indicating that CDC25C is a broad-spectrum biomarker. Taken together, our study demonstrates that CDC25C is a prognostic biomarker for LUAD patients, especially for patients treated with ICIs. Our study also provides strong evidence for the role of the cell cycle in ICIs therapy and tumor microenvironment.
Hypochlorous Acid: From Innate Immune Factor and Environmental Toxicant to Chemopreventive Agent Targeting Solar UV-Induced Skin Cancer
Authors: Snell Jeremy A. , Jandova Jana , Wondrak Georg T.
Published: April 2022

A multitude of extrinsic environmental factors (referred to in their entirety as the ‘skin exposome’) impact structure and function of skin and its corresponding cellular components. The complex (i.e. additive, antagonistic, or synergistic) interactions between multiple extrinsic (exposome) and intrinsic (biological) factors are important determinants of skin health outcomes. Here, we review the role of hypochlorous acid (HOCl) as an emerging component of the skin exposome serving molecular functions as an innate immune factor, environmental toxicant, and topical chemopreventive agent targeting solar UV-induced skin cancer. HOCl [and its corresponding anion (OCl-; hypochlorite)], a weak halogen-based acid and powerful oxidant, serves two seemingly unrelated molecular roles: (i) as an innate immune factor [acting as a myeloperoxidase (MPO)-derived microbicidal factor] and (ii) as a chemical disinfectant used in freshwater processing on a global scale, both in the context of drinking water safety and recreational freshwater use. Physicochemical properties (including redox potential and photon absorptivity) determine chemical reactivity of HOCl towards select biochemical targets [i.e. proteins (e.g. IKK, GRP78, HSA, Keap1/NRF2), lipids, and nucleic acids], essential to its role in innate immunity, antimicrobial disinfection, and therapeutic anti-inflammatory use. Recent studies have explored the interaction between solar UV and HOCl-related environmental co-exposures identifying a heretofore unrecognized photo-chemopreventive activity of topical HOCl and chlorination stress that blocks tumorigenic inflammatory progression in UV-induced high-risk SKH-1 mouse skin, a finding with potential implications for the prevention of human nonmelanoma skin photocarcinogenesis.
Targeting Mitochondrial Oxidative Phosphorylation Eradicates Acute Myeloid Leukemic Stem Cells
Authors: Peng Meixi , Huang Yongxiu , Zhang Ling , Zhao Xueya , Hou Yu
Published: April 2022

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by multiple cytogenetic and molecular abnormalities, with a very poor prognosis. Current treatments for AML often fail to eliminate leukemic stem cells (LSCs), which perpetuate the disease. LSCs exhibit a unique metabolic profile, especially dependent on oxidative phosphorylation (OXPHOS) for energy production. Whereas, normal hematopoietic stem cells (HSCs) and leukemic blasts rely on glycolysis for adenosine triphosphate (ATP) production. Thus, understanding the regulation of OXPHOS in LSCs may offer effective targets for developing clinical therapies in AML. This review summarizes these studies with a focus on the regulation of the electron transport chain (ETC) and tricarboxylic acid (TCA) cycle in OXPHOS and discusses potential therapies for eliminating LSCs.
Family Size and the Age at Infancy-Childhood Transition Determine a Child’s Compromised Growth in Large Families
Authors: German Alina , Rubin Lisa , Raisin Galiya , Hochberg Ze’ev
Published: April 2022

Background

Data on growth of Israeli school children show that children from Jewish ultra-orthodox Haredi and Bedouin Arab families have a higher prevalence of stature below the 3rd percentile. While these populations are usually from lower socioeconomic strata, they also have larger families. This study aimed to evaluate if family structure and the timing of a child’s infancy–childhood transition (ICT) are central to variations in stature.

Study Design

We analyzed the association between family size, birth order and inter-birth interval with child growth and the age at ICT in 3 groups of children, 148 high birth order children from large families (LF ≥ 6), 118 low birth order children from large families (LF ≤ 3) and 150 children from small families (SF).

Results

High birth order children from large families were shorter in childhood than children from small families with a difference of 0.5 SDS in length. We found that birth length and birth order explained 35% of the total variance in infancy length whereas ICT age and infancy length explained 72% of the total variance in childhood length.

Conclusion

Infancy and childhood length are compromised in children from large families. As the family grows larger the younger children tend to be shorter. Reduced length gain in the period between infancy to childhood is when growth is most affected.
Comparative Study of the Perspectives on the Impact of a Culturally Responsive Picture Exchange Communication System for Children With Autism Spectrum Disorder in the United Arab Emirates
Authors: Safi Mohammed , Opoku Maxwell Peprah , Alshamsi Mariam , Abu-shariha Ahmad Hassan
Published: April 2022

Background

The Picture Exchange Communication System (PECS) is a widely accepted way to develop the communication skills of children with developmental disabilities such as autism spectrum disorder (ASD). However, the efficacy of PECS has been largely studied in Western societies and little research is available regarding its role in the development of children with ASD in a non-Western cultural context. The purpose of this study was to compare the parent and the practitioner perceptions of the use of PECS for children with ASD in the United Arab Emirates.

Method

A new scale made up of three subscales was used to collect the data from the parents and the practitioners who were either related to or working with a cohort of children with ASD. The data were analyzed using Statistical Package for the Social Sciences (SPSS) and subjected to the computation of means, t-tests, analysis of variance (ANOVA), binary logistical regression, and two-way factorial ANOVA.

Results

The results showed uncertainty or neutrality among the parents and the practitioners toward the use of PECS. Variables such as age, years of experience using PECS, and gender were noted to influence perceptions of PECS.

Conclusion

The need for policymakers to consider developing regular training for parents and practitioners on the use of PECS and other implications are discussed.
A Phenotypic-Driven Approach for the Diagnosis of WOREE Syndrome
Authors: Riva Antonella , Nobile Giulia , Giacomini Thea , Ognibene Marzia , Scala Marcello , Balagura Ganna , Madia Francesca , Accogli Andrea , Romano Ferruccio , Tortora Domenico , Severino Mariasavina , Scudieri Paolo , Baldassari Simona , Musante Ilaria , Uva Paolo , Salpietro Vincenzo , Torella Annalaura , Nigro Vincenzo , Capra Valeria , Nobili Lino , Striano Pasquale , Mancardi Maria Margherita , Zara Federico , Iacomino Michele
Published: April 2022

Background

WOREE syndrome is a rare neurodevelopmental disorder featuring drug-resistant epilepsy and global developmental delay. The disease, caused by biallelic pathogenic variants in the WWOX gene, usually leads to severe disability or death within the first years of life. Clinicians have become more confident with the phenotypic picture of WOREE syndrome, allowing earlier clinical diagnosis. We report a boy with a peculiar clinic-radiological pattern supporting the diagnosis of WOREE syndrome.

Methods

DNA was extracted from blood samples of the proband and his parents and subjected to Exome Sequencing (ES). Agarose gel electrophoresis, real-time quantitative PCR (Q-PCR), and array-CGH 180K were also performed.

Results

ES detected a pathogenic stop variant (c.790C > T, p.Arg264*) in one allele of WWOX in the proband and his unaffected mother. A 180K array-CGH analysis revealed a 84,828-bp (g.chr16:78,360,803–78,445,630) deletion encompassing exon 6. The Q-PCR product showed that the proband and his father harbored the same deleted fragment, fusing exons 5 and 7 of WWOX.

Conclusions

Genetic testing remains crucial in establishing the definitive diagnosis of WOREE syndrome and allows prenatal interventions/parental counseling. However, our findings suggest that targeted Next Generation Sequencing-based testing may occasionally show technical pitfalls, prompting further genetic investigation in selected cases with high clinical suspicion.
Oxidative Stress and Hyper-Inflammation as Major Drivers of Severe COVID-19 and Long COVID: Implications for the Benefit of High-Dose Intravenous Vitamin C
Authors: Vollbracht Claudia , Kraft Karin
Published: April 2022

Oxidative stress is a pivotal point in the pathophysiology of COVID-19 and presumably also in Long-COVID. Inflammation and oxidative stress are mutually reinforcing each other, thus contributing to the systemic hyperinflammatory state and coagulopathy which are cardinal pathological mechanisms of severe stages. COVID-19 patients, like other critically ill patients e.g. with pneumonia, very often show severe deficiency of the antioxidant vitamin C. So far, it has not been investigated how long this deficiency lasts or whether patients with long COVID symptoms also suffer from deficiencies. A vitamin C deficit has serious pathological consequences because vitamin C is one of the most effective antioxidants, but also co-factor of many enzymatic processes that affect the immune and nervous system, blood circulation and energy metabolism. Because of its anti-oxidative, anti-inflammatory, endothelial-restoring, and immunomodulatory effects the supportive intravenous (iv) use of supraphysiological doses has been investigated so far in 12 controlled or observational studies with altogether 1578 inpatients with COVID-19. In these studies an improved oxygenation, a decrease in inflammatory markers and a faster recovery were observed. In addition, early treatment with iv high dose vitamin C seems to reduce the risks of severe courses of the disease such as pneumonia and also mortality. Persistent inflammation, thrombosis and a dysregulated immune response (auto-immune phenomena and/or persistent viral load) seem to be major contributors to Long-COVID. Oxidative stress and inflammation are involved in the development and progression of fatigue and neuro-psychiatric symptoms in various diseases by disrupting tissue (e.g. autoantibodies), blood flow (e.g. immune thrombosis) and neurotransmitter metabolism (e.g. excitotoxicity). In oncological diseases, other viral infections and autoimmune diseases, which are often associated with fatigue, cognitive disorders, pain and depression similar to Long-COVID, iv high dose vitamin C was shown to significantly relieve these symptoms. Supportive iv vitamin C in acute COVID-19 might therefore reduce the risk of severe courses and also the development of Long-COVID.
DAPT Attenuates Cadmium-Induced Toxicity in Mice by Inhibiting Inflammation and the Notch/HES-1 Signaling Axis
Authors: Yang Jia-Ying , Shen Dan-Yang , Wang Jun , Dai Jing-Feng , Qin Xiao-Yan , Hu Yang , Lan Rongfeng
Published: April 2022

The small molecule DAPT inhibits the Notch signaling pathway by blocking γ-secretase mediated Notch cleavage. Given the critical role of the Notch signaling axis in inflammation, we asked whether DAPT could block Notch-mediated inflammation and thus exert neuronal protection. We established a mouse model of chronic exposure to cadmium (Cd)-induced toxicity and treated it with DAPT. DAPT was effective in ameliorating Cd-induced multi-organ damage and cognitive impairment in mice, as DAPT restored abnormal performance in the Y-maze, forced swimming and Morris water maze (MWM) tests. DAPT also reversed Cd-induced neuronal loss and glial cell activation to normal as observed by immunofluorescence and immunohistochemistry of brain tissue sections. In addition, Cd-intoxicated mice showed significantly increased levels of the Notch/HES-1 signaling axis and NF-κB, as well as decreased levels of the inflammatory inhibitors C/EBPβ and COP1. However, DAPT down regulated the elevated Notch/HES-1 signaling axis to normal, eliminating inflammation and thus protecting the nervous system. Thus, DAPT effectively eliminated the neurotoxicity of Cd, and blocking γ-secretase as well as Notch signaling axis may be a potential target for the development of neuronal protective drugs.
Enhanced Terahertz Generation From the Lithium Niobate Metasurface
Authors: Tu Yanyun , Sun Xu , Wu Haizhong , Zan Xiaolei , Yang Yan , Liu Ning , Wang Xiaowei , Meng Congsen , Lyu Zhihui , Zhu Zhihong , Liu Ken , Zhang Dongwen , Zhao Zengxiu
Published: April 2022

The lithium niobate (LiNbO3) metasurface is an attractive platform for nonlinear frequency conversion due to its excellent nonlinearity, high damage threshold, and strong enhancement of the driving field. Here, we demonstrated the nonlinear metasurface for terahertz (THz) generation from LiNbO3on an insulator. The THz electric field from the LiNbO3metasurface of 300 nm thickness is enhanced by more than one order of magnitude compared to the unstructured sample. The enhanced terahertz electric field is very selective in the excitation wavelength due to its resonant feature and is highly anisotropic with respect to the excitation polarization. The polarization direction of the THz electric field can be controlled by rotating the optical axis of the LiNbO3metasurface. By combining the nanofabrication technology of the LiNbO3metasurface and ultrafast nonlinear optics, our work paves the way for the design of new compact terahertz photonic devices that integrate THz emitters into LiNbO3-based chips with multifaceted capabilities.
Portal Vein Pulsatility Index as a Potential Risk of Venous Congestion Assessed by Magnetic Resonance Imaging: A Prospective Study on Healthy Volunteers
Authors: Abou-Arab Osama , Beyls Christophe , Moussa Mouhamed Djahoum , Huette Pierre , Beaudelot Elodie , Guilbart Mathieu , De Broca Bruno , Yzet Thierry , Dupont Hervé , Bouzerar Roger , Mahjoub Yazine
Published: April 2022

High values of the portal vein pulsatility index (PI) have been associated with adverse outcomes in perioperative or critically ill patients. However, data on dynamic changes of PI related to fluid infusion are scarce. We aimed to determine if dynamic changes in PI are associated with the fluid challenge (FC). To address this challenge, we conducted a prospective single-center study. The population study included healthy subjects. FC consisted in the administration of 500 ml of Ringer lactate infusion over 5 min. The portal blood flow and PI were assessed by magnetic resonance imaging. The responsiveness to FC was defined as an increase in the cardiac stroke volume of at least 10% as assessed by echocardiography. We included 24 healthy volunteers. A total of fourteen (58%) subjects were responders, and 10 (42%) were non-responders. In the responder group, FC induced a significant increase in portal blood flow from 881 (762–1,001) at the baseline to 1,010 (778–1,106) ml min−1 (p = 0.005), whilst PI remained stable (from 31 [25–41] to 35 (25–42) %; p = 0.12). In the non-responder group, portal blood flow remained stable after FC (from 1,042 to 1,034 ml min−1; p = 0.084), whereas PI significantly increased from 32 (22–40) to 48% *(25–85) after FC (p = 0.027). PI was negatively correlated to portal blood flow (Rho coefficient = −0.611; p = 0.002). To conclude, PI might be a sensitive marker of early congestion in healthy subjects that did not respond to FC. This finding requires further validation in clinical settings with a larger sample size.
Enhanced Degradation of Juvenile Hormone Promotes Reproductive Diapause in the Predatory Ladybeetle Coccinella Septempunctata
Authors: Li Yu-Yan , Chen Jun-Jie , Liu Meng-Yao , He Wei-Wei , Reynolds Julie A , Wang Ya-Nan , Wang Meng-Qing , Zhang Li-Sheng
Published: April 2022

Improved knowledge on the regulation of reproductive diapause in Coccinella septempunctata, an important predator of aphids, is crucial for improving shelf-life and mass production of the ladybeetles. In many insects, the absence of juvenile hormone (JH) is a central regulator of reproductive diapause. JH is principally degraded by JH esterase (JHE) and JH epoxide hydrolase (JHEH). Previous studies have shown that genes encoding these enzymes were upregulated in early diapause of C. septempunctata, but whether increased JH degradation contributes to the reduction of JH levels and facilitates reproductive diapause remains unknown. Here, we investigate the role of JH and JH degradation genes during reproductive diapause in C. septempunctata females. Applying methoprene, a JH analogue, to the diapause preparation females clearly elevated JH signaling and reversed diapause program, suggesting that a lower level of JH is critical for the induction of reproductive diapause in the ladybeetle. Full-length cDNA sequences of JHE and JHEH were cloned and characterized, and their deduced proteins contain all the conserved active domains and typical motifs as identified in other insects. The expressions of JHE and JHEH were both significantly increased in diapause preparation and remained at a high level for a period throughout diapause, and then decreased after the termination of diapause. Knocking down these JH degradation genes clearly increased the expression levels of JH-inducible genes Krüppel-homolog 1 (Kr-h1) and vitellogenin (Vg), indicating an elevated JH level. Simultaneously, silencing JH degradation genes distinctly reduced diapause-related features and promotes reproduction, indicated by accelerated ovary growth, yolk deposition, and suppressed lipid accumulation. These results indicate that the enhanced JH degradation plays a critical role in regulating reproductive diapause of C. septempunctata.