bluuebunny/crossref_metadata_2025 huggingface dataset:
Culprits of PDAC resistance to gemcitabine and immune checkpoint inhibitor: Tumour microenvironment components
Authors: Hsu Sheng-Kai , Jadhao Mahendra , Liao Wei-Ting , Chang Wen-Tsan , Hung Chun-Tzu , Chiu Chien-Chih
Published: October 2022

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and lethal cancer with a dismal five-year survival rate of 11%. Despite remarkable advancements in cancer therapeutics, PDAC patients rarely benefit from it due to insurmountable treatment resistance. Notably, PDAC is pathologically characterized by an extensive desmoplastic reaction and an extremely immunosuppressive tumour microenvironment (TME). The PDAC TME consists of cell components (e.g., tumour, immune and stromal cells) and noncellular components (e.g., extracellular matrix), exhibiting high complexity and their interplay resulting in resistance to chemotherapeutics and immune checkpoint inhibitors. In our review, we shed light on how crosstalk of complex environmental components modulates PDAC drug resistance, and we summarize related clinical trials. Moreover, we extend our discussion on TME exploration and exosome analysis, providing new insights into clinical applications, including personalized medicine, disease monitoring and drug carriers.
Global, regional, and national burden of Alzheimer's disease and other dementias, 1990–2019
Authors: Li Xue , Feng Xiaojin , Sun Xiaodong , Hou Ningning , Han Fang , Liu Yongping
Published: October 2022

Background

With the increase in the aging population worldwide, Alzheimer's disease has become a rapidly increasing public health concern. Monitoring the dementia disease burden will support health development strategies by providing scientific data.

Methods

Based on the data obtained from the 2019 Global Burden of Disease (GBD) database, the numbers and age-standardized rates (ASRs) of incidence, prevalence, death, and disability-adjusted life-years (DALYs) of Alzheimer's disease and other dementias from 1990 to 2019 were analyzed. Calculated estimated annual percentage changes (EAPCs) and Joinpoint regression analyses were performed to evaluate the trends during this period. We also evaluated the correlations between the epidemiology and the sociodemographic index (SDI), an indicator to evaluate the level of social development in a country or region considering the education rate, economic situation, and total fertility rate.

Results

From 1990 to 2019, the incidence and prevalence of Alzheimer's disease and other dementias increased by 147.95 and 160.84%, respectively. The ASR of incidence, prevalence, death, and DALYs in both men and women consistently increased over the study period. All the ASRs in women were consistently higher than those in men, but the increases were more pronounced in men. In addition, the ASRs of incidence, prevalence, and DALYs were positively correlated with the SDI. Moreover, the proportion of patients over 70 years old with dementia was also positively correlated with the SDI level. Smoking was a major risk factor for the disease burden of dementia in men, while obesity was the major risk factor for women.

Conclusion

From 1990 to 2019, the Alzheimer's disease burden increased worldwide. This trend was more serious in high-SDI areas, especially among elderly populations in high-SDI areas, who should receive additional attention. Policy-makers should take steps to reverse this situation. Notably, women were at a higher risk for the disease, but the risk in men showed a faster increase. We should give attention to the aging population, attach importance to interventions targeting dementia risk factors, and formulate action plans to address the increasing incidence of dementia.
Functional topologies of spatial cognition predict cognitive and motor progression in Parkinson’s
Authors: Harrington Deborah L. , Shen Qian , Wei Xiangyu , Litvan Irene , Huang Mingxiong , Lee Roland R.
Published: October 2022

Background

Spatial cognition deteriorates in Parkinson’s disease (PD), but the neural substrates are not understood, despite the risk for future dementia. It is also unclear whether deteriorating spatial cognition relates to changes in other cognitive domains or contributes to motor dysfunction.

Objective

This study aimed to identify functional connectivity abnormalities in cognitively normal PD (PDCN) in regions that support spatial cognition to determine their relationship to interfacing cognitive functions and motor disability, and to determine if they predict cognitive and motor progression 2 years later in a PDCN subsample.

Methods

Sixty-three PDCN and 43 controls underwent functional MRI while judging whether pictures, rotated at various angles, depicted the left or right hand. The task activates systems that respond to increases in rotation angle, a proxy for visuospatial difficulty. Angle-modulated functional connectivity was analyzed for frontal cortex, posterior cortex, and basal ganglia regions.

Results

Two aberrant connectivity patterns were found in PDCN, which were condensed into principal components that characterized the strength and topology of angle-modulated connectivity. One topology related to a marked failure to amplify frontal, posterior, and basal ganglia connectivity with other brain areas as visuospatial demands increased, unlike the control group (control features). Another topology related to functional reorganization whereby regional connectivity was strengthened with brain areas not recruited by the control group (PDCN features). Functional topologies correlated with diverse cognitive domains at baseline, underscoring their influences on spatial cognition. In PDCN, expression of topologies that were control features predicted greater cognitive progression longitudinally, suggesting inefficient communications within circuitry normally recruited to handle spatial demands. Conversely, stronger expression of topologies that were PDCN features predicted less longitudinal cognitive decline, suggesting functional reorganization was compensatory. Parieto-occipital topologies (control features) had different prognostic implications for longitudinal changes in motor disability. Expression of one topology predicted less motor decline, whereas expression of another predicted increased postural instability and gait disturbance (PIGD) feature severity. Concurrently, greater longitudinal decline in spatial cognition predicted greater motor and PIGD feature progression, suggesting deterioration in shared substrates.

Conclusion

These novel discoveries elucidate functional mechanisms of visuospatial cognition in PDCN, which foreshadow future cognitive and motor disability.
Cortical control of chandelier cells in neural codes
Authors: Jung Kanghoon , Choi Youngjin , Kwon Hyung-Bae
Published: October 2022

Various cortical functions arise from the dynamic interplay of excitation and inhibition. GABAergic interneurons that mediate synaptic inhibition display significant diversity in cell morphology, electrophysiology, plasticity rule, and connectivity. These heterogeneous features are thought to underlie their functional diversity. Emerging attention on specific properties of the various interneuron types has emphasized the crucial role of cell-type specific inhibition in cortical neural processing. However, knowledge is still limited on how each interneuron type forms distinct neural circuits and regulates network activity in health and disease. To dissect interneuron heterogeneity at single cell-type precision, we focus on the chandelier cell (ChC), one of the most distinctive GABAergic interneuron types that exclusively innervate the axon initial segments (AIS) of excitatory pyramidal neurons. Here we review the current understanding of the structural and functional properties of ChCs and their implications in behavioral functions, network activity, and psychiatric disorders. These findings provide insights into the distinctive roles of various single-type interneurons in cortical neural coding and the pathophysiology of cortical dysfunction.
Modulating swallowing-related functional connectivity and behavior via modified pharyngeal electrical stimulation: A functional near-infrared spectroscopy evidence
Authors: Zhang Xue , Xie Hui , Wang Xiaolu , Li Zengyong , Song Rong , Shan Yilong , Li Chao , Chen Jiemei , Hong Jiena , Li Xin , Wan Guifang , Zhang Yaowen , An Delian , Dou Zulin , Wen Hongmei
Published: October 2022

Introduction

Modified pharyngeal electrical stimulation (mPES) is a novel therapeutic modality for patients with neurogenic dysphagia. However, the underlying neural mechanism remains poorly understood. This study aimed to use functional near-infrared spectroscopy (fNIRS) to explore the influence of mPES on swallowing-related frequency-specific neural networks and ethology.

Methods

Twenty-two healthy right-handed volunteers participated in the study. Each participant was randomly assigned to either the sham or the mPES group and provided a 10-min intervention program every day for 5 days. Oxyhemoglobin and deoxyhemoglobin concentration changes verified by fNIRS were recorded on days 1, 3, and 5. Five characteristic frequency signals (0.0095–2 Hz) were identified using the wavelet transform method. To calculate frequency-specific functional connectivity, wavelet phase coherence (WPCO) was adopted. Furthermore, behavioral performance was assessed pre- and post-mPES using a 150 ml-water swallowing stress test.

Results

Compared with sham stimulation on day 1, the significantly decreased WPCO values were mainly associated with the dorsolateral prefrontal lobe, Broca's area, and middle temporal lobe. Compared with the sham mPES on day 1, the mPES showed a noticeable effect on the total swallow duration. Compared with the baseline, the WPCO values on days 3 and 5 showed a stepwise decrease in connectivity with the application of mPES. Furthermore, the decreased WPCO was associated with a shortened time per swallow after mPES.

Conclusions

The mPES could modulate swallowing-related frequency-specific neural networks and evoke swallowing cortical processing more efficiently. This was associated with improved performance in a water swallowing stress test in healthy participants.
Relationship between dietary selenium intake and serum thyroid function measures in U.S. adults: Data from NHANES 2007–2012
Authors: Liu Fang , Wang Kai , Nie Jiaqi , Feng Qianqian , Li Xiaosong , Yang Yichi , Deng Ming-Gang , Zhou Huanhuan , Wang Suqing
Published: October 2022

Although numerous studies have explored the relationship between selenium intake and thyroid diseases, few epidemiological studies have investigated the association between selenium intake and thyroid hormones. Therefore, we conducted this analysis to investigate the association between dietary selenium intake and thyroid hormones. Our sample included 5,575 adults (age ≥ 20) years from the National Health and Nutrition Examination Survey (NHANES) 2007–2012. Thyroid hormones, including total triiodothyronine (T3), total thyroxine (T4), free T3 (FT3), free T4 (FT4), and thyroid-stimulating hormone (TSH), were detected. Multivariable linear regression models showed that log10-transformed selenium intake (LogSe) was negatively correlated with TT4 (β = −0.383, 95% CI: −0.695, −0.070) and TT4/TT3 (β = −0.003, 95% CI: −0.006, −0.0004) in U.S. adults. Besides, additional stratified analyses by sex demonstrated that LogSe was negatively associated with TT4 (β = −0.007, 95% CI: −0.013, −0.001) and TT4/TT3 (β = −0.664, 95% CI: −1.182, −0.146) and positively associated with FT4/TT4 (β = 0.031, 95% CI: 0.004, 0.059) in male adults. Meanwhile, subgroup analysis by iodine status showed that LogSe was negatively associated with TT4 (β = −0.006, 95% CI: −0.011, −0.002), FT4/FT3 (β = −0.011, 95% CI: −0.023, −0.00002) and TT4/TT3 (β = −0.456, 95% CI: −0.886, −0.026) in iodine sufficiency but not in iodine deficiency adults. Our results demonstrated that the increased dietary selenium intake was negatively correlated with TT4 and TT4/TT3 in U.S. adults. Furthermore, the association between dietary selenium intake and thyroid hormones was more pronounced in males and iodine sufficiency adults.
Association between ultra-processed food consumption and gut microbiota in senior subjects with overweight/obesity and metabolic syndrome
Authors: Atzeni Alessandro , Martínez María Ágeles , Babio Nancy , Konstanti Prokopis , Tinahones Francisco J. , Vioque Jesús , Corella Dolores , Fitó Montserrat , Vidal Josep , Moreno-Indias Isabel , Pertusa-Martinez Salvador , Álvarez-Sala Andrea , Castañer Olga , Goday Albert , Damas-Fuentes Miguel , Belzer Clara , Martínez-Gonzalez Miguel Á. , Hu Frank B. , Salas-Salvadó Jordi
Published: October 2022

The production and consumption of ultra-processed foods (UPF) has increased considerably during the last years worldwide. Collective evidence shows the association between UPF consumption and adverse health outcomes, including inflammatory gastro-intestinal disorders and obesity. The gut microbiota has been suggested as potential mediator of the effects of UPF consumption on metabolism and health. However, few studies have been conducted in order to elucidate these aspects. Therefore, the aim of the present study was to assess the cross-sectional associations between UPF consumption and gut microbiota in a population of senior subjects (n = 645) within the frame of the PREDIMED-Plus trial. Eligible participants were men and women (aged 55–75 years), without documented history of cardiovascular disease at enrollment, with overweight/obesity (body mass index ≤ 27 and <40 kg/m2) and metabolic syndrome. Using the information of food frequency questionnaires, the consumption of UPF, expressed as a percentage of total dietary energy intake in kcal/day, was calculated considering those food items classified in group 4 of NOVA system. Population was categorized according to tertiles of UPF consumption. Taxonomic fecal microbiota information, along with blood biochemical parameters, anthropometric measurements and clinical data were obtained. Bioinformatics analysis was performed to study the association between fecal microbiota composition and UPF consumption. We observed that subjects allocated in the highest tertile of UPF consumption (21.4 ± 5.0 % kcal/day) presented lower adherence to MedDiet (p < 0.001) and higher total energy intake (p < 0.001). The taxonomic analysis of the fecal microbiota revealed a significant (Benjamini-Hochberg adjusted p < 0.2) positive association between specific taxa and tertiles (T) of UPF consumption: Alloprevotella (p = 0.041 vs. T2; p = 0.065 vs. T3), Negativibacillus (p = 0.096 vs. T3), Prevotella (p = 0.116 vs. T3), and Sutterella (p = 0.116 vs. T2). UPF consumption was positively associated with lower adherence to MedDiet and higher total energy intake in senior subjects with overweight obesity and metabolic syndrome. In addition, positive association with specific fecal microbiota taxa related to inflammatory gastro-intestinal diseases and low consumption of fruits and vegetables, was observed.
Targeting aldehyde dehydrogenase for prostate cancer therapies
Authors: Ma Miao , He Wenyou , Zhao Keyu , Xue Linyuan , Xia Siyuan , Zhang Baotong
Published: October 2022

Prostate cancer (PCa) is the most common cancer in men in the United States. About 10 – 20% of PCa progress to castration-resistant PCa (CRPC), which is accompanied by metastasis and therapeutic resistance. Aldehyde dehydrogenase (ALDH) is famous as a marker of cancer stem-like cells in different cancer types, including PCa. Generally, ALDHs catalyze aldehyde oxidation into less toxic carboxylic acids and give cancers a survival advantage by reducing oxidative stress caused by aldehyde accumulation. In PCa, the expression of ALDHs is associated with a higher tumor stage and more lymph node metastasis. Functionally, increased ALDH activity makes PCa cells gain more capabilities in self-renewal and metastasis and reduces the sensitivity to castration and radiotherapy. Therefore, it is promising to target ALDH or ALDHhighcells to eradicate PCa. However, challenges remain in moving the ALDH inhibitors to PCa therapy, potentially due to the toxicity of pan-ALDH inhibitors, the redundancy of ALDH isoforms, and the lack of explicit understanding of the metabolic signaling transduction details. For targeting PCa stem-like cells (PCSCs), different regulators have been revealed in ALDHhighcells to control cell proliferation and tumorigenicity. ALDH rewires essential signaling transduction in PCa cells. It has been shown that ALDHs produce retinoic acid (RA), bind with androgen, and modulate diverse signaling. This review summarizes and discusses the pathways directly modulated by ALDHs, the crucial regulators that control the activities of ALDHhighPCSCs, and the recent progress of ALDH targeted therapies in PCa. These efforts will provide insight into improving ALDH-targeted treatment.
Presenting features of neuroblastoma with spinal canal invasion. A prospective study of the International Society of Pediatric Oncology Europe - Neuroblastoma (SIOPEN)
Authors: Sorrentino Stefania , Ash Shifra , Haupt Riccardo , Plantaz Dominique , Schiff Isabelle , Hero Barbara , Simon Thorsten , Kachanov Denis , Shamanskaya Tatyana , Kraal Katheljine , Littooij Annemieke , Wieczoreck Alexsandra , Balwierz Walentyna , Laureys Geneviève , Trager Catherine , Sertorio Fiammetta , Erminio Giovanni , Fragola Martina , Beck Popovic Maja , De Bernardi Bruno , Trahair Toby
Published: October 2022

Introduction

Between 5 and 15% of children with neuroblastoma (NB) present with or develop spinal canal invasion (SCI). The majority of these children have symptoms of epidural compression of spinal cord and/or spinal nerves. Treatment of NB-SCI is considered an emergency but its modalities are not yet well-established. Independently of treatment, NB-SCI may result in significant long-term disabilities. We report on the first prospective study of NB-SCI focused on presenting characteristics of both symptomatic and asymptomatic patients and correlation between SCI-related symptoms and imaging features.

Materials and methods

This SIOPEN prospective NB-SCI study opened in June 2014. Patient data including SCI symptoms evaluated by standardized measures and spinal cord imaging studies were collected for each patient. For the purpose of this study data entry was locked on July 2021.

Results

Of the 208 NB-SCI patients registered, 196 were evaluable for this analysis of whom 67% were symptomatic and 33% asymptomatic. Median age was 11 months. The thorax was the commonest primary tumor site. The median intervals between initial symptoms and diagnosis and between first medical visit and diagnosis were 14 and 3 days, respectively. The was no statistical difference in frequency of presenting characteristics between symptomatic and asymptomatic patients. Presenting features of NB-SCI patients differed from other NBs for older median age, prevalence of thoracic vs. abdominal primary site, prevalence of localized vs. metastatic disease and lower incidence of MYCN gene amplification. The most common SCI features were motor deficit in the younger and pain in the older patients that correlated on imaging with both transverse and longitudinal extent but not with the level of intraspinal tumor. Spinal cord T2-hyperintensity was more frequently detected in symptomatic patients (not significant).

Conclusion

This prospective study confirms that children with NB-SCI differ from NBs without SCI. Compared to previous studies, it provides more detailed information regarding presenting symptoms, time intervals between SCI symptoms, medical visit and diagnosis, and correlations between symptoms and imaging features.
Clinical outcomes following pre-, pro- and synbiotic supplementation after caesarean birth or antibiotic exposure in the first week of life in term born infants: A systematic review of the literature
Authors: Kamphorst Kim , Carpay Nora C. , de Meij Tim G. J. , Daams Joost G. , van Elburg Ruurd M. , Vlieger Arine M.
Published: October 2022

Background

Caesarean section and early exposure to antibiotics disrupt the developing gastrointestinal microbiome, which is associated with long-term health effects.

Objective

The aim of this systematic review was to summarise the impact of prebiotics, probiotics, or synbiotics supplementation on clinical health outcomes of term infants born by caesarean section or exposed to antibiotics in the first week of life.

Design

A systematic search was performed in Medline and Embase from inception to August 2021. Title and abstract screening (n = 11,248), full text screening (n = 48), and quality assessment were performed independently by two researchers.

Results

Six RCTs studying caesarean born infants were included, group sizes varied between 32–193 with in total 752 children. No studies regarding supplementation after neonatal antibiotic exposure were found. Three studies administered a probiotic, one a prebiotic, one a synbiotic, and one study investigated a prebiotic and synbiotic. Several significant effects were reported at follow-up varying between 10 days and 13 years: a decrease in atopic diseases (n = 2 studies), higher immune response to tetanus and polio vaccinations (n = 2), lower response to influenza vaccination (n = 1), fewer infectious diseases (n = 2), and less infantile colic (n = 1), although results were inconsistent.

Conclusions

Supplementation of caesarean-born infants with prebiotics, probiotics, or synbiotics resulted in significant improvements in some health outcomes as well as vaccination responses. Due to the variety of studied products and the paucity of studies, no recommendations can be given yet on the routine application of prebiotics, probiotics, or synbiotics to improve health outcomes after caesarean section or neonatal antibiotic exposure.
Efficacy and safety of CO2 cryotherapy in the treatment of infants with tracheobronchial tuberculosis
Authors: Zhao Yidi , Zhang Tongqiang , Yang Nan , Xu Yongsheng , Guo Wei
Published: October 2022

Objective

This study aimed to investigate the efficacy and safety of CO2 cryotherapy for lymph node fistula tracheobronchial tuberculosis (TBTB) in infants.

Patients and methods

A retrospective analysis was undertaken on seven patients with lymph node fistula tracheobronchial tuberculosis who underwent fiberoptic bronchoscopy (FB) interventional therapy in the respiratory department of Tianjin Children's Hospital from July 2012 to July 2020. The efficacy, safety, and prognosis of CO2 cryotherapy intervention for the treatment of lymph node fistula TBTB in infants were summarized and analyzed.

Results

Seven patients with lymph node fistula TBTB were included in this study. Their ages ranged from 6–13 months. The course of the disease from onset to TBTB ranged from 20 to 70 days. The pathological diagnoses of seven cases by FB combined with tissue biopsy were lymph node fistula TBTB, of which 28.57% (two cases) were in the early stage of rupture and 71.43% (five cases) were in the rupture stage. All patients were treated with CO2 cryotherapy combined with foreign body forceps and local injection drugs based on systemic antituberculosis chemotherapy. Two patients were treated once with CO2 cryotherapy, and five were treated three times. According to the comparison of the clinical symptoms, imaging results, and endoscopic presentations before and after the intervention, six patients achieved clinical cure, and one achieved clinical improvement. No severe intraoperative or postoperative complications were observed. The clinical symptoms, endoscopic findings, radiological manifestations, and quality of life of all patients showed marked improvement. No recurrence occurred after 3–6 months of follow-up with FB.

Conclusion

CO2 cryotherapy can improve the treatment effect of lymph node fistula in infants with TBTB and reduce the incidence of complications. This treatment is safe and reliable in infants.
Rituximab in patients with membranous nephropathy and kidney insufficiency
Authors: Guo Yanhong , Wang Liuwei , Wang Yulin , Li Xiaodan , Zhai Zihan , Yu Lu , Liang Yan , Liu Peipei , Tang Lin
Published: October 2022

Introduction: Patients with membranous nephropathy and kidney insufficiency have an extremely high risk of progression to end-stage renal disease. Whether rituximab can effectively treat membranous nephropathy patients with renal dysfunction remains unknown at present. The aim of our study was to evaluate the effectiveness and safety of rituximab (RTX) in membranous nephropathy with kidney insufficiency.

Methods: We retrospectively analyzed the clinical data of 35 membranous nephropathy patients with kidney insufficiency administered in the First Affiliated Hospital of Zhengzhou University between January 2020 and December 2021. Patients were followed every 1–3 months for a total of 6 months. Clinical data were collected including anti-phospholipase A2 receptor antibody (anti-PLA2R antibody) quantification, 24-h urinary protein, serum albumin, and serum creatinine. The percentage of patients who achieved clinical remission was measured.

Results: There were 7 (20%) patients who achieved complete or partial response at 6 months after RTX treatment. After 6 months of treatment, patients were clinically improved as evidenced by significant improvements in anti- PLA2R antibody titer [7.70 (5.72, 16.72) vs. 59.20 (17.70, 187.50) RU/ml, p < 0.001], 24-h urine protein [7.04 (4.43, 8.90) vs. 10.15 (4.83, 13.57) g/d, p < 0.001], serum albumin [30.55 (24.97, 33.27) vs. 21.40 (16.75, 25.00)g/L, p < 0.001], serum creatinine [99.50 (75.25, 140.25) vs. 152.00 (134.50, 232.50) µmol/L, p = 0.022], and estimated glomerular filtration rate (eGFR) [78.29 (50.15, 101.55) vs. 41.12 (26.53, 51.41) ml/min/1.73 m2, p = 0.045]. There were no significantly differences between responders and nonresponders in the baseline levels of anti-PLA2R antibodies, proteinuria, serum albumin, and renal function. After the RTX treatment, anti-PLA2R antibodies turned negative in all responders, but the antibody level persisted maintained positive in all but 5 nonresponders. The patients who achieved response maintained a stable kidney function during the study period, with eGFR 29.03 (28.76, 35.07) ml/min/1.73 m2 before rituximab treatment and 62.73 (62.34, 63.13) ml/min/1.73 m2 at the end of follow-up (p = 0.053).

Conclusion: RTX therapy might be an alternative treatment in reducing proteinuria and maintaining stable renal function among membranous nephropathy patients even with kidney insufficiency.
Effects of tocotrienol on aging skin: A systematic review
Authors: Ghazali Nur Izyani , Mohd Rais Rahimah Zahidah , Makpol Suzana , Chin Kok Yong , Yap Wei Ney , Goon Jo Aan
Published: October 2022

The skin is the largest organ of the body that protects from mechanical, thermal, and physical injury. However, the function and appearance of skin visibly degenerates with age due to its frequent exposure to harmful effects of the environment, including ultraviolet irradiation and hazardous substances, in addition to the progression of oxidative stress in aging. These factors result in phenotypic changes in the skin, including wrinkling, pigmentation, reduced elasticity, and hydration during aging. Many natural antioxidant compounds have been studied extensively to reverse the signs of aging skin. Tocotrienols are a subfamily of vitamin E with potent antioxidant activity. Therefore, supplementation with vitamin E in the form of tocotrienol may efficiently protect skin from aging. In this review, the effects of tocotrienol on skin health, including pigmentation, moisture, and wrinkles during aging and UV exposure, were systematically evaluated based on a literature search of the PubMed and Scopus databases. The present data showed that tocotrienols protect the skin from inflammation, UV radiation and melanin accumulation. As the therapeutic value of tocotrienols grows, the potential of these vitamin E analogs to the skin requires further investigation.
The neuroprotective effects of fisetin, a natural flavonoid in neurodegenerative diseases: Focus on the role of oxidative stress
Authors: Hassan Syed Shams ul , Samanta Saptadip , Dash Raju , Karpiński Tomasz M. , Habibi Emran , Sadiq Abdul , Ahmadi Amirhossein , Bungau Simona
Published: October 2022

Oxidative stress (OS) disrupts the chemical integrity of macromolecules and increases the risk of neurodegenerative diseases. Fisetin is a flavonoid that exhibits potent antioxidant properties and protects the cells against OS. We have viewed the NCBI database, PubMed, Science Direct (Elsevier), Springer-Nature, ResearchGate, and Google Scholar databases to search and collect relevant articles during the preparation of this review. The search keywords are OS, neurodegenerative diseases, fisetin, etc. High level of ROS in the brain tissue decreases ATP levels, and mitochondrial membrane potential and induces lipid peroxidation, chronic inflammation, DNA damage, and apoptosis. The subsequent results are various neuronal diseases. Fisetin is a polyphenolic compound, commonly present in dietary ingredients. The antioxidant properties of this flavonoid diminish oxidative stress, ROS production, neurotoxicity, neuro-inflammation, and neurological disorders. Moreover, it maintains the redox profiles, and mitochondrial functions and inhibits NO production. At the molecular level, fisetin regulates the activity of PI3K/Akt, Nrf2, NF-κB, protein kinase C, and MAPK pathways to prevent OS, inflammatory response, and cytotoxicity. The antioxidant properties of fisetin protect the neural cells from inflammation and apoptotic degeneration. Thus, it can be used in the prevention of neurodegenerative disorders.
Effective targeting of microglial P2X7 following intracerebroventricular delivery of nanobodies and nanobody-encoding AAVs
Authors: Pinto-Espinoza Carolina , Guillou Charlotte , Rissiek Björn , Wilmes Maximilian , Javidi Ehsan , Schwarz Nicole , Junge Marten , Haag Friedrich , Liaukouskaya Nastassia , Wanner Nicola , Nicke Annette , Stortelers Catelijne , Tan Yossan-Var , Adriouch Sahil , Magnus Tim , Koch-Nolte Friedrich
Published: October 2022

The P2X7 ion channel is a key sensor for extracellular ATP and a key trigger of sterile inflammation. Intravenous injection of nanobodies that block P2X7 has shown to be beneficial in mouse models of systemic inflammation. P2X7 has also emerged as an attractive therapeutic target for inflammatory brain diseases. However, little is known about the ability of nanobodies to cross the BBB. Here we evaluated the ability of P2X7-specific nanobodies to reach and to block P2X7 on microglia following intravenous or intracerebral administration. For this study, we reformatted and sequence-optimized P2X7 nanobodies for higher stability and elevated isoelectric point. Following injection of nanobodies or nanobody-encoding adeno-associated viral vectors (AAV), we monitored the occupancy and blockade of microglial P2X7in vivousingex vivoflow cytometry. Our results show that P2X7 on microglia was within minutes completely occupied and blocked by intracerebroventricularly injected nanobodies, even at low doses. In contrast, very high doses were required to achieve similar effects when injected intravenously. The endogenous production of P2X7-antagonistic nanobodies following intracerebral or intramuscular injection of nanobody-encoding AAVs resulted in a long-term occupancy and blockade of P2X7 on microglia. Our results provide new insights into the conditions for the delivery of nanobodies to microglial P2X7 and point to AAV-mediated delivery of P2X7 nanobodies as a promising strategy for the treatment of sterile brain inflammation.
Application of traditional Chinese medicine in film drug delivery system
Authors: Li Qianhang , Luo Feng , Jiang Pingnan , Feng Chenxi , He Feifei , Dong Lina , Xu Delin , Shi Junhua
Published: October 2022

Film drug delivery systems have the advantages of precise administration, simple process and easy portability, compared with other traditional drug delivery systems such as tablets, capsules, syrups, ointments, etc. The traditional Chinese medicine (TCM) are normally developed in four categories of film agent like patch film, coating, spray film and gel film, which are applied to the treatment of oral ulcers, chronic diseases of lower limbs, burns, scalds, gynecological disease and body care. So the TCM film has great research value and prominent market prospect. In this review, we summarized the research progress of the material composition, pharmaceutical production, clinical application and pharmacology mechanism of various TCM film agents. It may provide a comprehensive reference for further development and utilization of TCM film agents.
Acacetin protects against depression-associated dry eye disease by regulating ubiquitination of NLRP3 through gp78 signal
Authors: Xie Mingxia , Wang Hanqing , Peng Jun , Qing Dongqin , Zhang Xi , Guo Dongwei , Meng Pan , Luo Zhihong , Wang Xiaoye , Peng Qinghua
Published: October 2022

Dry eye disease (DED) is a multifactorial syndrome that commonly occurs with depression. However, therapies targeting depression-related dry eye disease are rare. In the current study, we studied the beneficial effect of a natural flavone, acacetin, in depression-associated dry eye disease by utilizing the chronic unpredictable mild stress (CUMS) depression model. Our data showed that acacetin improved the depressive behaviors in sucrose preference test (SPT), tail suspension test (TST) and forced swim test (FST); relieved the dry eye symptoms including corneal epithelial impairments, tear production decrease and goblet cell loss in CUMS mice. Acacetin also inhibited NOD-like receptor protein 3 (NLRP3) inflammasome expression levels and suppressed inflammatory responses via enhancing glycoprotein 78 (gp78)/Insulin induced gene-1 (Insig-1)-controlled NLRP3 ubiquitination in CUMS mice. Furthermore, knockdown of gp78 compromised acacetin-conferred protective efficacy in depression-related dry eye disease. In summary, our findings indicated that acacetin exerts beneficial effect in depression-associated dry eye disease, which is tightly related to gp78-mediated NLRP3 ubiquitination.
Drugs for the prevention and treatment of COVID-19 and its complications: An update on what we learned in the past 2 years
Authors: Remuzzi Giuseppe , Schiaffino Stefano , Santoro Maria Gabriella , FitzGerald Garret A. , Melino Gennaro , Patrono Carlo
Published: October 2022

The COVID-19 Committee of the Lincei Academy has reviewed the scientific evidence supporting the efficacy and safety of existing and new drugs/biologics for the preventing and treating of COVID-19 and its complications. This position paper reports what we have learned in the field in the past 2 years. The focus was on, but not limited to, drugs and neutralizing monoclonal antibodies, anti-SARS-CoV-2 agents, anti-inflammatory and immunomodulatory drugs, complement inhibitors and anticoagulant agents. We also discuss the risks/benefit of using cell therapies on COVID-19 patients. The report summarizes the available evidence, which supports recommendations from health authorities and panels of experts regarding some drugs and biologics, and highlights drugs that are not recommended, or drugs for which there is insufficient evidence to recommend for or against their use. We also address the issue of the safety of drugs used to treat underlying concomitant conditions in COVID-19 patients. The investigators did an enormous amount of work very quickly to understand better the nature and pathophysiology of COVID-19. This expedited the development and repurposing of safe and effective therapeutic interventions, saving an impressive number of lives in the community as well as in hospitals.
Therapeutic drug monitoring practices of anti-infectives: An Asia-wide cross-sectional survey
Authors: Hou Jingjing , Marriott Debbie , Cattaneo Dario , Stocker Sophie , Stojanova Jana , Alffenaar Jan-Willem , Xiao Chenlin , Zhao Yichang , Gong Hui , Yan Miao
Published: October 2022

Objectives: The current practice of therapeutic drug monitoring (TDM) in Asia is poorly documented. Our aim was to capture and describe TDM services delivered in hospitals across Asia, including aspects such as assay availability, interpretation of results and clinical decision-making.

Methods: An online survey about anti-infective TDM practices, available in English and involving 50 questions, was promoted to people involved in TDM in Asia. The survey was open for responses from September to November 2021.

Results: Of 207 responses from participants working in 14 Asian countries, 150 responses from 10 countries could be included. TDM services are available for many anti-infectives, providing assays based on chromatographic assays (100.0%) or immunoassays (39.3%). Clinicians (82.6%) and pharmacists (86.8%) were responsible for ordering and interpreting TDM. Most services provided reference targets and dose recommendations. Interpretative support was available to a varying degree. Assay results were available and clinical decision-making could be completed within 24 h in most hospitals (87.9% and 88.9% respectively). As the turnaround time of assay results decreased, the proportion of clinical decision-making completed within 8 h increased. Barriers to implementation of TDM included lack of funding or equipment (71.1%), lack of clinician interest or cooperation (47.0%), and lack of expertise (42.3%). Lack of expertise was the primary barrier for using precision dosing software (50.5%).

Conclusion: There are significant differences and challenges in the development and practice of anti-infective TDM in Asian countries.
On the fractional weibull process
Authors: Deng Wujin , Song Wanqing , Cattani Carlo , Chen Jianxue , Chen Xiaolong
Published: October 2022

Engineering applications of the fractional Weibull distribution (fWd) are quite limited because a corresponding stochastic process is not yet constituted and completely analyzed of fundamental properties. In order to fill this gap, the fractional Weibull process (fWp) is defined in this paper with the realization algorithm. The self-similarity property as well as long range dependence (LRD) are proven for the future research. The simulation is conducted by the actual data. The fWd is utilized to fit the actual probability distribution and the corresponding process is generated to reflect the stochasticity of the data. The random walk based on the fWp expands the simulation to the planar space.
Resting-state EEG-based convolutional neural network for the diagnosis of depression and its severity
Authors: Li Mengqian , Liu Yuan , Liu Yan , Pu Changqin , Yin Ruocheng , Zeng Ziqiang , Deng Libin , Wang Xing
Published: October 2022

Purpose: The study aimed to assess the value of the resting-state electroencephalogram (EEG)-based convolutional neural network (CNN) method for the diagnosis of depression and its severity in order to better serve depressed patients and at-risk populations.

Methods: In this study, we used the resting state EEG-based CNN to identify depression and evaluated its severity. The EEG data were collected from depressed patients and healthy people using the Nihon Kohden EEG-1200 system. Analytical processing of resting-state EEG data was performed using Python and MATLAB software applications. The questionnaire included the Self-Rating Anxiety Scale (SAS), Self-Rating Depression Scale (SDS), Symptom Check-List-90 (SCL-90), and the Eysenck Personality Questionnaire (EPQ).

Results: A total of 82 subjects were included in this study, with 41 in the depression group and 41 in the healthy control group. The area under the curve (AUC) of the resting-state EEG-based CNN in depression diagnosis was 0.74 (95%CI: 0.70–0.77) with an accuracy of 66.40%. In the depression group, the SDS, SAS, SCL-90 subscales, and N scores were significantly higher in the major depression group than those in the non-major depression group (p < 0.05). The AUC of the model in depression severity was 0.70 (95%CI: 0.65–0.75) with an accuracy of 66.93%. Correlation analysis revealed that major depression AI scores were significantly correlated with SAS scores (r = 0.508, p = 0.003) and SDS scores (r = 0.765, p < 0.001).

Conclusion: Our model can accurately identify the depression-specific EEG signal in terms of depression diagnosis and severity identification. It would eventually provide new strategies for early diagnosis of depression and its severity.
A moderate reduction in irrigation and nitrogen improves water-nitrogen use efficiency, productivity, and profit under new type of drip irrigated spring wheat system
Authors: Wan Wenliang , Zhao Yanhui , Li Xiaofang , Xu Jing , Liu Kaige , Guan Sihui , Chai Yaqian , Xu Hongjun , Cui Hongxin , Chen Xianjun , Wu Pei , Diao Ming
Published: October 2022

Rational irrigation and nitrogen management strategies are crucial for wheat growth. However, the optimal amount of water and nitrogen for the newly developed drip irrigated spring wheat system (TR6S, one drip tube service for six rows of wheat, with a row spacing of 10 cm and an inter-block space of 25 cm, saves drip tubes and obtains higher profits) in dry and semi-arid areas remains unclear. Therefore, a field experiment was conducted with four nitrogen levels (300, 270, 240, and 0 kg ha−1 referred N300, N270, N240, and N0) and four irrigation levels (4500, 4200, 3900, and 3600 m3 ha−1 referred I4500, I4200, I3900, and I3600) during the 2021–2022 and 2022–2023 spring wheat seasons to analyze the effects of irrigation (I) and nitrogen (N) levels on grain yield, water-nitrogen use efficiency, profit, biomass accumulation, and nitrogen nutrient absorption status under TR6S. Compared with the traditional irrigation and nitrogen management strategy (N300–I4500, as control), lesser irrigation and nitrogen supply (I<3979 m3 ha−1 and N<273 kg ha−1) saved cost but led to lower grain yield, water use efficiency (WUE), agronomic efficiency of nitrogen fertilizer (AEN), and profit. However, a moderate reduction in irrigation and nitrogen supply (4500 m3 ha−1>I>3979 m3 ha−1 and 300 kg ha−1 >N>273 kg ha−1) improved grain yield, WUE, AEN, and profit. The increase in grain yield was mainly related to the rise in 1000-grain weight and kernels per spike. Although the moderate reduction in irrigation lowered soil moisture status, the dry matter pre-stored in the vegetative organs before anthesis that gets redistributed into grains during grain filling was improved. Moreover, the moderate reduction in nitrogen supply resulted in a more reasonable nitrogen nutrition index (NNI) of wheat plant, which improved flag leaf area and chlorophyll relative content (SPAD) at the anthesis stage. This also played a positive role in biomass accumulation and redistributed, yield structure optimization. Considering comprehensively yield, WUE, AEN and profit, combination of 285 kg ha−1 N and 4170 m3 ha−1 I was optimal irrigation and nitrogen application pattern for TR6S. This strategy can be applied to other arid and semi-arid regions.
Genetic basis analysis of key Loci in 23 Yannong series wheat cultivars/lines
Authors: Xiao Luning , Jin Yuli , Liu Wei , Liu Jie , Song Huajie , Li Dong , Zheng Jianpeng , Wang Dongmei , Yin Yan , Liu Yang , Wang Hao , Li Linzhi , Sun Nina , Liu Minxiao , Ma Pengtao
Published: October 2022

Fungal diseases, drought, pre-harvest sprouting (PHS) and other biotic and abiotic stresses have seriously affected the quality and yield in wheat production. Identifying related genes/loci in released cultivars/lines can provide reference information and theoretical basis for wheat improvement. Yannong series wheat cultivars/lines have distinctive characteristics in wheat cultivars and play an important role in genetic improvement and production of Chinese wheat production system. To dissect their genetic basis of the stress-resistant traits, in this study, 23 representative Yannong series wheat cultivars/lines were tested by 58 molecular markers for 40 genes related to adaptability, disease resistance and stress tolerance to clarify the genetic composition of the key loci. The results showed that most of the tested wheat accessions carried dwarfing genes RhtB1b/RhtD1b/Rht8 and recessive vernalization genes vrn-A1/vrn-B1/vrn-D1/vrn-B3. It was also consistent with the phenotypic traits of tested Yannong series wheat which were dwarf and winter or semi winter wheat. In addition, the overall level of seedling powdery mildew resistance in 23 Yannong wheat cultivars/lines was moderate or inadequate. Eleven accessions carried none of the tested Pm genes and twelve accessions carried Pm2, Pm6, Pm42 and Pm52 singly or in combination. Then, 23 wheat cultivars/lines were also tested by 17 diagnostic markers for 14 Yr genes. The results showed that 16 wheat cultivars/lines were likely to carry one or more of tested Yr genes, whereas Yannong 15, Yannong 17, Yannong 23, Yannong 24, Yannong 377, Yannong 572 and Yannong 999 carried none of the tested Yr genes. Moreover, in our study, nine markers for four genes related to drought tolerance and PHS were used to evaluate the stress tolerance of the 23 wheat cultivars/lines. The results indicated that all 23 wheat cultivars/lines carried drought resistance genes Ta-Dreb1/TaCRT-D, indicating that they had the drought resistance to the extent. Except for Yannong 30, Yannong 377, Yannong 390, Yannong 745 and Yannong 1766, other wheat cultivars/lines carried one to three elite PHS-resistant alleles Vp-1Bc/Vp-1Bf/TaAFP-1Bb.
The influencing factors of individual interest in physical education based on decision tree model: A cross-sectional study
Authors: Lin Jia Bin , Zhu Shan Shan
Published: October 2022

To identify the key influencing factors and analyze the internal relationship among the factors of individual interest in PE, we conducted a cross-sectional survey of a large sample of Chinese young students based on the decision tree model. A total of 3,640 young students (Mage = 14.16; 7–18 years; SD = 2.66, 47% boys) were investigated by using six questionnaires, including individual interest in physical PE, self-efficacy, achievement goals, expectancy value in PE, PE knowledge and skills and PE learning environment. Results showed there were a total of seven variables entered into the decision tree model, which was 3 layers high, including 38 nodes. The root node was expectancy value which was divided by sports knowledge and skills and self-efficacy. The third layer included mastery-approach goal, family sports environment, performance-avoidance goal and gender. The results depict that expectancy value of PE was the most important influencing factors of adolescent students’ individual interest in PE in this study, and the other important factors were sports knowledge and skills, self-efficacy, mastery-approach goal, family sports environment, performance-avoidance goal, and gender, respectively. The implications for PE are: (1) Improve the status of the PE curriculum and enhance students’ recognition of the value of PE; (2) Strengthen the teaching of knowledge and skills to avoid low-level repetitive teaching; (3) Enhance success experience and foster sports self-efficacy; and (4) Establish reasonable sports goals to foster individual interest in sports learning.
Team diversity, conflict, and trust: Evidence from the health sector
Authors: Nawaz Muhammad Rafay , Ishaq Muhammad Ishtiaq , Ahmad Rehan , Faisal Muhammad , Raza Ali
Published: October 2022

The current study aims to determine the impact of diversity and intra-team trust on conflict within the health sector of Pakistan. This study also measures the moderating role of trust in the relationship between diversity and conflict among team members. Data was collected using personally administered questionnaires from 61 teams, including 377 respondents working in 4 public sector hospitals in Pakistan, which were selected using a simple random sampling technique. The results revealed that diversity (as a composite) positively influences task conflict, while its two components—surface-level diversity and deep-level diversity—are associated positively with task conflict. Moreover, the results also lead to an exciting finding that trust among team members could reduce the positive influence of diversity on team members’ conflict. The implications for theory and practitioners are presented along with the avenues for future research directions.