bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessment of the Record-Breaking 2020 Rainfall in Guinea-Bissau and Impacts of Associated Floods
Authors: Mendes Orlando , Fragoso Marcelo
Published: January 2023

The impacts of Climate Change are quite visible in Guinea-Bissau. Greater irregularity at the beginning and end of the rainy season, as well as in relation to the interannual variability of precipitation, are evidence that shows these phenomena in West African countries and particularly in Guinea-Bissau, where the agriculture is rain-fed. The year 2020 was characterized as very rainy in comparison to the climatological average of 1981–2020, with positive anomalies throughout the country, despite the late arrival of the wet season, which usually occurs in May. July, August, and September 2020 were the rainiest months, registering above a normal frequency of days with precipitation greater than 50 mm. Bissau, the capital, registered a record-breaking annual rainfall and monthly amounts higher than the 90th and 95th percentiles in July and August, respectively. This heavy rain accompanied by strong winds caused flooding in several urban areas and agricultural fields, and the destruction of roads, houses, and infrastructures in different cities across the country. As a way of mitigating these impacts, the government, through the Ministry of Solidarity, made available 100 million CFA francs (6.5 million euros) to help families that were victims of the floods.
An Engaged Community of Faith to Decrease HIV Stigma in the U.S. South
Authors: Pichon Latrice C. , Jewell Erin N. , Williams Stubbs Andrea , Jones DeMarcus , Campbell Bettina , Kimble Katrina M. , Stewart Gina M. , Hurd-Sawyer LaRonia , Carroll Lacretia , Powell Terrinieka W.
Published: January 2023

Community members from a city in the U.S. Deep South identified root causes of HIV racial disparities, including stigma. This meeting report describes how we developed and implemented a conference series to address HIV stigma. We used community feedback and bidirectional learning to host two meetings in observance of National HIV Testing Day (June 2021) and National Southern HIV/AIDS Awareness Day (August 2021). We established a 10-member organizing committee workgroup that met monthly to plan the Faith Summit in honor of National Black HIV Awareness Day (February 2022). Lessons learned include (a) the effectiveness of different community engagement strategies, including participatory evaluative approaches, and (b) strategies to maintain engagement and increase participation, such as reliance on personal and professional networks and prompting the community about forthcoming interventions. Sustaining a conference series to end HIV stigma requires commitment and inclusive participation. This collaborative project offers additional evidence that faith communities can be a part of the solution to ending the HIV epidemic and related health disparities.
The Structure of Temperament in Caregivers of Patients with Schizophrenia
Authors: Sipowicz Kasper , Łuczyńska Kamila , Bąk Bartłomiej , Deska Kacper , Nowakowska-Domagała Katarzyna , Pietras Tadeusz , Podgórska-Jachnik Dorota , Małujło-Balcerska Elżbieta , Kosmalski Marcin
Published: January 2023

The onset of schizophrenia symptoms usually occurs in early youth. As a result, the parents of these patients usually become their caregivers. The role of a caregiver for a person with schizophrenia is a considerable mental and physical burden. Therefore, an interesting issue is what motivates these people to take up this challenge. It is probable that, apart from the moral imperative or kinship, the factor determining this decision is the personality structure of the caregiver. The aim of our study was to compare the structure of temperament (according to the model of temperament as formal characteristics of behavior developed by Jan Strelau) in caregivers of young adults (age 18–25 years) with schizophrenia with the structure of temperament of parents of healthy young adults still living in the family home under their care. The study group consisted of 64 people (51 women), who were taking care of young adults (aged 18–25 years) with schizophrenia, while the control group (53 people, 42 women) consisted of parents of healthy adults still living in the family home. Both groups were asked to complete a questionnaire of the authors’ own design on their demographic data as well as The Formal Characteristics of Behavior—Temperament Inventory to assess the temperament traits. The results were given in the number of points obtained on average in each dimension. Both groups did not differ in terms of size and age, with women predominating. Caregivers of young adults with schizophrenia had higher values of briskness (43.22 ± 4.45 vs. 42.90 ± 3.98, p = 0.032), emotional reactivity (46.02 ± 4.39 vs. 41.01 ± 3.12, p = 0.012) and activity level (44.01.89 ± 4.15 vs. 37.59 ± 4.77, p = 0.022) compared to the control group. The remaining dimensions of temperament: perseverance, sensory sensitivity, rhythmicity, and endurance did not differentiate between the two groups. The temperament structure of caregivers of young people with schizophrenia differs from the temperament structure of caregivers of healthy adults. Caregivers of sick people have higher values of briskness, emotional reactivity, and activity level compared to the control group.
Parenting Stress and Parenting Efficacy of Parents Having Children with Disabilities in China: The Role of Social Support
Authors: Fu Wangqian , Li Rui , Zhang Yaqian , Huang Ke
Published: January 2023

Raising children with disabilities is challenging for parents, who experience high parenting stress. The study aimed to understand the status quo of parenting efficacy of parents having children with disabilities and to analyze the association between parent efficacy, parenting stress, and social support in China. We surveyed 373 parents having children with disabilities enrolled in special education schools or rehabilitation institutions from 14 provinces in China. The online questionnaire including Parental Stress Index-Short Form, the Child Adjustment and Parent Efficacy Scale-Developmental Disability (CAPES-DD), and Social Support Scale was applied in the study. The results suggested that parenting efficacy of parents having children with disabilities in China was at the medium level. Parenting stress, social support, and parenting efficacy were significantly related with each other, and social support played a mediating role between parenting stress and parenting efficacy. The findings indicated that reducing parenting stress and improving social support might improve parenting efficacy. We also discussed the implications of providing intervention strategies or social support to improve parenting efficacy for parents with disabled children in China.
Designing a Nurse-Led Program for Self-Management of Substance Addiction Consequences: A Modified e-Delphi Study
Authors: Seabra Paulo , Nunes Inês , Sequeira Rui , Sequeira Ana , Simões Ana , Filipe Fernando , Amaral Paula , Abram Marissa , Sequeira Carlos
Published: January 2023

Therapeutic interventions for people with problematic use of psychoactive substances can help tackle specific needs related to substance addiction consequences. This modified e-Delphi study aimed to establish consensus on a training program for self-management of substance addiction consequences. The study was conducted between February and April 2022, with an experts’ sample of 28 participants in the first round and 24 in the second. A priori consensus criteria were defined for each round. The results revealed a very strong consensus was achieved on the structure of the program and on clinical areas, such as the problematic use of substances, general health knowledge, health-seeking behavior and adherence, self-knowledge and well-being, social role and personal dignity, and family process. Additionally, over 80% participant consensus was achieved on an extensive number of interventions categorized as psychoeducational, psychotherapeutic, socio therapeutic, brief interventions, social skills training, problem solving techniques, relaxation techniques, and counseling. These findings may be able to fulfill a gap concerning structured treatment approaches for people with problematic use of psychoactive substances. Supporting self-management of the consequences of substance addiction and its application can change nurses’ interventions.
Comparison of Diagnostic Profiles of Deaf and Hearing Children with a Diagnosis of Autism
Authors: Hodkinson Rachel , Phillips Helen , Allgar Victoria , Young Alys , Le Couteur Ann , Holwell Andrew , Teige Catarina , Wright Barry
Published: January 2023

There is limited research comparing the presentation of autism in deaf and hearing children and young people. These comparisons are important to facilitate accurate diagnosis, as rates of misdiagnosis and delay in diagnosis amongst deaf children and young people are high. The aim of this study was to compare diagnostic assessment profiles of a UK cohort of autistic deaf and hearing children and young people. The Autism Diagnostic Interview—Revised—Deaf adaptation was completed with the parents of 106 children and young people (deaf children = 65; hearing children = 41). The majority of items explored showed no significant differences between deaf and hearing children and young people. Differences were found in peer relationships, where autistic deaf participants were less likely to respond to the approaches of other children or play imaginatively with peers. These findings need to be taken into consideration by clinicians in the assessment process.
Early Gastric Cancer: Update on Prevention, Diagnosis and Treatment
Authors: Conti Clara Benedetta , Agnesi Stefano , Scaravaglio Miki , Masseria Pietro , Dinelli Marco Emilio , Oldani Massimo , Uggeri Fabio
Published: January 2023

Gastric cancer (GC) is a relevant public health issue as its incidence and mortality rates are growing worldwide. There are recognized carcinogen agents, such as obesity, tobacco, meat, alcohol consumption and some dietary protective factors. Strategies of early diagnosis through population-based surveillance programs have been demonstrated to be effective in lowering the morbidity and mortality related to GC in some countries. Indeed, the detection of early lesions is very important in order to offer minimally invasive treatments. Endoscopic resection is the gold standard for lesions with a low risk of lymph node metastasis, whereas surgical mini-invasive approaches can be considered in early lesions when endoscopy is not curative. This review outlines the role of lifestyle and prevention strategies for GC, in order to reduce the patients’ risk factors, implement the surveillance of precancerous conditions and, therefore, improve the diagnosis of early lesions. Furthermore, we summarize the available treatments for early gastric cancer.
Outcomes of Elderly Patients Hospitalized with the SARS-CoV-2 Omicron B.1.1.529 Variant: A Systematic Review
Authors: Fericean Roxana Manuela , Oancea Cristian , Reddyreddy Akash Reddy , Rosca Ovidiu , Bratosin Felix , Bloanca Vlad , Citu Cosmin , Alambaram Satish , Vasamsetti Neeharika Gayatri , Dumitru Catalin
Published: January 2023

The Omicron (B.1.1.529) variant of the severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) had an increased rate of spreading among the general population. Although this virus mutation resulted in milder symptoms, those on the vulnerable side of the population are still in danger of developing severe symptoms. Thus, this systematic review focused on identifying the clinical outcomes of older age patients (>65) that are hospitalized with the SARS-CoV-2 Omicron variant. The research was conducted using four electronic databases (PubMed, Scopus, Web of Science, and ProQuest Central), with a search query in December 2022 that comprised the duration of the COVID-19 pandemic. The inclusion criteria comprised (1) a population of patients older than 65 years, (2) a history of hospitalization for SARS-CoV-2 infection, and (3) infection with Omicron B.1.1.529 variant. The initial search generated 295 articles, out of which six were included in the systematic review, and a total of 7398 patients. The main findings were that when looking at the elderly population, the mortality and hospitalization rates remained high. This is because older people are more vulnerable and have more comorbidities that interfere with the virus’s progress. However, there is inconsistency in mortality rates, since the data reported by the included studies had different selection criteria based on the severity of the COVID-19 infection. Although no statistically significant differences were found between the unvaccinated and vaccinated groups, patients who got booster doses of vaccination had a lower likelihood of developing severe symptoms, serving as a protective factor for this population.
DeepTP: A Deep Learning Model for Thermophilic Protein Prediction
Authors: Zhao Jianjun , Yan Wenying , Yang Yang
Published: January 2023

Thermophilic proteins have important value in the fields of biopharmaceuticals and enzyme engineering. Most existing thermophilic protein prediction models are based on traditional machine learning algorithms and do not fully utilize protein sequence information. To solve this problem, a deep learning model based on self-attention and multiple-channel feature fusion was proposed to predict thermophilic proteins, called DeepTP. First, a large new dataset consisting of 20,842 proteins was constructed. Second, a convolutional neural network and bidirectional long short-term memory network were used to extract the hidden features in protein sequences. Different weights were then assigned to features through self-attention, and finally, biological features were integrated to build a prediction model. In a performance comparison with existing methods, DeepTP had better performance and scalability in an independent balanced test set and validation set, with AUC values of 0.944 and 0.801, respectively. In the unbalanced test set, DeepTP had an average precision (AP) of 0.536. The tool is freely available.
Isoindigo–Thiophene D–A–D–Type Conjugated Polymers: Electrosynthesis and Electrochromic Performances
Authors: Cao Jie , Luo Xiaoyu , Zhou Shenglong , Wu Zhixin , Zhao Qi , Gu Hua , Wang Wen , Zhang Zhilin , Zhang Kaiyue , Li Kaiyun , Xu Jingkun , Liu Ximei , Lu Baoyang , Lin Kaiwen
Published: January 2023

Four novel isoindigo–thiophene D–A–D–type precursors are synthesized by Stille coupling and electrosynthesized to yield corresponding hybrid polymers with favorable electrochemical and electrochromic performances. Intrinsic structure–property relationships of precursors and corresponding polymers, including surface morphology, band gaps, electrochemical properties, and electrochromic behaviors, are systematically investigated. The resultant isoindigo–thiophene D–A–D–type polymer combines the merits of isoindigo and polythiophene, including the excellent stability of isoindigo–based polymers and the extraordinary electrochromic stability of polythiophene. The low onset oxidation potential of precursors ranges from 1.10 to 1.15 V vs. Ag/AgCl, contributing to the electrodeposition of high–quality polymer films. Further kinetic studies illustrate that isoindigo–thiophene D–A–D–type polymers possess favorable electrochromic performances, including high optical contrast (53%, 1000 nm), fast switching time (0.8 s), and high coloration efficiency (124 cm2 C−1). These features of isoindigo–thiophene D–A–D–type conjugated polymers could provide a possibility for rational design and application as electrochromic materials.
Neural Tube Defects and Folate Deficiency: Is DNA Repair Defective?
Authors: Wang Xiuwei , Yu Jialu , Wang Jianhua
Published: January 2023

Neural tube defects (NTDs) are complex congenital malformations resulting from failure of neural tube closure during embryogenesis, which is affected by the interaction of genetic and environmental factors. It is well known that folate deficiency increases the incidence of NTDs; however, the underlying mechanism remains unclear. Folate deficiency not only causes DNA hypomethylation, but also blocks the synthesis of 2′-deoxythymidine-5′–monophosphate (dTMP) and increases uracil misincorporation, resulting in genomic instabilities such as base mismatch, DNA breakage, and even chromosome aberration. DNA repair pathways are essential for ensuring normal DNA synthesis, genomic stability and integrity during embryonic neural development. Genomic instability or lack of DNA repair has been implicated in risk of development of NTDs. Here, we reviewed the relationship between folate deficiency, DNA repair pathways and NTDs so as to reveal the role and significance of DNA repair system in the pathogenesis of NTDs and better understand the pathogenesis of NTDs.
Increased Hemichannel Activity Displayed by a Connexin43 Mutation Causing a Familial Connexinopathy Exhibiting Hypotrichosis with Follicular Keratosis and Hyperostosis
Authors: Crouthamel Olivia E. , Li Leping , Dilluvio Michael T. , White Thomas W.
Published: January 2023

Mutations in the GJA1 gene that encodes connexin43 (Cx43) cause several rare genetic disorders, including diseases affecting the epidermis. Here, we examined the in vitro functional consequences of a Cx43 mutation, Cx43-G38E, linked to a novel human phenotype of hypotrichosis, follicular keratosis and hyperostosis. We found that Cx43-G38E was efficiently translated in Xenopus oocytes and localized to gap junction plaques in transfected HeLa cells. Cx43-G38E formed functional gap junction channels with the same efficiency as wild-type Cx43 in Xenopus oocytes, although voltage gating of the gap junction channels was altered. Notably, Cx43-G38E significantly increased membrane current flow through the formation of active hemichannels when compared to wild-type Cx43. These data demonstrate the association of increased hemichannel activity to a connexin mutation linked to a skeletal-cutaneous phenotype, suggesting that augmented hemichannel activity could play a role in skin and skeletal disorders caused by human Cx43 mutations.
CD14+-Monocytes Exposed to Apolipoprotein CIII Express Tissue Factor
Authors: Olivieri Oliviero , Gasperini Sara , Calzetti Federica , Gardiman Elisa , Castagna Annalisa , Martinelli Nicola , Tamassia Nicola , Cassatella Marco A.
Published: January 2023

Apolipoprotein CIII (ApoCIII) represents a key regulator of plasma lipid metabolism and a recognized risk factor for atherosclerosis and cardiovascular diseases. Beyond the regulation of lipoprotein trafficking, ApoCIII is also involved in endothelial dysfunction and monocyte recruitment related to atherothrombosis. With tissue factor (TF) being the primary initiator of the blood coagulation cascade, we hypothesized that ApoCIII-treated monocytes could express it. Hence, human CD14+-monocytes and autologous neutrophils were incubated with ApoCIII and sera from human subjects containing previously measured ApoCIII amounts. By RT-qPCR and ELISA, CD14+-monocytes, but not neutrophils, were found to show increased mRNA expression and production of TNFα, IL-1β and IL-6 as well as TF mRNA once exposed to ultra-purified ApoCIII. By flow cytometry, CD14+-monocytes were found to rapidly express TF on their cell surface membrane when incubated with either ApoCIII or sera with known concentrations of ApoCIII. Finally, preincubation with specific ApoCIII-neutralizing antibodies significantly reduced the ability of most sera with known concentrations of ApoCIII to upregulate TF protein, other than partially inhibiting cytokine release, in CD14+-monocytes. In sum, herein we demonstrate that ApoCIII activates CD14+-monocytes to express TF. The data identify a potential mechanism which links circulating apolipoproteins with inflammation and atherothrombosis-related processes underlying cardiovascular risk.
Genome-Wide Identification of BES1 Gene Family in Six Cucurbitaceae Species and Its Expression Analysis in Cucurbita moschata
Authors: Xu Minyan , Wang Yanping , Zhang Mengting , Chen Meng , Ni Ying , Xu Xuewei , Xu Shengkai , Li Yuting , Zhang Xin
Published: January 2023

The BES1 (BRI1-EMSSUPPRESSOR1) gene family play a vital role in the BR (brassinosteroid) signaling pathway, which is involved in the growth and development, biotic, abiotic, and hormone stress response in many plants. However, there are few reports of BES1 in Cucurbita moschata. In this study, 50 BES1 genes were identified in six Cucurbitaceae species by genome-wide analysis, which could be classified into 3 groups according to their gene structural features and motif compositions, and 13 CmoBES1 genes in Cucurbita moschata were mapped on 10 chromosomes. Quantitative real-time PCR analysis showed that the CmoBES1 genes displayed differential expression under different abiotic stress and hormone treatments. Subcellular localization showed that the most of CmoBES1 proteins localized in nucleus and cytoplasm, and transactivation assay indicated 9 CmoBES1 proteins played roles as transcription factors. Our analysis of BES1s diversity, localization, and expression in Curcubitaceae contributes to the better understanding of the essential roles of these transcription factors in plants.
Tenebrio molitor as a Simple and Cheap Preclinical Pharmacokinetic and Toxicity Model
Authors: Brai Annalaura , Poggialini Federica , Vagaggini Chiara , Pasqualini Claudia , Simoni Sauro , Francardi Valeria , Dreassi Elena
Published: January 2023

The progression of drugs into clinical phases requires proper toxicity assessment in animals and the correct identification of possible metabolites. Accordingly, different animal models are used to preliminarily evaluate toxicity and biotransformations. Rodents are the most common models used to preliminarily evaluate the safety of drugs; however, their use is subject to ethical consideration and elevated costs, and strictly regulated by national legislations. Herein, we developed a novel, cheap and convenient toxicity model using Tenebrio molitor coleoptera (TMC). A panel of 15 drugs—including antivirals and antibacterials—with different therapeutic applications was administered to TMC and the LD50 was determined. The values are comparable with those already determined in mice and rats. In addition, a TMC model was used to determine the presence of the main metabolites and in vivo pharmacokinetics (PK), and results were compared with those available from in vitro assays and the literature. Taken together, our results demonstrate that TMC can be used as a novel and convenient preliminary toxicity model to preliminarily evaluate the safety of experimental compounds and the formation of main metabolites, and to reduce the costs and number of rodents, according to 3R principles.
TGF-Beta Induces Activin A Production in Dermal Fibroblasts Derived from Patients with Fibrodysplasia Ossificans Progressiva
Authors: de Ruiter Ruben D. , Wisse Lisanne E. , Schoenmaker Ton , Yaqub Maqsood , Sánchez-Duffhues Gonzalo , Eekhoff E. Marelise W. , Micha Dimitra
Published: January 2023

Fibrodysplasia ossificans progressiva (FOP) is a catastrophic, ultra-rare disease of heterotopic ossification caused by genetic defects in the ACVR1 gene. The mutant ACVR1 receptor, when triggered by an inflammatory process, leads to heterotopic ossification of the muscles and ligaments. Activin A has been discovered as the main osteogenic ligand of the FOP ACVR1 receptor. However, the source of Activin A itself and the trigger of its production in FOP individuals have remained elusive. We used primary dermal fibroblasts from five FOP patients to investigate Activin A production and how this is influenced by inflammatory cytokines in FOP. FOP fibroblasts showed elevated Activin A production compared to healthy controls, both in standard culture and osteogenic transdifferentiation conditions. We discovered TGFβ1 to be an FOP-specific stimulant of Activin A, shown by the upregulation of the INHBA gene and protein expression. Activin A and TGFβ1 were both induced by BMP4 in FOP and control fibroblasts. Treatment with TNFα and IL6 produced negligible levels of Activin A and TGFβ1 in both cell groups. We present for the first time TGFβ1 as a triggering factor of Activin A production in FOP. As TGFβ1 can promote the induction of the main driver of FOP, TGFβ1 could also be considered a possible therapeutic target in FOP treatment.
Detection of Circulating Tumor Cell-Related Markers in Gynecologic Cancer Using Microfluidic Devices: A Pilot Study
Authors: Law Kim-Seng , Huang Chung-Er , Chen Sheng-Wen
Published: January 2023

The detection of circulating tumor cells (CTCs) is an emerging strategy for the early detection, prognostication, and identification of recurrent cancer. The clinical utility of CTC detection has been established, but few studies have employed this strategy for the detection of gynecologic cancers. Here, we present a novel, biochip-based microfluidic device for the detection of CTCs in gynecologic cancers. The study cohort included three patients with cervical cancer, eight with endometrial cancer, two with ovarian cancer, two with breast cancer, and one with vaginal small cell carcinoma. Four cancer type-specific molecular markers (PanCK, GATA3, HER2, and HE4), as well as CD13, were used for prognostication and recurrence detection, along with downstream genomic analysis. GATA3 and HER2 were markedly expressed in the patients with cervical cancer, and this expression was strongly correlated with the early detection of recurrent disease. All four molecular markers were expressed preoperatively in the patients with endometrial cancer, and the re-expression of different markers was observed at follow-up before recurrence was confirmed. CD13 was identified as an alternative prognostic marker for both cervical and endometrial cancer. Our pilot study indicated that the novel CTC detection system can be used for prognostication and early detection of disease recurrence, which needed further investigation.
Knockdown of Amyloid Precursor Protein Increases Ion Channel Expression and Alters Ca2+ Signaling Pathways
Authors: Paschou Maria , Liaropoulou Danai , Kalaitzaki Vasileia , Efthimiopoulos Spiros , Papazafiri Panagiota
Published: January 2023

Although the physiological role of the full-length Amyloid Precursor Protein (APP) and its proteolytic fragments remains unclear, they are definitively crucial for normal synaptic function. Herein, we report that the downregulation of APP in SH-SY5Y cells, using short hairpin RNA (shRNA), alters the expression pattern of several ion channels and signaling proteins that are involved in synaptic and Ca2+ signaling. Specifically, the levels of GluR2 and GluR4 subunits of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptors (AMPAR) were significantly increased with APP knockdown. Similarly, the expression of the majority of endoplasmic reticulum (ER) residing proteins, such as the ER Ca2+ channels IP3R (Inositol 1,4,5-triphosphate Receptor) and RyR (Ryanodine Receptor), the Ca2+ pump SERCA2 (Sarco/endoplasmic reticulum Ca2+ ATPase 2) and the ER Ca2+ sensor STIM1 (Stromal Interaction Molecule 1) was upregulated. A shift towards the upregulation of p-AKT, p-PP2A, and p-CaMKIV and the downregulation of p-GSK, p-ERK1/2, p-CaMKII, and p-CREB was observed, interconnecting Ca2+ signal transduction from the plasma membrane and ER to the nucleus. Interestingly, we detected reduced responses to several physiological stimuli, with the most prominent being the ineffectiveness of SH-SY5Y/APP- cells to mobilize Ca2+ from the ER upon carbachol-induced Ca2+ release through IP3Rs and RyRs. Our data further support an emerging yet perplexing role of APP within a functional molecular network of membrane and cytoplasmic proteins implicated in Ca2+ signaling.
The COPD-Associated Polymorphism Impairs the CFTR Function to Suppress Excessive IL-8 Production upon Environmental Pathogen Exposure
Authors: Hinata Daichi , Fukuda Ryosuke , Okiyoneda Tsukasa
Published: January 2023

COPD is a lifestyle-related disease resulting from irreversible damage to respiratory tissues mostly due to chronic exposure to environmental pollutants, including cigarette smoke. Environmental pathogens and pollutants induce the acquired dysfunction of the CFTR Cl− channel, which is invoked in COPD. Despite the increased incidence of CFTR polymorphism R75Q or M470V in COPD patients, the mechanism of how the CFTR variant affects COPD pathogenesis remains unclear. Here, we investigated the impact of CFTR polymorphisms (R75Q, M470V) on the CFTR function in airway epithelial cell models. While wild-type (WT) CFTR suppressed the proinflammatory cytokine production induced by COPD-related pathogens including pyocyanin (PYO), R75Q- or M470V-CFTR failed. Mechanistically, the R75Q- or M470V-CFTR fractional PM activity (FPMA) was significantly lower than WT-CFTR in the presence of PYO. Notably, the CF drug Trikafta corrected the PM expression of R75Q- or M470V-CFTR even upon PYO exposure and consequently suppressed the excessive IL-8 production. These results suggest that R75Q or M470V polymorphism impairs the CFTR function to suppress the excessive proinflammatory response to environmental pathogens associated with COPD. Moreover, Trikafta may be useful to prevent the COPD pathogenesis associated with acquired CFTR dysfunction.
Activating Transcription Factor 3 Diminishes Ischemic Cerebral Infarct and Behavioral Deficit by Downregulating Carboxyl-Terminal Modulator Protein
Authors: Kao Mei-Han , Huang Chien-Yu , Cheung Wai-Mui , Yan Yu-Ting , Chen Jin-Jer , Ho Yuan-Soon , Hsu Chung Y. , Lin Teng-Nan
Published: January 2023

Activating transcription factor 3 (ATF3) is a stress-induced transcription factor and a familiar neuronal marker for nerve injury. This factor has been shown to protect neurons from hypoxic insult in vitro by suppressing carboxyl-terminal modulator protein (CTMP) transcription, and indirectly activating the anti-apoptotic Akt/PKB cascade. Despite prior studies in vitro, whether this neuroprotective pathway also exists in the brain in vivo after ischemic insult remains to be determined. In the present study, we showed a rapid and marked induction of ATF3 mRNA throughout ischemia-reperfusion in a middle cerebral artery (MCA) occlusion model. Although the level of CTMP mRNA was quickly induced upon ischemia, its level showed only a mild increase after reperfusion. With the gain-of-function approach, both pre- and post-ischemic administration of Ad-ATF3 ameliorated brain infarct and neurological deficits. Whereas, with the loss-of-function approach, ATF3 knockout (KO) mice showed bigger infarct and worse functional outcome after ischemia. In addition, these congenital defects were rescued upon reintroducing ATF3 to the brain of KO mice. ATF3 overexpression led to a lower level of CTMP and a higher level of p-Akt(473) in the ischemic brain. On the contrary, ATF3 KO resulted in upregulation of CTMP and downregulation of p-Akt(473) instead. Furthermore, post-ischemic CTMP siRNA knockdown led to smaller infarct and better behaviors. CTMP siRNA knockdown increased the level of p-Akt(473), but did not alter the ATF3 level in the ischemic brain, upholding the ATF3→CTMP signal cascade. In summary, our proof-of-principle experiments support the existence of neuroprotective ATF3→CTMP signal cascade regulating the ischemic brain. Furthermore, these results suggest the therapeutic potential for both ATF3 overexpression and CTMP knockdown for stroke treatment.
Aqua/Mechanochemical Mediated Synthesis of Novel Spiro [Indole–Pyrrolidine] Derivatives
Authors: Salami Sodeeq Aderotimi , Smith Vincent J. , Krause Rui Werner Maçedo
Published: January 2023

Spirocyclic scaffolds are found in many pharmacologically active natural and synthetic compounds. From time to time, efforts have been made to develop new or better processes for the synthesis of spirocyclic compounds. Spiro [Indole–pyrrolidine] Derivatives are readily synthesized in high to excellent yields by the Michael condensation of 3-dicyanomethylene-2H-indol-2-ones (produced via the Knoevenagel condensation of indole-2,3-dione with malononitrile) with isothiocyanate derivatives under aqueous and mechanochemical conditions. The advantages of this protocol are that the reactions are solvent-free, occur at ambient temperature, require short reaction times, have experimental simplicity, and produce excellent yields. These environmentally friendly reaction media are useful alternatives to volatile organic solvents.
Mechanic Insight into the Distinct and Common Roles of Ovariectomy Versus Adrenalectomy on Adipose Tissue Remodeling in Female Mice
Authors: Chen Weihao , Meng Fengyan , Zeng Xianyin , Cao Xiaohan , Bu Guixian , Du Xiaogang , Yu Guozhi , Kong Fanli , Li Yunkun , Gan Tian , Han Xingfa
Published: January 2023

Dysfunctions of the ovaries and adrenal glands are both evidenced to cause aberrant adipose tissue (AT) remodeling and resultant metabolic disorders, but their distinct and common roles are poorly understood. In this study, through biochemical, histological and RNA-seq analyses, we comprehensively explored the mechanisms underpinning subcutaneous (SAT) and visceral adipose tissue (VAT) remodeling, in response to ovariectomy (OVX) versus adrenalectomy (ADX) in female mice. OVX promoted adipocyte differentiation and fat accumulation in both SAT and VAT, by potentiating the Pparg signaling, while ADX universally prevented the cell proliferation and extracellular matrix organization in both SAT and VAT, likely by inactivating the Nr3c1 signaling, thus causing lipoatrophy in females. ADX, but not OVX, exerted great effects on the intrinsic difference between SAT and VAT. Specifically, ADX reversed a large cluster of genes differentially expressed between SAT and VAT, by activating 12 key transcription factors, and thereby caused senescent cell accumulation, massive B cell infiltration and the development of selective inflammatory response in SAT. Commonly, both OVX and ADX enhance circadian rhythmicity in VAT, and impair cell proliferation, neurogenesis, tissue morphogenesis, as well as extracellular matrix organization in SAT, thus causing dysfunction of adipose tissues and concomitant metabolic disorders.
Cabozantinib, Vandetanib, Pralsetinib and Selpercatinib as Treatment for Progressed Medullary Thyroid Cancer with a Main Focus on Hypertension as Adverse Effect
Authors: Højer Wang Linnea , Wehland Markus , Wise Petra M. , Infanger Manfred , Grimm Daniela , Kreissl Michael C.
Published: January 2023

This manuscript investigates cabozantinib, vandetanib, pralsetinib, and selpercatinib, four tyrosine kinase inhibitors (TKIs), which are used to treat advanced and/or metastatic medullary thyroid cancer (MTC). Data on efficacy and safety are presented with the main focus on treatment-related hypertension, a well-known adverse effect (AE) of these TKIs. Taken together, TKI-induced hypertension is rarely a dose-limiting side effect. However, with increasing survival times of patients under treatment, hypertension-associated complications can be expected to be on the rise without proper medication.
Dietary Walnuts Preserve Aspects of Health Span and Alter the Hippocampal Lipidome in Aged High-Fat Diet-Fed Mice
Authors: Novaj Ardijana , Engel Matthew G. , Wang Ruixuan , Mao Kai , Xue Xiaonan , Amir Yam , Atzmon Gil , Huffman Derek M.
Published: January 2023

Evidence continues to accrue that aging and its diseases can be delayed by pharmacologic and dietary strategies that target the underlying hallmarks of the aging process. However, identifying simple, safe, and effective dietary strategies involving the incorporation of whole foods that may confer some protection against the aging process is also needed. Recent observational studies have suggested that nut consumption can reduce mortality risk in humans. Among these, walnuts are particularly intriguing, given their high content of n-3 fatty acids, fiber, and antioxidant and anti-inflammatory compounds. To this end, 12-month-old male CB6F1 mice were provided either a defined control low-fat diet (LFD), a control high-fat diet (HFD), or an isocaloric HFD containing 7.67% walnuts by weight (HFD + W), and measures of healthspan and related biochemical markers (n = 10–19 per group) as well as survival (n = 20 per group) were monitored. Mice provided the HFD or HFD + W demonstrated marked weight gain, but walnuts lowered baseline glucose (p < 0.05) and tended to temper the effects of HFD on liver weight gain (p < 0.05) and insulin tolerance (p = 0.1). Additional assays suggested a beneficial effect on some indicators of health with walnut supplementation, including preservation of exercise capacity and improved short-term working memory, as determined by Y maze (p = 0.02). However, no effect was observed via any diet on inflammatory markers, antioxidant capacity, or survival (p = 0.2). Ingenuity Pathway Analysis of the hippocampal transcriptome identified two processes predicted to be affected by walnuts and potentially linked to cognitive function, including estrogen signaling and lipid metabolism, with changes in the latter confirmed by lipidomic analysis. In summary, while walnuts did not significantly improve survival on a HFD, they tended to preserve features of healthspan in the context of a metabolic stressor with aging.
Immunohistochemistry of the Gut-Associated Lymphoid Tissue (GALT) in African Bonytongue (Heterotis niloticus, Cuvier 1829)
Authors: Lauriano Eugenia Rita , Alesci Alessio , Aragona Marialuisa , Pergolizzi Simona , Miller Anthea , Zuwala Kristina , Kuciel Michal , Zaccone Giacomo , Germanà Antonino , Guerrera Maria Cristina
Published: January 2023

Heterotis niloticus is a basal teleost, belonging to the Osteoglossidae family, which is widespread in many parts of Africa. The digestive tract of H. niloticus presents similar characteristics to those of higher vertebrates, exhibiting a gizzard-like stomach and lymphoid aggregates in the intestinal lamina propria. The adaptive immune system of teleost fish is linked with each of their mucosal body surfaces. In fish, the gut-associated lymphoid tissue (GALT) is generally a diffuse immune system that represents an important line of defense against those pathogens inhabiting the external environment that can enter through food. The GALT comprises intraepithelial lymphocytes, which reside in the epithelial layer, and lamina propria leukocytes, which consist of lymphocytes, macrophages, granulocytes, and dendritic-like cells. This study aims to characterize, for the first time, the leukocytes present in the GALT of H. niloticus, by confocal immuno- fluorescence techniques, using specific antibodies: toll-like receptor 2, major histocompatibility complex class II, S100 protein, serotonin, CD4, langerin, and inducible nitric oxide synthetase. Our results show massive aggregates of immune cells in the thickness of the submucosa, arranged in circumscribed oval-shaped structures that are morphologically similar to the isolated lymphoid follicles present in birds and mammals, thus expanding our knowledge about the intestinal immunity shown by this fish.
Synthesis of Antimicrobial Chitosan-Silver Nanoparticles Mediated by Reusable Chitosan Fungal Beads
Authors: Hermosilla Edward , Díaz Marcela , Vera Joelis , Contreras María José , Leal Karla , Salazar Rodrigo , Barrientos Leticia , Tortella Gonzalo , Rubilar Olga
Published: January 2023

Nanoparticles, especially silver nanoparticles (Ag NPs), have gained significant attention in recent years as potential alternatives to traditional antibiotics for treating infectious diseases due to their ability to inhibit the growth of microorganisms effectively. Ag NPs can be synthesized using fungi extract, but the method is not practical for large-scale production due to time and biomass limitations. In this study, we explore the use of chitosan to encapsulate the mycelia of the white-rot fungus Stereum hirsutum and form chitosan fungal beads for use in multiple extractions and nanoparticle synthesis. The resulting nanoparticles were characterized using various techniques, including UV-vis spectrophotometry, transmission electron microscopy, dynamic light scattering, and X-ray diffraction analysis. The analysis revealed that the synthesized nanoparticles were composed of chitosan-silver nanoparticles (CS-Ag NPs) with a size of 25 nm. The chitosan fungal beads were reused in three extractions and nanoparticle synthesis before they lost their ability to produce CS-Ag NPs. The CS-Ag NPs showed potent antimicrobial activity against phytopathogenic and human pathogenic microorganisms, including Pseudomonas syringae, Escherichia coli, Staphylococcus aureus, and Candida albicans, with minimum inhibitory concentrations of 1.5, 1.6, 3.1, and 4 µg/mL, respectively. The antimicrobial activity of CS-Ag NPs was from 2- to 40-fold higher than Ag NPs synthesized using an aqueous extract of unencapsulated fungal biomass. The CS-Ag NPs were most effective at a pH of five regarding the antimicrobial activity. These results suggest that the chitosan fungal beads may be a promising alternative for the sustainable and cost-effective synthesis of CS-Ag NPs with improved antimicrobial activity.
PCSK9 Inhibitors Have Apolipoprotein C-III-Related Anti-Inflammatory Activity, Assessed by 1H-NMR Glycoprotein Profile in Subjects at High or very High Cardiovascular Risk
Authors: Rehues Pere , Girona Josefa , Guardiola Montse , Plana Núria , Scicali Roberto , Piro Salvatore , Muñiz-Grijalvo Ovidio , Díaz-Díaz José Luis , Recasens Lluís , Pinyol Marta , Rosales Roser , Esteban Yaiza , Amigó Núria , Masana Lluís , Ibarretxe Daiana , Ribalta Josep
Published: January 2023

Atherosclerosis is a chronic inflammatory disease caused by the accumulation of cholesterol in the intima. Proprotein convertase subtilisin/kexin type 9 inhibitors (iPCSK9) can reduce low-density lipoprotein (LDL) cholesterol levels by 60%, but there is still no evidence that they can lower markers of systemic inflammation such as high-sensitivity C-reactive protein (hsCRP). Acute-phase serum glycoproteins are upregulated in the liver during systemic inflammation, and their role as inflammatory biomarkers is under clinical evaluation. In this observational study, we evaluate the effects of iPCSK9 on glycoproteins (Glyc) A, B and F. Thirty-nine patients eligible for iPCSK9 therapy were enrolled. One sample before and after one to six months of iPCSK9 therapy with alirocumab was obtained from each patient. Lipids, apolipoproteins, hsCRP and PCSK9 levels were measured by biochemical analyses, and the lipoprotein and glycoprotein profiles were measured by 1H nuclear magnetic resonance (1H-NMR). The PCSK9 inhibitor reduced total (36.27%, p < 0.001), LDL (55.05%, p < 0.001) and non-high-density lipoprotein (HDL) (45.11%, p < 0.001) cholesterol, apolipoprotein (apo) C-III (10%, p < 0.001), triglycerides (9.92%, p < 0.001) and glycoprotein signals GlycA (11.97%, p < 0.001), GlycB (3.83%, p = 0.017) and GlycF (7.26%, p < 0.001). It also increased apoA-I (2.05%, p = 0.043) and HDL cholesterol levels (11.58%, p < 0.001). Circulating PCSK9 levels increased six-fold (626.28%, p < 0.001). The decrease in Glyc signals positively correlated with the decrease in triglycerides and apoC-III. In conclusion, in addition to LDL cholesterol, iPCSK9 therapy also induces a reduction in systemic inflammation measured by 1H-NMR glycoprotein signals, which correlates with a decrease in triglycerides and apoC-III.
Reovirus Type 3 Dearing Variants Do Not Induce Necroptosis in RIPK3-Expressing Human Tumor Cell Lines
Authors: van den Wollenberg Diana J. M. , Kemp Vera , Rabelink Martijn J. W. E. , Hoeben Rob C.
Published: January 2023

Reoviruses are used as oncolytic viruses to destroy tumor cells. The concomitant induction of anti-tumor immune responses enhances the efficacy of therapy in tumors with low amounts of immune infiltrates before treatment. The reoviruses should provoke immunogenic cell death (ICD) to stimulate a tumor cell-directed immune response. Necroptosis is considered a major form of ICD, and involves receptor-interacting protein kinase 1 (RIPK1), RIPK3 and phosphorylation of mixed-lineage kinase domain-like protein (MLKL). This leads to cell membrane disintegration and the release of damage-associated molecular patterns that can activate immune responses. Reovirus Type 3 Dearing (T3D) can induce necroptosis in mouse L929 fibroblast cells and mouse embryonic fibroblasts. Most human tumor cell lines have a defect in RIPK3 expression and consequently fail to induce necroptosis as measured by MLKL phosphorylation. We used the human colorectal adenocarcinoma HT29 cell line as a model to study necroptosis in human cells since this cell line has frequently been described in necroptosis-related studies. To stimulate MLKL phosphorylation and induce necroptosis, HT29 cells were treated with a cocktail consisting of TNFα, the SMAC mimetic BV6, and the caspase inhibitor Z-VAD-FMK. While this treatment induced necroptosis, three different reovirus T3D variants, i.e., the plasmid-based reverse genetics generated virus (T3DK), the wild-type reovirus T3D isolate R124, and the junction adhesion molecule-A-independent reovirus mutant (jin-1) failed to induce necroptosis in HT29 cells. In contrast, these viruses induced MLKL phosphorylation in murine L929 cells, albeit with varying efficiencies. Our study shows that while reoviruses efficiently induce necroptosis in L929 cells, this is not a common phenotype in human cell lines. This study emphasizes the difficulties of translating the results of ICD studies from murine cells to human cells.
The Contribution of the Zebrafish Model to the Understanding of Polycomb Repression in Vertebrates
Authors: Hanot Mariette , Raby Ludivine , Völkel Pamela , Le Bourhis Xuefen , Angrand Pierre-Olivier
Published: January 2023

Polycomb group (PcG) proteins are highly conserved proteins assembled into two major types of complexes, PRC1 and PRC2, involved in the epigenetic silencing of a wide range of gene expression programs regulating cell fate and tissue development. The crucial role of PRC1 and PRC2 in the fundamental cellular processes and their involvement in human pathologies such as cancer attracted intense attention over the last few decades. Here, we review recent advancements regarding PRC1 and PRC2 function using the zebrafish model. We point out that the unique characteristics of the zebrafish model provide an exceptional opportunity to increase our knowledge of the role of the PRC1 and PRC2 complexes in tissue development, in the maintenance of organ integrity and in pathology.