bluuebunny/crossref_metadata_2025 huggingface dataset:
Kompetensi Aparatur Sipil Negara Badan Penelitian dan Pengembangan Daerah dalam pengisian indeks inovasi daerah kabupaten Banggai provinsi Sulawesi Tengah
Authors: Kartika Ray Septianis
Published: February 2021

Balitbangda sebagai salah satu OPD di Kabupaten Banggai, memiliki sumber daya manusia yang handal terutama kompetensinya. Terbukti mereka dalam rangka pengisian indeks inovasi daerah mampu menghimpun data inovasi daerah sebanyak 20 inovasi daerah dengan terpenuhinya 35 indikator yang dibutuhkan dalam indeks. Kajian ini bertujuan untuk melihat kompetensi SDM balitbangda dalam pengisian indeks inovasi daerah serta hambatan yang dihadapinya. Metode kajian dengan deskriptif kualitatif, teknik wawancara dan penelusuran studi pustaka.Teknik analisanya menggunakan triangulasi data dengan hasil kajian sebagai berikut Pertama kompetensi SDM Balitbangda Kabupaten Banggai mencakup kompetensi task achievement, kompetensi relationship, kompetensi personal atribute, kompetensi managerial, dan kompetensi leadership. Kendala yang dihadapinya adalah terbatasnya penyediaan infrastruktur seperti komputer dan jaringan internet, tidak adanya dukungan anggaran, dan keterbatasan penyediaan data yang ada di OPD-OPD selaku pelaksana inovasi daerah. Saran yang dapat TIM sampaikan adalah Pertama, memperkuat data inovasi daerah Kabupaten Banggai agar update dan lebih sistematis. Kedua, Balitbangda dalam mempersiapkan pengisian indeks di tahun mendatang, perlu mengagendakan sistem penganggaran yang efektif dan efisien dalam mengakomodir kebutuhan pengisian indeks. Ketiga, Balitbangda Kabupaten Banggai dapat mewujudkan sistem indeks inovasi daerah ke dalam aplikasi yang lebih cepat dan tepat sekaligus pemanfaatannya dapat menjadi data base inovasi daerah yang dimiliki Kabupaten Banggai. Dengan demikian indeks inovasi daerah Kabupaten Banggai di tahun mendatang akan dapat lebih bersaing dengan daerah lainnya, karena secara sistem telah terkoordinasi dengan baik baik dalam hal penyediaan data maupun kualitas inovasinya.
Upaya penurunan jumlah kematian ibu dan bayi melalui peran stakeholder
Authors: Sitorus Jonni
Published: February 2021

The number of maternal deaths in North Sumatra in 2017 was recorded in Labuhanbatu Regency and Deli Serdang Regency as many as 15 deaths, Langkat Regency with 13 deaths, and Batubara Regency with 11 deaths. Efforts to accelerate the reduction of Maternal Mortality Rate (MMR) and Infant Mortality Rate (IMR) are carried out to ensure that every mother is able to access quality maternal health services, such as maternal health services, delivery assistance by trained health personnel in health care facilities, postpartum care for mothers and babies, special care and referrals if complications occur, the ease of obtaining maternity and childbirth leave and family planning services. Efforts to reduce MMR and IMR are not only the responsibility of one sector, but need the involvement and roles of other stakeholders to accelerate the reduction of MMR/IMR. This study aims to provide recommendations for the reduction of MMR/IMR through the role of stakeholders in North Sumatra. The study used a qualitative method with a phenomenological approach which was conducted from May to September 2019. The research locations were: Mandailing Natal Regency, Deli Serdang Regency, Simalungun Regency, and Sibolga City. The research subjects consisted of 3 (three) elements, namely: Government, Private and Community. Data collection was carried out through observation and through Focus Group Discussion (FGD). This study concludes that the model of efforts to reduce maternal and infant mortality rates must be carried out in a holistic and integrative manner with medical, social, and cultural approaches, starting from health services for adolescent girls, women of productive age, pregnant women, maternity, newborns and toddlers. Efforts to reduce MMR and IMR are the responsibility of all DPOs and elements of academia, business and community, whose programs and activities are integrated. Efforts to reduce MMR and IMR must be viewed from various perspectives, including from a medical, social and cultural perspective.
What Do We Mean by Smart Contracts? Open Challenges in Smart Contracts
Authors: Vigliotti Maria G.
Published: February 2021

Contracts regulate most of our professional and personal life: they enable modern society to operate. The term “Smart Contract,” coined in 1994 by Nick Szabo, means different things to different people. This editorial perspective explores the meanings of the term “smart contract” and the challenges about the legality of “smart contracts.” We are familiar with contracts written in natural language, yet our relationships with smart contracts is yet to be defined. The advent of blockchain technology seems to have accelerated the development and the opportunities for the adoption of smart contracts. The purpose of this editorial is to create an interdisciplinary section where computer scientists and members of the legal profession participate in a constructive debate around smart contracts to positively influence future development.
Improved Bio-Synthesis of 2,5-bis(hydroxymethyl)furan by Burkholderia contaminans NJPI-15 With Co-substrate
Authors: Chang Siyuan , He Xuejun , Li Bingfeng , Pan Xin
Published: February 2021

Upgrading of biomass derived 5-hydroxymethylfurfural (HMF) has attracted considerable interest recently. A new highly HMF-tolerant strain of Burkholderia contaminans NJPI-15 was isolated in this study, and the biocatalytic reduction of HMF into 2,5-bis(hydroxymethyl)furan (BHMF) using whole cells was reported. Co-substrate was applied to improve the BHMF yield and selectivity of this strain as well as HMF-tolerant level. The catalytic capacity of the cells can be substantially improved by Mn2+ ion. The strain exhibited good catalytic performance at a pH range of 6.0–9.0 and a temperature range of 25°C–35°C. In addition, 100 mM HMF could be reduced to BHMF by the B. contaminans NJPI-15 resting cells in presence of 70 mM glutamine and 30 mM sucrose, with a yield of 95%. In the fed-batch strategy, 656 mM BHMF was obtained within 48 h, giving a yield of 93.7%. The reported utilization of HMF to produce BHMF is a promising industrially sound biocatalytic process.
Development and Validation of a Prediction Rule for Growth Hormone Deficiency Without Need for Pharmacological Stimulation Tests in Children With Risk Factors
Authors: Clément Florencia , Grinspon Romina P. , Yankelevich Daniel , Martín Benítez Sabrina , De La Ossa Salgado María Carolina , Ropelato María Gabriela , Ballerini María Gabriela , Keselman Ana C. , Braslavsky Débora , Pennisi Patricia , Bergadá Ignacio , Finkielstain Gabriela P. , Rey Rodolfo A.
Published: February 2021

Introduction

Practice guidelines cannot recommend establishing a diagnosis of growth hormone deficiency (GHD) without performing growth hormone stimulation tests (GHST) in children with risk factors, due to the lack of sufficient evidence.

Objective

Our goal was to generate an evidence-based prediction rule to diagnose GHD in children with growth failure and clinically identifiable risk factors.

Methods

We studied a cohort of children with growth failure to build the prediction model, and a second, independent cohort to validate the prediction rule. To this end, we assessed the existence of: pituitary dysgenesis, midline abnormalities, (supra)sellar tumor/surgery, CNS infection, traumatic brain injury, cranial radiotherapy, chemotherapy, genetic GHD, pituitary hormone deficiencies, and neonatal hypoglycemia, cholestasis, or hypogenitalism. Selection of variables for model building was performed using artificial intelligence protocols. Specificity of the prediction rule was the main outcome measure in the validation set.

Results

In the first cohort (n=770), the resulting prediction rule stated that a patient would have GHD if (s)he had: pituitary dysgenesis, or two or more anterior pituitary deficiencies, or one anterior pituitary deficiency plus: neonatal hypoglycemia or hypogenitalism, or diabetes insipidus, or midline abnormalities, or (supra)sellar tumor/surgery, or cranial radiotherapy ≥18 Gy. In the validation cohort (n=161), the specificity of the prediction rule was 99.2% (95% CI: 95.6–100%).

Conclusions

This clinical rule predicts the existence of GHD with high specificity in children with growth disorders and clinically identifiable risk factors, thus providing compelling evidence to recommend that GHD can be safely diagnosed without recurring to GHST in neonates and children with growth failure and specific comorbidities.
Identification of Regulatory circRNAs Involved in the Pathogenesis of Acute Myocardial Infarction
Authors: Zhao Cuimei , Liu Jingjing , Ge Wen , Li Zhi , Lv Mengwei , Feng Yipeng , Liu Xuebo , Liu Ban , Zhang Yangyang
Published: February 2021

Background

Acute myocardial infarction (AMI) has high morbidity and mortality worldwide. However, the pathogenesis of AMI is still unclear, and the impact of circular RNAs (circRNAs) on AMI has rarely been recognized and needs to be explored.

Materials and Methods

The circRNA array was applied to investigate the expression level of circRNAs in the blood samples of coronary arteries of three AMI patients and three normal persons. Principal component analysis (PCA) and unsupervised clustering analysis were performed to reveal the distinguished expression patterns of circRNAs. The miRNA expression profiles of AMI patients were identified from a public dataset from the Gene Expression Omnibus (GEO) database (GSE31568). The miRNA binding sites on the circRNAs were predicted by miRanda. The miRNA enrichment analysis and annotation tool were used to explore the pathways that the dysregulated circRNAs may participate in.

Results

In total, 142 differentially expressed circRNAs, including 89 upregulated and 53 downregulated in AMI samples, were identified by the differential expression analysis. AMI patients had quite different circRNA expression profiles to those of normal controls. Functional characterization revealed that circRNAs that had the potential to regulate miRNAs were mainly involved in seven pathways, such as the Runt-related transcription factor-1 (RUNX1) expression and activity-related pathway. Specifically, hsa_circRNA_001654, hsa_circRNA_091761, hsa_circRNA_405624, and hsa_circRNA_406698 were predicted to sponge four miRNAs including hsa-miR-491-3p, hsa-miR-646, hsa-miR-603, and hsa-miR-922, thereby regulating RUNX1 expression or activity.

Conclusion

We identified dysregulated blood circRNAs in the coronary arteries of AMI patients and predicted that four upregulated circRNAs were involved in the regulation of RUNX1 expression or activity through sponging four miRNAs.
Alteration of mRNA 5-Methylcytosine Modification in Neurons After OGD/R and Potential Roles in Cell Stress Response and Apoptosis
Authors: Jian Huan , Zhang Chi , Qi ZhangYang , Li Xueying , Lou Yongfu , Kang Yi , Deng Weimin , Lv Yigang , Wang Chaoyu , Wang Wei , Shang Shenghui , Hou Mengfan , Zhou Hengxing , Feng Shiqing
Published: February 2021

Epigenetic modifications play an important role in central nervous system disorders. As a widespread posttranscriptional RNA modification, the role of the m5C modification in cerebral ischemia-reperfusion injury (IRI) remains poorly defined. Here, we successfully constructed a neuronal oxygen-glucose deprivation/reoxygenation (OGD/R) model and obtained an overview of the transcriptome-wide m5C profiles using RNA-BS-seq. We discovered that the distribution of neuronal m5C modifications was highly conserved, significantly enriched in CG-rich regions and concentrated in the mRNA translation initiation regions. After OGD/R, modification level of m5C increased, whereas the number of methylated mRNA genes decreased. The amount of overlap of m5C sites with the binding sites of most RNA-binding proteins increased significantly, except for that of the RBM3-binding protein. Moreover, hypermethylated genes in neurons were significantly enriched in pathological processes, and the hub hypermethylated genes RPL8 and RPS9 identified by the protein-protein interaction network were significantly related to cerebral injury. Furthermore, the upregulated transcripts with hypermethylated modification were enriched in the processes involved in response to stress and regulation of apoptosis, and these processes were not identified in hypomethylated transcripts. In final, we verified that OGD/R induced neuronal apoptosis in vitro using TUNEL and western blot assays. Our study identified novel m5C mRNAs associated with ischemia-reperfusion in neurons, providing valuable perspectives for future studies on the role of the RNA methylation in cerebral IRI.
Regulatory T Cells Developing Peri-Weaning Are Continually Required to Restrain Th2 Systemic Responses Later in Life
Authors: Knoop Kathryn A. , McDonald Keely G. , Hsieh Chyi-Song , Tarr Phillip I. , Newberry Rodney D.
Published: February 2021

Atopic disorders including allergic rhinitis, asthma, food allergy, and dermatitis, are increasingly prevalent in Western societies. These disorders are largely characterized by T helper type 2 (Th2) immune responses to environmental triggers, particularly inhaled and dietary allergens. Exposure to such stimuli during early childhood reduces the frequency of allergies in at-risk children. These allergic responses can be restrained by regulatory T cells (Tregs), particularly Tregs arising in the gut. The unique attributes of how early life exposure to diet and microbes shape the intestinal Treg population is a topic of significant interest. While imprinting during early life promotes the development of a balanced immune system and protects against immunopathology, it remains unclear if Tregs that develop in early life continue to restrain systemic inflammatory responses throughout adulthood. Here, an inducible deletion strategy was used to label Tregs at specified time points with a targeted mechanism to be deleted later. Deletion of the Tregs labeled peri-weaning at day of life 24, but not before weaning at day of life 14, resulted in increased circulating IgE and IL-13, and abrogated induction of tolerance towards new antigens. Thus, Tregs developing peri-weaning, but not before day of life 14 are continually required to restrain allergic responses into adulthood.
In Situ Characterization of Follicular Helper CD4 T Cells Using Multiplexed Imaging
Authors: Ioannidou Kalliopi , Ndiaye Daba-Rokhya , Noto Alessandra , Fenwick Craig , Fortis Sotirios P. , Pantaleo Giuseppe , Petrovas Constantinos , de Leval Laurence
Published: February 2021

Follicular helper CD4 T (Tfh) cells play an essential role in the formation of germinal centers (GCs), where mature B cells proliferate, differentiate, and provide long-term protective humoral responses. Despite the extensive phenotypic characterization and identification of human Tfh cell subsets, their spatial positioning at tissue level is not well understood. Here, we describe a quantitative multiplexed immunofluorescence approach allowing for the comprehensive in situ characterization of Tfh cells in human tonsils and lymph nodes (LNs) from individuals with angioimmunoblastic T-cell lymphoma (AITL). We have developed eight multiplexed panels comprising a spectrum of Tfh cell markers, like PD-1, CXCR5, and ICOS, along with transcription factors (Bcl6, Tbet, GATA3), to assess their expression, frequencies, spatial distribution and co-localization in a quantitative manner. Combined analysis of relevant markers revealed the presence of several Tfh cell subsets at tissue level based on the differential expression of surface receptors, nuclear factors as well as their distinct localization within the follicular areas. Interestingly, we found a considerable amount of tonsillar Tfh cells expressing high levels of the Th2 regulator GATA3. The co-expression of GATA3, CXCR5, and BCL6, points to an important role of GATA3 for the generation of effector human Tfh cells. Furthermore, our data revealed significantly different Tfh cell profile signatures between health and disease. Therefore, our imaging platform generates meaningful information for the in situ characterization of human Tfh cells and could provide the base for future studies aiming to a comprehensive understanding of Tfh cell tissue heterogeneity.
Parallels in Sepsis and COVID-19 Conditions: Implications for Managing Severe COVID-19
Authors: Olwal Charles Ochieng’ , Nganyewo Nora Nghuchuzie , Tapela Kesego , Djomkam Zune Alexandra Lindsey , Owoicho Oloche , Bediako Yaw , Duodu Samuel
Published: February 2021

Sepsis is a life-threatening systemic illness attributed to a dysregulated host response to infection. Sepsis is a global burden killing ~11 million persons annually. In December 2019, a novel pneumonia condition termed coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged and has resulted in more than 1,535,982 deaths globally as of 8th December 2020. These two conditions share many pathophysiological and clinical features. Notably, both sepsis and COVID-19 patients experience consumptive thrombocytopenia, haemolytic anaemia, vascular microthrombosis, multi-organ dysfunction syndrome, coagulopathy, septic shock, respiratory failure, fever, leukopenia, hypotension, leukocytosis, high cytokine production and high predisposition to opportunistic infections. Considering the parallels in the immunopathogenesis and pathophysiological manifestations of sepsis and COVID-19, it is highly likely that sepsis care, which has a well-established history in most health systems, could inform on COVID-19 management. In view of this, the present perspective compares the immunopathogenesis and pathophysiology of COVID-19 and non-SARS-CoV-2 induced sepsis, and lessons from sepsis that can be applicable to COVID-19 management.
Plasmid-Borne and Chromosomal ESBL/AmpC Genes in Escherichia coli and Klebsiella pneumoniae in Global Food Products
Authors: Kurittu Paula , Khakipoor Banafsheh , Aarnio Maria , Nykäsenoja Suvi , Brouwer Michael , Myllyniemi Anna-Liisa , Vatunen Elina , Heikinheimo Annamari
Published: February 2021

Plasmid-mediated extended-spectrum beta-lactamase (ESBL), AmpC, and carbapenemase producing Enterobacteriaceae, in particular Escherichia coli and Klebsiella pneumoniae, with potential zoonotic transmission routes, are one of the greatest threats to global health. The aim of this study was to investigate global food products as potential vehicles for ESBL/AmpC-producing bacteria and identify plasmids harboring resistance genes. We sampled 200 food products purchased from Finland capital region during fall 2018. Products originated from 35 countries from six continents and represented four food categories: vegetables (n = 60), fruits and berries (n = 50), meat (n = 60), and seafood (n = 30). Additionally, subsamples (n = 40) were taken from broiler meat. Samples were screened for ESBL/AmpC-producing Enterobacteriaceae and whole genome sequenced to identify resistance and virulence genes and sequence types (STs). To accurately identify plasmids harboring resistance and virulence genes, a hybrid sequence analysis combining long- and short-read sequencing was employed. Sequences were compared to previously published plasmids to identify potential epidemic plasmid types. Altogether, 14 out of 200 samples were positive for ESBL/AmpC-producing E. coli and/or K. pneumoniae. Positive samples were recovered from meat (18%; 11/60) and vegetables (5%; 3/60) but were not found from seafood or fruit. ESBL/AmpC-producing E. coli and/or K. pneumoniae was found in 90% (36/40) of broiler meat subsamples. Whole genome sequencing of selected isolates (n = 21) revealed a wide collection of STs, plasmid replicons, and genes conferring multidrug resistance. blaCTX–M–15-producing K. pneumoniae ST307 was identified in vegetable (n = 1) and meat (n = 1) samples. Successful IncFII plasmid type was recovered from vegetable and both IncFII and IncI1-Iγ types from meat samples. Hybrid sequence analysis also revealed chromosomally located beta-lactamase genes in two of the isolates and indicated similarity of food-derived plasmids to other livestock-associated sources and also to plasmids obtained from human clinical samples from various countries, such as IncI type plasmid harboring blaTEM–52C from a human urine sample obtained in the Netherlands which was highly similar to a plasmid obtained from broiler meat in this study. Results indicate certain foods contain bacteria with multidrug resistance and pose a possible risk to public health, emphasizing the importance of surveillance and the need for further studies on epidemiology of epidemic plasmids.
A Risk Prediction Model for Breast Cancer Based on Immune Genes Related to Early Growth Response Proteins Family
Authors: Zhou Xin , Zhang Fang-yuan , Liu Yan , Wei Dong-xin
Published: February 2021

Early growth response proteins (EGRs), a transcriptional regulatory family comprised of EGR1, EGR2, EGR3, and EGR 4, are reportedly involved in a vast array of functions. However, EGRs, as a whole, are rarely studied in breast cancer cases. This research was performed based on public datasets. The results demonstrated that, except EGR4, the other EGRs were differentially expressed genes in breast cancer. Subsequently, this study determined the prognosis significance of the EGR family, higher expression levels of EGRs indicating better overall survival (OS) and disease-free survival (DFS), except EGR4. So we attempted to explore the potential mechanism behind the prognostic value of EGRs. At the DNA level, however, neither DNA methylation status nor genetic alterations of EGRs contributed to the prognosis significance. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that EGRs were involved in several immune-related functions. Afterward, we assessed the correlation between EGRs and the immune system before establishing a risk prediction model with a 14-gene immune signature associated with EGRs, a prognostic nomogram predicting individuals’ 1-, 3-, and 5-year survival probabilities. The risk score was an independent prognosis predictor in the breast cancer cohorts. This study evidenced EGRs’ significance for tumor immunity, demonstrating that the EGR family may be a potential immunotherapeutic target for breast cancer. The 14-gene immune signature is a promising prognostic biomarker in breast cancer.
Irisin Contributes to Neuroprotection by Promoting Mitochondrial Biogenesis After Experimental Subarachnoid Hemorrhage
Authors: Tu Tianqi , Yin Shigang , Pang Jinwei , Zhang Xianhui , Zhang Lifang , Zhang Yuxuan , Xie Yuke , Guo Kecheng , Chen Ligang , Peng Jianhua , Jiang Yong
Published: February 2021

Subarachnoid hemorrhage (SAH) is a devastating form of stroke, which poses a series of intractable challenges to clinical practice. Imbalance of mitochondrial homeostasis has been thought to be the crucial pathomechanism in early brain injury (EBI) cascade after SAH. Irisin, a protein related to metabolism and mitochondrial homeostasis, has been reported to play pivotal roles in post-stroke neuroprotection. However, whether this myokine can exert neuroprotection effects after SAH remains unknown. In the present study, we explored the protective effects of irisin and the underlying mechanisms related to mitochondrial biogenesis in a SAH animal model. Endovascular perforation was used to induce SAH, and recombinant irisin was administered intracerebroventricularly. Neurobehavioral assessments, TdT-UTP nick end labeling (TUNEL) staining, dihydroethidium (DHE) staining, immunofluorescence, western blot, and transmission electron microscopy (TEM) were performed for post-SAH assessments. We demonstrated that irisin treatment improved neurobehavioral scores, reduced neuronal apoptosis, and alleviated oxidative stress in EBI after SAH. More importantly, the administration of exogenous irisin conserved the mitochondrial morphology and promoted mitochondrial biogenesis. The protective effects of irisin were partially reversed by the mitochondrial uncoupling protein-2 (UCP-2) inhibitor. Taken together, irisin may have neuroprotective effects against SAH via improving the mitochondrial biogenesis, at least in part, through UCP-2 related targets.
Administration of N-acetylcysteine Plus Acetylsalicylic Acid Markedly Inhibits Nicotine Reinstatement Following Chronic Oral Nicotine Intake in Female Rats
Authors: Quintanilla María Elena , Morales Paola , Ezquer Fernando , Ezquer Marcelo , Herrera-Marschitz Mario , Israel Yedy
Published: February 2021

Background

Nicotine is the major addictive component of cigarette smoke and the prime culprit of the failure to quit smoking. Common elements perpetuating the use of addictive drugs are (i) cues associated with the setting in which drug was used and (ii) relapse/reinstatement mediated by an increased glutamatergic tone (iii) associated with drug-induced neuroinflammation and oxidative stress.

Aims

The present study assessed the effect of the coadministration of the antioxidant N-acetylcysteine (NAC) plus the anti-inflammatory acetylsalicylic acid (ASA) on oral nicotine reinstatement intake following a post-deprivation re-access in female rats that had chronically and voluntarily consumed a nicotine solution orally. The nicotine-induced oxidative stress and neuroinflammation in the hippocampus and its effects on the glutamate transporters GLT-1 and XCT mRNA levels in prefrontal cortex were also analyzed.

Results

The oral coadministration of NAC (40 mg/kg/day) and ASA (15 mg/kg/day) inhibited by 85% of the oral nicotine reinstatement intake compared to control (vehicle), showing an additive effect of both drugs. Acetylsalicylic acid and N-acetylcysteine normalized hippocampal oxidative stress and blunted the hippocampal neuroinflammation observed upon oral nicotine reinstatement. Nicotine downregulated GLT-1 and xCT gene expression in the prefrontal cortex, an effect reversed by N-acetylcysteine, while acetylsalicylic acid reversed the nicotine-induced downregulation of GLT-1 gene expression. The inhibitory effect of N-acetylcysteine on chronic nicotine intake was blocked by the administration of sulfasalazine, an inhibitor of the xCT transporter.

Conclusion

Nicotine reinstatement, following post-deprivation of chronic oral nicotine intake, downregulates the mRNA levels of GLT-1 and xCT transporters, an effect reversed by the coadministration of N-acetylcysteine and acetylsalicylic acid, leading to a marked inhibition of nicotine intake. The combination of these drugs may constitute a valuable adjunct in the treatment of nicotine-dependent behaviors.
Characteristics of Patients Returning to Work After Brain Tumor Surgery
Authors: Schiavolin Silvia , Mariniello Arianna , Broggi Morgan , Acerbi Francesco , Schiariti Marco , Franzini Angelo , Di Meco Francesco , Ferroli Paolo , Leonardi Matilde
Published: February 2021

Objective: To investigate the differences between patients returning to work and those who did not after brain tumor surgery.

Methods: Patients were evaluated before surgery and after 3 months. The Montreal Cognitive Assessment test, Trail-Making Test (parts A and B), 15-word Rey–Osterrieth Word List (immediate and delayed recall), F-A-S tests, and Karnosfky Performance Status were used to assess cognitive status, attention, executive functions, memory, word fluency, and functional status. Patient-reported outcome measures (PROMs) used to evaluate emotional distress and disability were the Hospital Anxiety and Depression Scale and World Health Organization Disability Assessment Schedule. Clinical and work-related variables, PROMs, and cognitive tests were compared using chi-squared, t-test or Mann–Whitney U test.

Results: Sixty patients were included. Patients returning to work were 61.3 and 31.0% among people with meningioma and glioma, respectively. They reported lower postoperative disability and lesser home-to-work travel time. Patients with meningioma also showed better preoperative and postoperative attention and executive functions, better postoperative functional and cognitive status, and lower frequency of treatments.

Conclusions: These variables should be considered in a clinical context to plan interventions for people who need support during return to work and in future research to investigate preoperative and postoperative predictive factors of going back to work.
Endocannabinoid Signaling for GABAergic-Microglia (Mis)Communication in the Brain Aging
Authors: Carrera Jorge , Tomberlin Jensen , Kurtz John , Karakaya Eda , Bostanciklioglu Mehmet , Albayram Onder
Published: February 2021

The aging brain seems to be characterized by neuronal loss leading to cognitive decline and progressively worsening symptoms related to neurodegeneration. Also, pro-inflammatory states, if prolonged, may increase neuronal vulnerability via excessive activation of microglia and their pro-inflammatory by-products, which is seen as individuals increase in age. Consequently, microglial activity is tightly regulated by neuron-microglia communications. The endocannabinoid system (ECS) is emerging as a regulator of microglia and the neuronal-microglia communication system. Recently, it has been demonstrated that cannabinoid 1 (CB1) receptor signaling on GABAergic interneurons plays a crucial role in regulating microglial activity. Interestingly, if endocannabinoid signaling on GABAergic neurons are disturbed, the phenotypes mimic central nervous system insult models by activating microglia and leading to accelerated brain aging. Investigating the endocannabinoid receptors, ligands, and genetic deletions yields the potential to understand the communication system and mechanism by which the ECS regulates glial cells and aspects of aging. While there remains much to discover with the ECS, the information gathered and identified already could lead to the development of cell-specific therapeutic interventions that help in reducing the effects of age-related pro-inflammatory states and neurodegeneration.
The Protective Effects of Perceived Control During Repeated Exposure to Aversive Stimuli
Authors: Wang Kainan S. , Delgado Mauricio R.
Published: February 2021

The ability to perceive and exercise control is a major contributor to our mental and physical wellbeing. When faced with uncontrollable aversive stimuli, organisms develop heightened anxiety and become unwilling to exert effort to avoid the stimuli. In contrast, when faced with controllable aversive stimuli, organisms demonstrate behavioral vigor via avoidance attempts toward trying to seek and exercise control over the environment. As such, controllability confers protective effects against reduced avoidance motivation trigged by aversive environments. These observations beg the question of whether controllability can be potent enough to reverse passivity following repeated exposure to uncontrollable aversive stimuli and how this protective effect is encoded neurally. Human participants performed a Control in Aversive Domain (CAD) task where they were first subjected to a series of repeated uncontrollable aversive stimuli (i.e., aversive tones) across several contexts that were followed by a series of controllable aversive stimuli in a novel context. Faced with persistent uncontrollability, participants significantly reduced their avoidance attempts over time and biased toward giving up. However, the subsequent presence of controllability rescued participants’ avoidance behavior. Strikingly, participants who responded more strongly to the protective effects of control also had greater ventromedial prefrontal cortical (vmPFC) activation—a region previously observed to be associated with encoding the subjective value of control. Taken together, these findings highlighted the protective effect conferred by perceived control against passivity and offered insights into the potential role of the vmPFC in controllable environments, with implications for understanding the beneficial influence of perceived control on adaptive behavior.
Rapid and Reversible Development of Axonal Varicosities: A New Form of Neural Plasticity
Authors: Gu Chen
Published: February 2021

Axonal varicosities are enlarged, heterogeneous structures along axonal shafts, profoundly affecting axonal conduction and synaptic transmission. They represent a key pathological feature believed to develop via slow accumulation of axonal damage that occurs during irreversible degeneration, for example in mild traumatic brain injury (mTBI), Alzheimer's and Parkinson's diseases, and multiple sclerosis. Here this review first discusses recentin vitroresults showing that axonal varicosities can be rapidly and reversibly induced by mechanical stress in cultured primary neurons from the central nervous system (CNS). This notion is further supported byin vivostudies revealing the induction of axonal varicosities across various brain regions in different mTBI mouse models, as a prominent feature of axonal pathology. Limited progress in understanding intrinsic and extrinsic regulatory mechanisms of axonal varicosity induction and development is further highlighted. Rapid and reversible formation of axonal varicosities likely plays a key role in CNS neuron mechanosensation and is a new form of neural plasticity. Future investigation in this emerging research field may reveal how to reverse axonal injury, contributing to the development of new strategies for treating brain injuries and related neurodegenerative diseases.
The Role of Autophagy in Inflammatory Bowel Disease
Authors: Shao Bo-Zong , Yao Yi , Zhai Jun-Shan , Zhu Jian-Hua , Li Jin-Ping , Wu Kai
Published: February 2021

Inflammatory bowel disease (IBD) is an idiopathic intestinal inflammatory disease, including ulcerative colitis (UC) and Crohn’s disease (CD). The abnormality of inflammatory and immune responses in the intestine contributes to the pathogenesis and progression of IBD. Autophagy is a vital catabolic process in cells. Recent studies report that autophagy is highly involved in various kinds of diseases, especially inflammation-related diseases, such as IBD. In this review, the biological characteristics of autophagy and its role in IBD will be described and discussed based on recent literature. In addition, several therapies for IBD through modulating the inflammasome and intestinal microbiota taking advantage of autophagy regulation will be introduced. We aim to bring new insight in the exploration of mechanisms for IBD and development of novel therapeutic strategies against IBD.
Cell Deformation at the Air-Liquid Interface Evokes Intracellular Ca2+ Increase and ATP Release in Cultured Rat Urothelial Cells
Authors: Wen Jiliang , Chen Zhenghao , Zhao Mengmeng , Zu Shulu , Zhao Shengtian , Wang Shaoyong , Zhang Xiulin
Published: February 2021

Urothelial cells have been implicated in bladder mechanosensory transduction, and thus, initiation of the micturition reflex. Cell deformation caused by tension forces at an air-liquid interface (ALI) can induce an increase in intracellular Ca2+ concentration ([Ca2+]i) and ATP release in some epithelial cells. In this study, we aimed to examine the cellular mechanisms underlying ALI-induced [Ca2+]i increase in cultured urothelial cells. The ALI was created by stopping the influx of the perfusion but maintaining efflux. The [Ca2+]i increase was measured using the Ca2+ imaging method. The ALI evoked a reversible [Ca2+]i increase and ATP release in urothelial cells, which was almost abolished by GdCl3. The specific antagonist of the transient receptor potential vanilloid (TRPV4) channel (HC0674) and the antagonist of the pannexin 1 channel (10panx) both diminished the [Ca2+]i increase. The blocker of Ca2+-ATPase pumps on the endoplasmic reticulum (thapsigargin), the IP3 receptor antagonist (Xest-C), and the ryanodine receptor antagonist (ryanodine) all attenuated the [Ca2+]i increase. Degrading extracellular ATP with apyrase or blocking ATP receptors (P2X or P2Y) with pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS) significantly attenuated the [Ca2+]i increase. Our results suggest that both Ca2+ influx via TRPV4 or pannexin 1 and Ca2+ release from intracellular Ca2+ stores via IP3 or ryanodine receptors contribute to the mechanical responses of urothelial cells. The release of ATP further enhances the [Ca2+]i increase by activating P2X and P2Y receptors via autocrine or paracrine mechanisms.
The Relationship Between Future Time Perspective and Psychological Violence Among Chinese College Students
Authors: Zhi Kuiyun , Yang Jian , Chen Yongjin , Akebaijiang Niyazi , Liu Meimei , Yang Xiaofei , Zhang Shurui
Published: February 2021

Based on early experiences and current conditions, a future time perspective influences college students’ behaviors, while psychological violence critically threatens college students’ health. This study explored the relationship between a future time perspective and the psychological violence of perpetrators based on an online investigation of 1424 college students (87.1% women) aged 17 to 31 in China. The results showed that a future time perspective is significantly positively associated with psychological violence. Positive future orientation is negatively associated with psychological violence. Negative and confused future orientations are positively associated with psychological violence. These findings support the need to introduce an intervention regarding a future time perspective to reduce psychological violence among college students.
Inhibitory Control and Craving in Dual Disorders and Recurrent Substance Use. Preliminary Findings
Authors: Beerten-Duijkers Judith C. L. M. , Vissers Constance Th. W. M. , Rinck Mike , Egger Jos I. M.
Published: February 2021

Objective: In Dual Disorders (DD), which involves the co-occurrence of a disorder in substance use and a mental disorder, recurrent struggles with addictive behavior are frequent. Neuropsychological knowledge concerning the profile of inhibitory control and the irresistible urge to use substances (craving) within the DD patient group may contribute to the prevention of this recurrent addictive behavior.

Methods: Inhibitory control and craving were assessed in 25 patients with DD and 25 healthy controls (HC). Inhibitory control tasks (Go/No-go task and Stop Signal Task) were performed combined with brain measurements (Event Related Potentials) mapping inhibitory control. Moreover, implicit and explicit measures concerning craving were administered. Statistical DD and HC comparisons, correlational and regression analyses on exploratory base were conducted.

Results: DD patients committed more inhibitory control errors than HC when confronted with (alcohol) consumption-related picture stimuli. Furthermore, patients with DD showed higher levels of implicit and explicit craving. The number of inhibitory control errors was positively related to levels of implicit and explicit craving. Moreover, explicit craving and impulsivity (as a dimension of inhibitory control) predicted the severity of addictive behavior. Event Related Potential analyses did not show differences in inhibitory control-associated brain activity between DD patients and HC; both groups showed reduction of P300 amplitudes in response to alcohol pictures.

Conclusions: Impulsivity and craving are elevated in DD patients and show predictive value for the severity of addictive behavior. One's level of impulsive action tendency may trigger less effort to control (recurrent) substance use. The findings may contribute to existing DD treatment indications by the promotion of impulse control training via “stop-think-act” methods for DD patients.
Gabapentinoid Abuse in France: Evidence on Health Consequences and New Points of Vigilance
Authors: Tambon Marine , Ponté Camille , Jouanjus Emilie , Fouilhé Nathalie , Micallef Joelle , Lapeyre-Mestre Maryse ,   the French Addictovigilance Network (FAN)
Published: February 2021

Introduction: Gabapentinoid drugs (gabapentin and pregabalin) are widely used worldwide for epileptic and pain disorders. First signals of gabapentinoid abuse occurred in the last decade. This study aims to describe clinical characteristics of gabapentinoid use related disorders and health consequences in France.

Materials and Methods: We designed a multisource investigation reviewing data reported to the French Addictovigilance Network (FAN) with pregabalin and gabapentin from 2010 to 2019. Information was obtained through the analysis of Spontaneous Reports (SRs) notified by health professionals and the pharmacoepidemiological surveys OSIAP (suspicious prescriptions forms indicators of potential abuse), OPPIDUM (observation of illicit drugs and misuse of psychotropic medications), DRAMES (death related to prescription drugs and other substances), and DTA (toxic deaths due to analgesics).

Results: Over 2010–2019 period, were collected: (i) 265 SRs (258 pregabalin; 7 gabapentin); (ii) 816 forged prescription forms (805 pregabalin, 10 gabapentin, 1 involving both drugs); (iii) 145 cases of gabapentinoid use in people who use drugs (121 pregabalin; 24 gabapentin) and (iv) 31 cases of gabapentinoid-related deaths (25 pregabalin; 6 gabapentin). Risk factors of gabapentinoid abuse were opioid use disorders or psychiatric history, but cases of primary abuse in subjects without any substance abuse history were observed. Adverse outcomes concern almost exclusively pregabalin, with coma, dyspnea, convulsion, and conduction disorders. Treatment demands increased from 10.6% in 2018 to 23.1% in 2019, with pregabalin cited as the first substance leading to addictological care in the 2019 OPPIDUM survey. Gabapentinoid-related deaths increased over time. Pregabalin has become the first drug mentioned in forged prescriptions in 2019 (23.8% of OSIAP), while it ranked at the 15th position in 2017 (2.6%).

Discussion: This study shows the importance of addictovigilance monitoring for gabapentinoids. Addictovigilance data helped to make visible the gabapentinoid-abuse related health harms (hospitalization for serious neurologic, psychiatric or cardiac effects, requests for addictological support and deaths) and to confirm the intrinsic abuse potential of pregabalin. These data highlight new points of vigilance considering observed primary abuse. At this point in France, the risk of abuse and related complications is very apparent with pregabalin. Still, it is identical to that observed elsewhere with gabapentin.
Impact of Tumor Site and Adjuvant Radiotherapy on Survival of Patients with Adenoid Cystic Carcinoma: A SEER Database Analysis
Authors: Tasoulas Jason , Divaris Kimon , Theocharis Stamatios , Farquhar Douglas , Shen Colette , Hackman Trevor , Amelio Antonio L.
Published: February 2021

Adenoid cystic carcinoma (ACC) is a rare salivary gland tumor, displaying aggressive behavior with frequent recurrence and metastasis. Little information exists regarding the impact of clinicopathological parameters and adjuvant radiotherapy (aRT) on ACC disease specific (DSS) and overall survival (OS). We extracted demographic, treatment, and survival information of 1439 patients with major or minor intraoral salivary gland ACC from the Surveillance, Epidemiology, and End Results (SEER) database. The associations between tumor characteristics and aRT with OS and DSS were estimated using hazard ratios (HR) and 95% confidence intervals (CI). Submandibular gland ACCs had the worst prognosis (adjusted DSS HR = 1.48; 95% CI = 0.99–2.20, compared to parotid), and this difference was more pronounced among patients with advanced-stage tumors (adjusted DSS HR = 1.93; 95% CI = 1.13–3.30). aRT was associated with increased overall survival only among stage III submandibular ACC patients (HR = 0.64; 95% CI = 0.42–0.98) and had no benefit in any other group. In conclusion, submandibular gland ACC carries a worse prognosis than other gland subsites and may benefit from aRT. The different outcomes between submandibular gland and other major or minor gland ACCs warrant further mechanistic investigation.
Killing the Invaders: NK Cell Impact in Tumors and Anti-Tumor Therapy
Authors: Molgora Martina , Cortez Victor S. , Colonna Marco
Published: February 2021

Natural Killer cells belong to group 1 innate lymphoid cells, which also includes ILC1s. NK/ILC1s are highly heterogeneous cell types showing distinct phenotypes across tissues and conditions. NK cells have long been described as innate lymphocytes able to directly and rapidly kill tumor cells without antigen-restriction. Different mechanisms were shown to modulate NK cell activation and tumor resistance, mainly based on cytokine stimulation and receptor–ligand interactions, and several strategies have been developed to target NK cells in tumor immunotherapy to promote NK cell function and overcome tumor evasion. The characterization of ILC1 distinct phenotype and function and the specific role in tumors still needs further investigation and will be essential to better understand the impact of innate lymphoid cells in tumors. Here, we review key aspects of NK cell biology that are relevant in tumor immune surveillance, emphasizing the most recent findings in the field. We describe the novel therapeutical strategies that have been developed in tumor immunotherapy targeting NK cells, and we summarize some recent findings related to NK cell/ILC1 transition in tumor models.
TP53 Mutations as a Driver of Metastasis Signaling in Advanced Cancer Patients
Authors: Pandey Ritu , Johnson Nathan , Cooke Laurence , Johnson Benny , Chen Yuliang , Pandey Manjari , Chandler Jason , Mahadevan Daruka
Published: February 2021

Molecular profiling with next generation sequencing (NGS) delivers key information on mutant gene sequences, copy number alterations, gene-fusions, and with immunohistochemistry (IHC), is a valuable tool in clinical decision making for patients entering investigational agent trials. Our objective was to elucidate mutational profiles from primary versus metastatic sites from advanced cancer patients to guide rational therapy. All phase I patients (n = 203) with advanced cancer were profiled by commercially available NGS platforms. The samples were annotated by histology, primary and metastatic site, biopsy site, gene mutations, mutation count/gene, and mutant TP53. A molecular profile of each patient was categorized into common and unique mutations, signaling pathways for each profile and TP53 mutations mapped to 3D-structure of p53 bound to DNA and pre/post therapy molecular response. Of the 171 patients analyzed, 145 had genetic alterations from primary and metastatic sites. The predominant histology was adenocarcinoma followed by squamous cell carcinoma, carcinoma of unknown primary site (CUPS), and melanoma. Of 790 unique mutations, TP53 is the most common followed by APC, KRAS, PIK3CA, ATM, PTEN, NOTCH1, BRCA2, BRAF, KMT2D, LRP1B, and CDKN2A. TP53 was found in most metastatic sites and appears to be a key driver of acquired drug resistance. We highlight examples of acquired mutational profiles pre-/post- targeted therapy in multiple tumor types with a menu of potential targeted agents. Conclusion: The mutational profiling of primary and metastatic lesions in cancer patients provides an opportunity to identify TP53 driver ‘pathways’ that may predict for drug sensitivity/resistance and guide rational drug combinations in clinical trials.