bluuebunny/crossref_metadata_2025 huggingface dataset:
Ca2+/Calmodulin-NOS/NO-TNFs Pathway Hallmarks the Inflammation Response of Oyster During Aerial Exposure
Authors: Chen Hao , Xin Lusheng , Wang Lin , Zhang Huan , Liu Rui , Wang Hao , Qiao Xue , Wang Lingling , Song Linsheng
Published: January 2021

Aerial exposure (emersion) due to the periodical ebb and flow of tides is a major stressor for intertidal organisms and a key environmental factor in shaping their local communities. Oysters are among the most emersion-tolerant mollusk species and can survive for several days under aerial exposure. Noticeably, overwhelming inflammation responses could occur during the emersion stress. However, mechanisms beneath the activation and modulation of emersion-induced inflammation response have remained largely unknown. Ca2+ is an important intracellular second messenger that plays indispensable roles in inflammation response by cooperation with calmodulin (CaM) genes. Here, we showed that intracellular Ca2+ accumulates rapidly in oyster hemocytes during emersion stress along with the changes in the protein levels of three CaM genes, which function as intracellular sensors of Ca2+. As downstream effector of Ca2+/CaM complex, nitric oxide synthase (NOS) activity in hemocytes was enhanced during the emersion stress, facilitating a greater production of nitrite oxide (NO). Augmentation of NO concentration was associated with the increased mRNA expression levels of two oyster cytokines (CgTNFs) during aerial exposure. The robust accumulation of cytokines and severe injury of tissues in oysters have been regarded as potential cause and marker of their death in prolonged emersion stress. Here, both the expression levels of CgTNFs and the tissue injuries of oysters were attenuated when Ca2+/CaM complex or NOS activity were repressed in vivo during the emersion stress. These findings indicate that Ca2+/CaM-NOS/NO-CgTNFs pathway is critically involved in the emersion-induced inflammation response in oysters and plays a role in the resistance against long-term aerial exposure.
Distinct Cause of Death Profiles of Hospitalized Non-alcoholic Fatty Liver Disease: A 10 Years' Cross-Sectional Multicenter Study in China
Authors: Lin Yansong , Gong Xiaorong , Li Xin , Shao Congxiang , Wu Tingfeng , Li Minrui , Li Fuxi , Ma Qianqian , Ye Junzhao , Zhong Bihui
Published: January 2021

Background: The clinical burden and natural history of non-alcoholic fatty liver disease (NAFLD) vary globally. We aimed to investigate NAFLD-related mortality profiles in hospitalized patients in southern China.

Methods: A multicenter retrospective investigation with a 10-year study period (2009–2018) analyzed 10,071 deaths during hospitalization (NAFLD: 2,015; other liver diseases: 1,140; without liver diseases: 6,916) was performed using a multiple cause of death analysis. Medical histories and biochemistry and imaging findings were extracted from the electronic medical record system. The underlying causes of death were classified by 10th Revision of the International Classification of Diseases (ICD-10) codes.

Results: The distribution of death causes in patients with NAFLD has stabilized over time, with cardio- and cerebral vascular disease (CVD) ranked first (35.6%), followed by extrahepatic malignancies (22.6%), infection (11.0%), kidney disease (7.5%), liver-related diseases (5.2%), respiratory diseases (3.9%), digestive diseases (3.5%), endocrine diseases (3.5%), and other diseases (7.2%). NAFLD patients had more deaths attributable to CVD, extrahepatic malignancies, liver-related diseases (all P < 0.001) and multiorgan failure than the deceased controls. The severity of steatosis was independently associated with these relationships (liver-related diseases: OR = 1.37, 95% CI: 1.20–1.59, cardio- and cerebrovascular diseases: OR = 1.23, 95% CI: 1.19–1.31, infectious diseases: OR = 1.14, 95% CI: 1.04–1.26, and renal diseases: OR = 1.21, 95% CI: 1.02–1.47, all P < 0.05) after adjustment for sex, body mass index (BMI), fasting blood glucose, low-density lipoprotein cholesterol, uric acid, metabolic syndromes and fibrosis index based on the 4 factors.

Conclusion : NAFLD patients had higher proportions of death due to underlying CVD and liver-related diseases than the general population in China; these proportions positively correlated with steatosis degree.
Dynamic Manugraphy as a Promising Tool to Assess the Outcome of Limited Aponeurectomy in Patients With Dupuytren's Contracture
Authors: Garkisch Angelina , Mittlmeier Thomas , Kalpen Axel , Mühldorfer-Fodor Marion , Fischer Dagmar-C. , Wichelhaus Alice
Published: January 2021

Background: Dupuytren's contractures interfere with physiological gripping. While limited aponeurectomy is an accepted treatment modality to restore finger mobility, methods to objectify functional outcome beyond determination of the range of motion are scarce.

Methods: Patients with Dupuytren's contracture being scheduled for unilateral limited aponeurectomy were invited to participate. Clinical data were gathered prospectively by chart review and interview. The DASH-score and flexion contracture for fingers were registered prior to surgery, 3 and 6 months afterwards. At the same time, dynamic manugraphy for simultaneous recording of the grip pattern and forces generated by the affected hand and anatomic areas (i.e., thumb, index finger, middle finger, ring finger, little finger and palm) were performed. All findings obtained during the follow-up period were compared to the situation at baseline. Comparison between paired samples was done using Wilcoxon rank test. All p-values are two-sided and p < 0.05 was considered to be significant.

Results: Out of 23 consecutively enrolled patients, 19 (15 men, 4 women) completed follow-up examinations. Manugraphy confirmed the impairment of physiological gripping with concomitant pathological load distribution at base line. Limited aponeurectomy significantly reduced flexion contractures. However, the DASH-score remained at an excellent level in one patient, indicated improvement in 11 and worsening in seven patients. Six patients had lower grip force at t6 compared to the preoperative condition, although the preoperative flexion contracture (≥110°) was considerably improved in all of them. In four of those, the DASH-score improved while it turned worse in two of them. The force of surgically treated fingers remained unchanged in three patients while it was improved and worsened in half of the remaining patients, respectively. Manugraphy revealed physiological gripping by enlargement of contact area and higher force transmission by the fingertips in 10 of 12 patients with constant or even improved DASH-score and in three of seven patients with a worsened DASH-score.

Conclusions: Assessing the reduction of flexion contracture and grip force alone is not sufficient to comprehensively reflect the functional outcome of aponeurectomy for Dupuytren's disease. Visualizing physiological grip pattern provides an additional tool to objectify the success of surgical treatment.
ISEc69-Mediated Mobilization of the Colistin Resistance Gene mcr-2 in Escherichia coli
Authors: He Yu-Zhang , Long Teng-Fei , He Bing , Li Xing-Ping , Li Gong , Chen Liang , Liao Xiao-Ping , Liu Ya-Hong , Sun Jian
Published: January 2021

Objectives

The emergence of mobile colistin resistance genes has compromised the efficacy of the last resort antibiotic, colistin, in clinical treatment. The mcr-2 gene was first identified in Belgium in association with the insertion sequence ISEc69. However, the molecular mechanisms of mcr-2 mobilization are not well understood.

Methods

To further explore the mobilization of mcr-2 gene via ISEc69, we constructed a conjugative plasmid that carries an intact composite transposon Tn7052. Transposition assays were performed by conjugation, the transposition sites were characterized by arbitrary primed PCR and DNA sequencing.

Results

In this study, we experimentally demonstrated that mcr-2 could be mobilized as a composite transposon Tn7052 and its transposition generated 8-bp AT-rich duplications in the host genome.

Conclusion

These results indicate that mcr-2 gene could be mobilized by ISEc69, the current investigations provide mechanistic insights in the transposition of mcr-2.
Self-Adaptation of Pseudomonas fluorescens Biofilms to Hydrodynamic Stress
Authors: Jara Josué , Alarcón Francisco , Monnappa Ajay K. , Santos José Ignacio , Bianco Valentino , Nie Pin , Ciamarra Massimo Pica , Canales Ángeles , Dinis Luis , López-Montero Iván , Valeriani Chantal , Orgaz Belén
Published: January 2021

In some conditions, bacteria self-organize into biofilms, supracellular structures made of a self-produced embedding matrix, mainly composed of polysaccharides, DNA, proteins, and lipids. It is known that bacteria change their colony/matrix ratio in the presence of external stimuli such as hydrodynamic stress. However, little is still known about the molecular mechanisms driving this self-adaptation. In this work, we monitor structural features of Pseudomonas fluorescens biofilms grown with and without hydrodynamic stress. Our measurements show that the hydrodynamic stress concomitantly increases the cell density population and the matrix production. At short growth timescales, the matrix mediates a weak cell-cell attractive interaction due to the depletion forces originated by the polymer constituents. Using a population dynamics model, we conclude that hydrodynamic stress causes a faster diffusion of nutrients and a higher incorporation of planktonic bacteria to the already formed microcolonies. This results in the formation of more mechanically stable biofilms due to an increase of the number of crosslinks, as shown by computer simulations. The mechanical stability also relies on a change in the chemical compositions of the matrix, which becomes enriched in carbohydrates, known to display adhering properties. Overall, we demonstrate that bacteria are capable of self-adapting to hostile hydrodynamic stress by tailoring the biofilm chemical composition, thus affecting both the mesoscale structure of the matrix and its viscoelastic properties that ultimately regulate the bacteria-polymer interactions.
Molecular Characterization of Bacteria, Detection of Enterotoxin Genes, and Screening of Antibiotic Susceptibility Patterns in Traditionally Processed Meat Products of Sikkim, India
Authors: Bhutia Meera Ongmu , Thapa Namrata , Tamang Jyoti Prakash
Published: January 2021

The lesser-known traditionally processed meat products such as beef kargyong, pork kargyong, satchu, and khyopeh are popular food items in the Himalayan state of Sikkim in India. The present study aimed to assess the microbiological safety of traditional meat products by identifying the potential spoilage or pathogenic bacteria, detecting the enterotoxins, and screening the antibiotic susceptibility patterns. The pH and moisture contents of the meat products varied from 5.3 to 5.9 and from 1.5 to 18%, respectively. The microbial loads of aerobic bacteria were 105 to 107 cfu/g, Staphylococcus 103 to 106 cfu/g, Bacillus 104 to 106 cfu/g, and total coliform 102 to 107 cfu/g, respectively. Based on 16S rRNA gene sequencing, the bacterial species isolated from traditionally processed meat products were Staphylococcus piscifermentans, Citrobacter freundii, Enterococcus faecalis, Salmonella enterica, Staphylococcus aureus, Citrobacter werkmanii, Klebsiella pneumoniae, Macrococcus caseolyticus, Klebsiella aerogenes, Staphylococcus saprophyticus, Pseudocitrobacter anthropi, Citrobacter europaeus, Shigella sonnei, Escherichia fergusonii, Klebsiella grimontii, Burkholderia cepacia, and Bacillus cereus. The enzyme-linked immunosorbent assay (ELISA) tests detected Salmonella spp. and enterotoxins produced by B. cereus well as Staphylococcus in a few tested samples. However, the PCR method did not detect the virulence genes of B. cereus and Salmonella in the isolates. Virulence gene (sea) was detected in S. piscifermentans BSLST44 and S. piscifermentans BULST54 isolated from beef kargyong and in S. aureus PSST53 isolated from pork kargyong. No enterotoxins were detected in khyopeh samples. The antibiotic sensitivity test showed that all bacterial strains were susceptible toward gentamicin, cotrimoxazole, norfloxacin, and trimethoprim. Gram-positive bacteria showed 100% sensitivity against clindamycin and erythromycin; however, 50% of the resistance pattern was observed against oxacillin followed by penicillin (33%) and ampicillin (27%).
A Model System for Feralizing Laboratory Mice in Large Farmyard-Like Pens
Authors: Arnesen Henriette , Knutsen Linn Emilie , Hognestad Bente Wabakken , Johansen Grethe Marie , Bemark Mats , Pabst Oliver , Storset Anne Kristine , Boysen Preben
Published: January 2021

Laboratory mice are typically housed under extremely clean laboratory conditions, far removed from the natural lifestyle of a free-living mouse. There is a risk that this isolation from real-life conditions may lead to poor translatability and misinterpretation of results. We and others have shown that feral mice as well as laboratory mice exposed to naturalistic environments harbor a more diverse gut microbiota and display an activated immunological phenotype compared to hygienic laboratory mice. We here describe a naturalistic indoors housing system for mice, representing a farmyard-type habitat typical for house mice. Large open pens were installed with soil and domestic animal feces, creating a highly diverse microbial environment and providing space and complexity allowing for natural behavior. Laboratory C57BL/6 mice were co-housed in this system together with wild-caught feral mice, included as a source of murine microbionts. We found that mice feralized in this manner displayed a gut microbiota structure similar to their feral cohabitants, such as higher relative content of Firmicutes and enrichment of Proteobacteria. Furthermore, the immunophenotype of feralized mice approached that of feral mice, with elevated levels of memory T-cells and late-stage NK cells compared to laboratory-housed control mice, indicating antigenic experience and immune training. The dietary elements presented in the mouse pens could only moderately explain changes in microbial colonization, and none of the immunological changes. In conclusion, this system enables various types of studies using genetically controlled mice on the background of adaptation to a high diversity microbial environment and a lifestyle natural for the species.
Giardia spp. and the Gut Microbiota: Dangerous Liaisons
Authors: Fekete Elena , Allain Thibault , Siddiq Affan , Sosnowski Olivia , Buret Andre G.
Published: January 2021

Alteration of the intestinal microbiome by enteropathogens is commonly associated with gastrointestinal diseases and disorders and has far-reaching consequences for overall health. Significant advances have been made in understanding the role of microbial dysbiosis during intestinal infections, including infection with the protozoan parasite Giardia duodenalis, one of the most prevalent gut protozoa. Altered species composition and diversity, functional changes in the commensal microbiota, and changes to intestinal bacterial biofilm structure have all been demonstrated during the course of Giardia infection and have been implicated in Giardia pathogenesis. Conversely, the gut microbiota has been found to regulate parasite colonization and establishment and plays a critical role in immune modulation during mono and polymicrobial infections. These disruptions to the commensal microbiome may contribute to a number of acute, chronic, and post-infectious clinical manifestations of giardiasis and may account for variations in disease presentation within and between infected populations. This review discusses recent advances in characterizing Giardia-induced bacterial dysbiosis in the gut and the roles of dysbiosis in Giardia pathogenesis.
Pseudomonas aeruginosa Elastase Contributes to the Establishment of Chronic Lung Colonization and Modulates the Immune Response in a Murine Model
Authors: Cigana Cristina , Castandet Jérôme , Sprynski Nicolas , Melessike Medede , Beyria Lilha , Ranucci Serena , Alcalá-Franco Beatriz , Rossi Alice , Bragonzi Alessandra , Zalacain Magdalena , Everett Martin
Published: January 2021

Chronic infection by Pseudomonas aeruginosa in cystic fibrosis (CF) patients is a major contributor to progressive lung damage and is poorly treated by available antibiotic therapy. An alternative approach to the development of additional antibiotic treatments is to identify complementary therapies which target bacterial virulence factors necessary for the establishment and/or maintenance of the chronic infection. The P. aeruginosa elastase (LasB) has been suggested as an attractive anti-virulence target due to its extracellular location, its harmful degradative effects on host tissues and the immune system, and the potential to inhibit its activity using small molecule inhibitors. However, while the relevance of LasB in acute P. aeruginosa infection has been demonstrated, it is still unclear whether this elastase might also play a role in the early phase of chronic lung colonization. By analyzing clinical P. aeruginosa clonal isolates from a CF patient, we found that the isolate RP45, collected in the early phase of persistence, produces large amounts of active LasB, while its clonal variant RP73, collected after years of colonization, does not produce it. When a mouse model of persistent pneumonia was used, deletion of the lasB gene in RP45 resulted in a significant reduction in mean bacterial numbers and incidence of chronic lung colonization at Day 7 post-challenge compared to those mice infected with wild-type (wt) RP45. Furthermore, deletion of lasB in strain RP45 also resulted in an increase in immunomodulators associated with innate and adaptive immune responses in infected animals. In contrast, deletion of the lasB gene in RP73 did not affect the establishment of chronic infection. Overall, these results indicate that LasB contributes to the adaptation of P. aeruginosa to a persistent lifestyle. In addition, these findings support pharmacological inhibition of LasB as a potentially useful therapeutic intervention for P. aeruginosa-infected CF patients prior to the establishment of a chronic infection.
Genomic Insights Into the Lifestyles of Thaumarchaeota Inside Sponges
Authors: Haber Markus , Burgsdorf Ilia , Handley Kim M. , Rubin-Blum Maxim , Steindler Laura
Published: January 2021

Sponges are among the oldest metazoans and their success is partly due to their abundant and diverse microbial symbionts. They are one of the few animals that have Thaumarchaeota symbionts. Here we compare genomes of 11 Thaumarchaeota sponge symbionts, including three new genomes, to free-living ones. Like their free-living counterparts, sponge-associated Thaumarchaeota can oxidize ammonia, fix carbon, and produce several vitamins. Adaptions to life inside the sponge host include enrichment in transposases, toxin-antitoxin systems and restriction modifications systems, enrichments previously reported also from bacterial sponge symbionts. Most thaumarchaeal sponge symbionts lost the ability to synthesize rhamnose, which likely alters their cell surface and allows them to evade digestion by the host. All but one archaeal sponge symbiont encoded a high-affinity, branched-chain amino acid transporter system that was absent from the analyzed free-living thaumarchaeota suggesting a mixotrophic lifestyle for the sponge symbionts. Most of the other unique features found in sponge-associated Thaumarchaeota, were limited to only a few specific symbionts. These features included the presence of exopolyphosphatases and a glycine cleavage system found in the novel genomes. Thaumarchaeota have thus likely highly specific interactions with their sponge host, which is supported by the limited number of host sponge species to which each of these symbionts is restricted.
Cytologic and Molecular Diagnostics for Vitreoretinal Lymphoma: Current Approaches and Emerging Single-Cell Analyses
Authors: Tan Wei Jian , Wang Mona Meng , Ricciardi-Castagnoli Paola , Chan Anita Sook Yee , Lim Tong Seng
Published: January 2021

Vitreoretinal lymphoma (VRL) is a rare ocular malignancy that manifests as diffuse large B-cell lymphoma. Early and accurate diagnosis is essential to prevent mistreatment and to reduce the high morbidity and mortality associated with VRL. The disease can be diagnosed using various methods, including cytology, immunohistochemistry, cytokine analysis, flow cytometry, and molecular analysis of bulk vitreous aspirates. Despite these options, VRL diagnosis remains challenging, as samples are often confounded by low cellularity, the presence of debris and non-target immunoreactive cells, and poor cytological preservation. As such, VRL diagnostic accuracy is limited by both false-positive and false-negative outcomes. Missed or inappropriate diagnosis may cause delays in treatment, which can have life-threatening consequences for patients with VRL. In this review, we summarize current knowledge and the diagnostic modalities used for VRL diagnosis. We also highlight several emerging molecular techniques, including high-resolution single cell-based analyses, which may enable more comprehensive and precise VRL diagnoses.
SARS-CoV-2 and Glutamine: SARS-CoV-2 Triggered Pathogenesis via Metabolic Reprograming of Glutamine in Host Cells
Authors: Bharadwaj Shiv , Singh Mahendra , Kirtipal Nikhil , Kang Sang Gu
Published: January 2021

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, as coronavirus disease 2019 (COVID-19) pandemic, has killed more than a million people worldwide, and researchers are constantly working to develop therapeutics in the treatment and prevention of this new viral infection. To infect and induced pathogenesis as observed in other viral infections, we postulated that SARS-CoV-2 may also require an escalation in the anabolic metabolism, such as glucose and glutamine, to support its energy and biosynthetic requirements during the infection cycle. Recently, the requirement of altered glucose metabolism in SARS-CoV-2 pathogenesis was demonstrated, but the role of dysregulated glutamine metabolism is not yet mentioned for its infection. In this perspective, we have attempted to provide a summary of possible biochemical events on putative metabolic reprograming of glutamine in host cells upon SARS-CoV-2 infection by comparison to other viral infections/cancer metabolism and available clinical data or research on SARS-CoV-2 pathogenesis. This systematic hypothesis concluded the vital role of glutaminase-1 (GLS1), phosphoserine aminotransferase (PSAT1), hypoxia-inducible factor-1 alpha (HIF-1α), mammalian target of rapamycin complex 1 (mTORC1), glutamine-fructose amidotransferase 1/2 (GFAT1/2), and transcription factor Myc as key cellular factors to mediate and promote the glutamine metabolic reprogramming in SARS-CoV-2 infected cells. In absence of concrete data available for SARS-CoV-2 induced metabolic reprogramming of glutamine, this study efforts to connect the gaps with available clinical shreds of evidence in SARS-CoV-2 infection with altered glutamine metabolism and hopefully could be beneficial in the designing of strategic methods for therapeutic development with elucidation usingin vitroorin vivoapproaches.
Plasma β-Amyloid Levels Associated With Structural Integrity Based on Diffusion Tensor Imaging in Subjective Cognitive Decline: The SILCODE Study
Authors: Wang Xiaoni , Zhao Mingyan , Lin Li , Han Ying
Published: January 2021

Background: Accumulating evidence has demonstrated that plasma β-amyloid (Aβ) levels are useful biomarkers to reflect brain amyloidosis and gray matter structure, but little is known about their correlation with subclinical white matter (WM) integrity in individuals at risk of Alzheimer's disease (AD). Here, we investigated the microstructural changes in WM between subjects with low and high plasma Aβ levels among individuals with subjective cognitive decline (SCD).

Methods: This study included 142 cognitively normal individuals with SCD who underwent a battery of neuropsychological tests, plasma Aβ measurements, and diffusion tensor imaging (DTI) based on the Sino Longitudinal Study on Cognitive Decline (SILCODE). Using tract-based spatial statistics (TBSS), we compared fractional anisotropy (FA), and mean diffusivity (MD) in WM between subjects with low (N = 71) and high (N = 71) plasma Aβ levels (cut-off: 761.45 pg/ml for Aβ40 and 10.74 pg/ml for Aβ42).

Results: We observed significantly decreased FA and increased MD in the high Aβ40 group compared to the low Aβ40 group in various regions, including the body, the genu, and the splenium of the corpus callosum; the superior longitudinal fasciculus; the corona radiata; the thalamic radiation; the external and internal capsules; the inferior fronto-occipital fasciculus; and the sagittal stratum [p < 0.05, familywise error (FWE) corrected]. Average FA values were associated with poor performance on executive and memory assessments. No significant differences were found in either MD or FA between the low and high Aβ42 groups.

Conclusion: Our results suggest that a correlation exists between WM integrity and plasma Aβ40 levels in individuals with SCD.
Sporadic Parkinson’s Disease Potential Risk Loci Identified in Han Ancestry of Chinese Mainland
Authors: Wang Bo , Liu Xin , Xu Shengyuan , Liu Zheng , Zhu Yu , Zhang Xiong , Xu Renshi
Published: January 2021

Recent investigations demonstrated that genetic factors might play an important role in sporadic Parkinson’s disease (sPD). To clarify the specific loci susceptibility to sPD, we analyze the relationship between 30 candidate single nucleotide polymorphisms (SNPs) and sPD in the population of Han ancestry from Chinese mainland (HACM) by using genome-wide association study, sequenom massARRAY, DNA sequence, and biological information analysis. Results showed that the subjects carrying the T allele of rs863108 and rs28499371 exhibited a decreased risk for sPD. The subjects carrying the T allele of rs80315856 exhibited an increased risk for sPD. The A/T genotype of rs863108 and the C/T genotype of rs28499371 were a potential increased risk for sPD, and the G/T genotype of rs80315856 and T/T genotype of rs2270568 were a potential decreased risk for sPD. The minor allele frequency (MAF) of rs80315856 and rs2270568 was higher in sPD. The T allele of rs80315856 and rs2270568 might be a risk locus for sPD. Our data suggested that the alteration of these SNPs might play some roles through changing/affecting LINC01524/LOC105372666, DMRT2/SMARCA2, PLEKHN1, and FLJ23172/FNDC3B genes in the pathogenesis of sPD.
Involvement of Peripheral Opioid Receptors in the Realization of Food Motivation Into Eating Behavior
Authors: Sudakov Sergey , Bogdanova Natalia
Published: January 2021

The involvement of peripheral opioid receptors in the mechanisms of eating behavior is still unclear. The aim of this work was to study the role of peripheral, predominantly gastric mu and delta opioid receptors in the realization of food motivation in conditions of different energy costs for eating behavior. Experiments were performed under a between-sessions progressive ratio schedule of reinforcement in food-deprived rats. The level of food motivation was calculated using a self-developed method. Food intake, motor activity, and metabolic rate were recorded in fed and hungry animals. Results showed that intragastric administration of the mu opioid receptor agonist DAMGO led to an increase in the level of food motivation in the light variant of operant feeding behaviors. Food consumption did not change. At high costs for feeding behavior, the administration of DAMGO did not alter food motivation; however, food consumption and motor activity were reduced. Intragastric administration of the delta opioid receptor agonist DADLE did not lead to changes in the level of food motivation and physical activity, but inhibition of feeding behavior was observed in all reinforcement schedules. Three regulatory pathways of eating behavior in difficult food conditions by peripheral, predominantly gastric opioid receptors are hypothesized: environmental-inhibitory afferentations and suppression of the realization of food motivation into behavior; homeostatic-inhibitory action on food motivation; and rewarding-suppression of the anticipatory reinforcement.
Cannabinoids: A New Perspective on Epileptogenesis and Seizure Treatment in Early Life in Basic and Clinical Studies
Authors: Vega-García Angélica , Feria-Romero Iris , García-Juárez Anais , Munguia-Madera Ana Ch. , Montes-Aparicio Alexia V. , Zequeida-Muñoz Esli , Garcia-Albavera Estefany , Orozco-Suárez Sandra
Published: January 2021

Neural hyperexcitability in the event of damage during early life, such as hyperthermia, hypoxia, traumatic brain injury, status epilepticus, or a pre-existing neuroinflammatory condition, can promote the process of epileptogenesis, which is defined as the sequence of events that converts a normal circuit into a hyperexcitable circuit and represents the time that occurs between the damaging event and the development of spontaneous seizure activity or the establishment of epilepsy. Epilepsy is the most common neurological disease in the world, characterized by the presence of seizures recurring without apparent provocation. Cannabidiol (CBD), a phytocannabinoid derived from the subspecies Cannabis sativa (CS), is the most studied active ingredient and is currently studied as a therapeutic strategy: it is an anticonvulsant mainly used in children with catastrophic epileptic syndromes and has also been reported to have anti-inflammatory and antioxidant effects, supporting it as a therapeutic strategy with neuroprotective potential. However, the mechanisms by which CBD exerts these effects are not entirely known, and the few studies on acute and chronic models in immature animals have provided contradictory results. Thus, it is difficult to evaluate the therapeutic profile of CBD, as well as the involvement of the endocannabinoid system in epileptogenesis in the immature brain. Therefore, this review focuses on the collection of scientific data in animal models, as well as information from clinical studies on the effects of cannabinoids on epileptogenesis and their anticonvulsant and adverse effects in early life.
Deletion of MicroRNA-144/451 Cluster Aggravated Brain Injury in Intracerebral Hemorrhage Mice by Targeting 14-3-3ζ
Authors: Wang Xiaohong , Hong Yin , Wu Lei , Duan Xiaochun , Hu Yue , Sun Yongan , Wei Yanqiu , Dong Zhen , Wu Chenghao , Yu Duonan , Xu Jun
Published: January 2021

This study aims at evaluating the importance and its underlying mechanism of the cluster of microRNA-144/451 (miR-144/451) in the models with intracerebral hemorrhage (ICH). A model of collagenase-induced mice with ICH and a model of mice with simple miR-144/451 gene knockout (KO) were used in this study. Neurodeficits and the water content of the brain of the mice in each group were detected 3 days after collagenase injection. The secretion of proinflammatory cytokines, such as tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β), as well as certain biomarkers of oxidative stress, was determined in this study. The results revealed that the expression of miR-451 significantly decreased in the mice with ICH, whereas miR-144 showed no significant changes. KO of the cluster of miR-144/451 exacerbated the neurological deficits and brain edema in the mice with ICH. Further analyses demonstrated that the KO of the cluster of miR-144/451 significantly promoted the secretion of TNF-α and IL-1β and the oxidative stress in the perihematomal region of the mice with ICH. In addition, the miR-144/451's depletion inhibited the regulatory axis' activities of miR-451-14-3-3ζ-FoxO3 in the mice with ICH. In conclusion, these data demonstrated that miR-144/451 might protect the mice with ICH against neuroinflammation and oxidative stress by targeting the pathway of miR-451-14-3-3ζ-FoxO3.
Decompressive Hemicraniectomy Associated With Ultrasound-Guided Minimally Invasive Puncture and Drainage Has Better Feasibility Than the Traditional Hematoma Evacuation for Deteriorating Spontaneous Intracranial Hemorrhage in the Basal Ganglia Region: A Retrospective Observational Cohort Study
Authors: Cheng Yuan , Chen Jin , Zhao Guanjian , Xie Zongyi , Huang Ning , Yang Qiang , Chen Weifu , Huang Qin
Published: January 2021

Objectives: Spontaneous intracerebral hemorrhage (ICH) is a devastating disease with higher mortality and disability rates; however, ideal surgical management is still to be determined for critical ICH. The purpose of this study was to prove the feasibility and unique clinical value of a novel combination, decompressive hemicraniectomy associated with ultrasound-guided minimally invasive puncture and drainage (DH + MIPD), for deteriorating ICH in the basal ganglia region.

Methods: According to the enrollment criteria, 168 ICH patients were analyzed retrospectively, of which 86 patients received DH + MIPD and 82 patients received DH associated with traditional hematoma evacuation as the control group. The change process of three parameters, including hematoma size, peri-hematoma edema, and intracranial pressure (ICP), in a period of time after operation, as well as the short- and long-term therapeutic effect, was compared.

Results: The DH + MIPD method could effectively achieve the evacuation rate of hematoma up to 87% at 5 days post-operation and had the significant advantages of minimal injury to cerebral tissue, less degree of edema, better effect of decreasing ICP, shorter operation time, less blood loss, and lower mortality compared with the control method. The DH + MIPD group had a significantly higher survival rate within 1 year post-operation (P = 0.007) and better functional outcome at 90 and 180 days post-operation (P = 0.004). A subgroup analysis pointed out that the DH + MIPD method had a definite survival advantage for critical ICH patients older than 60 years old and with hematoma located in the left dominant hemisphere.

Conclusions: Our results proved the better feasibility of DH + MIPD on hematoma evacuation and implicated its significant advantages of reducing mortality and improving functional recovery. This method provides one more choice for the individualized therapy of ICH in the basal ganglia region.
Association of the CHA2D(S2)-VASc Score and Its Components With Overt and Silent Ischemic Brain Lesions in Patients With Atrial Fibrillation
Authors: Steiner Fabienne , Meyre Pascal B. , Aeschbacher Stefanie , Coslovsky Michael , Sinnecker Tim , Blum Manuel R. , Rodondi Nicolas , Cereda Carlo W. , di Valentino Marcello , Wenger Florence , Cussigh Andrea , Krisai Philipp , Roten Laurent , Reichlin Tobias , Conen David , Osswald Stefan , Bonati Leo H. , Kühne Michael ,   The Swiss-AF Investigators
Published: January 2021

Background: Silent and overt ischemic brain lesions are common and associated with adverse outcome. Whether the CHA2DS2-VASc score and its components predict magnetic resonance imaging (MRI)-detected ischemic silent and overt brain lesions in patients with atrial fibrillation (AF) is unclear.

Methods: In this cross-sectional analysis, patients with AF were enrolled in a multicenter cohort study in Switzerland. Outcomes were clinically overt, silent [in the absence of a history of stroke/transient ischemic attack (TIA)] and any MRI-detected ischemic brain lesions. Logistic regression analyses were performed to assess the relationship of the CHA2DS2-VASc score and its components with ischemic brain lesions. An adapted CHA2D-VASc score (excluding history of stroke/TIA) for the analyses of clinically overt and silent ischemic brain lesions was used.

Results: Overall, 1,741 patients were included in the analysis (age 73 ± 8 years, 27.4% female). At least one ischemic brain lesion was observed in 36.8% (clinically overt: 10.5%; silent: 22.9%; transient ischemic attack: 3.4%). The CHA2D-VASc score was strongly associated with clinically overt and silent ischemic brain lesions {odds ratio (OR) [95% confidence interval (CI)] 1.32 (1.17–1.49), p < 0.001 and 1.20 (1.10–1.30), p < 0.001, respectively}. Age 65–74 years (OR 2.58; 95%CI 1.29–5.90; p = 0.013), age ≥75 years (4.13; 2.07–9.43; p < 0.001), hypertension (1.90; 1.28–2.88; p = 0.002) and diabetes (1.48; 1.00–2.18; p = 0.047) were associated with clinically overt brain lesions, whereas age 65–74 years (1.95; 1.26–3.10; p = 0.004), age ≥75 years (3.06; 1.98–4.89; p < 0.001) and vascular disease (1.39; 1.07–1.79; p = 0.012) were associated with silent ischemic brain lesions.

Conclusions: A higher CHA2D-VASc score was associated with a higher risk of both overt and silent ischemic brain lesions.

Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT02105844.
Measurement of the Intracochlear Hypothermia Distribution Utilizing Tympanic Cavity Hypothermic Rinsing Technique in a Cochlea Hypothermia Model
Authors: Bader Werner , Gottfried Timo , Degenhart Gerald , Johnson Chacko Lejo , Sieber Daniel , Riechelmann Herbert , Fischer Natalie , Hoermann Romed , Glueckert Rudolf , Schrott-Fischer Anneliese , Schmutzhard Joachim
Published: January 2021

Introduction: Cochlea implants can cause severe trauma leading to intracochlear apoptosis, fibrosis, and eventually to loss of residual hearing. Mild hypothermia has been shown to reduce toxic or mechanical noxious effects, which can result in inflammation and subsequent hearing loss. This paper evaluates the usability of standard surgical otologic rinsing as cooling medium during cochlea implantation as a potential hearing preservation technique.

Material and Methods: Three human temporal bones were prepared following standard mastoidectomy and posterior tympanotomy. Applying a retrocochlear approach leaving the mastoidectomy side intact, temperature probes were placed into the basal turn (n = 4), the middle turn (n = 2), the helicotrema, and the modiolus. Temperature probe positions were visualized by microcomputed tomography (μCT) imaging and manually segmented using Amira® 7.6. Through the posterior tympanotomy, the tympanic cavity was rinsed at 37°C in the control group, at room temperature (in the range between 22 and 24°C), and at iced water conditions. Temperature changes were measured in the preheated temporal bone. In each temperature model, rinsing was done for 20 min at the pre-specified temperatures measured in 0.5-s intervals. At least five repetitions were performed. Data were statistically analyzed using pairwise t-tests with Bonferroni correction.

Results: Steady-state conditions achieved in all three different temperature ranges were compared in periods between 150 and 300 s. Temperature in the inner ear started dropping within the initial 150 s. Temperature probes placed at basal turn, the helicotrema, and middle turn detected statistically significant fall in temperature levels following body temperature rinses. Irrigation at iced conditions lead to the most significant temperature drops. The curves during all measurements remained stable with 37°C rinses.

Conclusion: Therapeutic hypothermia is achieved with standard surgical irrigation fluid, and temperature gradients are seen along the cochlea. Rinsing of 120 s duration results in a therapeutic local hypothermia throughout the cochlea. This otoprotective procedure can be easily realized in clinical practice.
The Oscillatory Basis of Working Memory Function and Dysfunction in Epilepsy
Authors: Arski Olivia N. , Young Julia M. , Smith Mary-Lou , Ibrahim George M.
Published: January 2021

Working memory (WM) deficits are pervasive co-morbidities of epilepsy. Although the pathophysiological mechanisms underpinning these impairments remain elusive, it is thought that WM depends on oscillatory interactions within and between nodes of large-scale functional networks. These include the hippocampus and default mode network as well as the prefrontal cortex and frontoparietal central executive network. Here, we review the functional roles of neural oscillations in subserving WM and the putative mechanisms by which epilepsy disrupts normative activity, leading to aberrant oscillatory signatures. We highlight the particular role of interictal epileptic activity, including interictal epileptiform discharges and high frequency oscillations (HFOs) in WM deficits. We also discuss the translational opportunities presented by greater understanding of the oscillatory basis of WM function and dysfunction in epilepsy, including potential targets for neuromodulation.
Safety and Efficacy of Magnetic Resonance-Guided Focused Ultrasound Surgery With Autofocusing Echo Imaging
Authors: Chang Kyung Won , Rachmilevitch Itay , Chang Won Seok , Jung Hyun Ho , Zadicario Eyal , Prus Oleg , Chang Jin Woo
Published: January 2021

Objective

Magnetic resonance-guided focused ultrasound surgery (MRgFUS) lesioning is a new treatment for brain disorders. However, the skull is a major barrier of ultrasound sonication in MRgFUS because it has an irregular surface and varies its size and shape among individuals. We recently developed the concept of skull density ratio (SDR) to select candidates for MRgFUS from among patients with essential tremor (ET). However, SDR is not the only factor contributing to successful MRgFUS lesioning treatment—refining the target through exact measurement of the ultrasonic echo in the transducer also improves treatment efficacy. In the present study, we carried out MRgFUS lesioning using an autofocusing echo imaging technique. We aimed to evaluate the safety and efficacy of this new approach, especially in patients with low SDR in whom previous focusing methods have failed.

Methods

From December 2019 to March 2020, we recruited 10 patients with ET or Parkinson’s disease (PD) who had a low SDR. Two patients dropped out of the trial due to the screening failure of other medical diseases. In total, eight patients were included: six with ET who underwent MRgFUS thalamotomy and two with PD who underwent MRgFUS pallidotomy. The autofocusing echo imaging technique was used in all cases.

Results

The mean SDR of the patients with ET was 0.34 (range: 0.29–0.39), while that of the patients with PD was 0.41 (range: 0.38–0.44). The mean skull volume of patients with ET was 280.57 cm3 (range: 227–319 cm3), while that of the patients with PD was 287.13 cm3 (range: 271–303 cm3). During MRgFUS, a mean of 15 sonications were performed, among which a mean of 5.63 used the autofocusing technique. The mean maximal temperature (Tmax) achieved was 55.88°C (range: 52–59°C), while the mean energy delivered was 34.75 kJ (range: 20–42 kJ) among all patients. No serious adverse events occurred during or after treatment. Tmax or sonication factors (skull volume, SDR, sonication number, autofocusing score, similarity score, energy range, and power) were not correlated with autofocusing technique (p > 0.05, autofocusing score showed a p-value of 0.071).

Conclusion

Using autofocusing echo imaging lesioning, a safe and efficient MRgFUS treatment, is available even for patients with a low SDR. Therefore, the indications for MRgFUS lesioning could be expanded to include patients with ET who have an SDR < 0.4 and those with PD who have an SDR < 0.45.

Clinical Trial Registration

clinicaltrials.gov, identifier: NCT03935581.
Research Advances on Therapeutic Approaches to Congenital Central Hypoventilation Syndrome (CCHS)
Authors: Di Lascio Simona , Benfante Roberta , Cardani Silvia , Fornasari Diego
Published: January 2021

Congenital central hypoventilation syndrome (CCHS) is a genetic disorder of neurodevelopment, with an autosomal dominant transmission, caused by heterozygous mutations in thePHOX2Bgene. CCHS is a rare disorder characterized by hypoventilation due to the failure of autonomic control of breathing. Until now no curative treatment has been found. PHOX2B is a transcription factor that plays a crucial role in the development (and maintenance) of the autonomic nervous system, and in particular the neuronal structures involved in respiratory reflexes. The underlying pathogenetic mechanism is still unclear, although studiesin vivoand in CCHS patients indicate that some neuronal structures may be damaged. Moreover,in vitroexperimental data suggest that transcriptional dysregulation and protein misfolding may be key pathogenic mechanisms. This review summarizes latest researches that improved the comprehension of the molecular pathogenetic mechanisms responsible for CCHS and discusses the search for therapeutic intervention in light of the current knowledge aboutPHOX2Bfunction.
Genomic Profiling and Prognostic Value Analysis of Genetic Alterations in Chinese Resected Lung Cancer With Invasive Mucinous Adenocarcinoma
Authors: Cai Lei , Wang Jiangfeng , Yan Junrong , Zeng Jian , Zhu Liang , Liang Jinxiao , Pan Chao , Huang Xiancong , Jin Ju , Xu Yang , Wang Fufeng , Shao Yang , Xu Qinqin , Xia Guojie , Xing Minyan , Xu Xiaoling , Jiang Youhua
Published: January 2021

Background

Invasive mucinous adenocarcinoma (IMA) of the lung is a distinct histological subtype with unique clinical and pathological features. Despite previous genomic studies on lung IMA, the genetic characteristics and the prognosis-related biomarkers in Chinese surgically resected lung IMA remain unclear.

Methods

We collected 76 surgically resected primary tumors of invasive lung adenocarcinoma, including 51 IMA and 25 non-mucinous adenocarcinomas (non-IMA). IMA was further divided into pure-IMA (mucinous features≥90%) and mixed-IMA subgroups. Comprehensive genomic profiling based on targeted next-generation sequencing (NGS) of 425 genes was explored and genomic characteristics were evaluated for the correlation with postoperative disease-free survival (DFS).

Results

IMA had a unique genetic profile, with more diverse driver mutations and more tumor drivers/suppressors co-occurrence than that of non-IMA. The frequency of EGFR (72.0% vs. 40.0% vs. 23.1%, p=0.002) and ALK (undetected vs. 20.0% vs. 26.9%, p=0.015) alterations showed a trend of gradual decrease and increase from non-IMA to mixed-IMA to pure-IMA, respectively. The frequency of KRAS mutations in pure-IMA was higher than that in mixed-IMA, albeit statistically insignificant (23.1% vs. 4.0%, p=0.10). TP53 mutation was significantly less in pure-IMA compared to mixed-IMA and non-IMA (23.1% vs. 52.0% vs. 56.0%, p=0.03). Besides, IMA exhibited less arm-level amplifications (p=0.04) and more arm-level deletions (p=0.004) than non-IMA, and the frequency of amplification and deletion also showed a trend of gradual decrease and increase from non-IMA to mixed-IMA to pure-IMA, respectively. Furthermore, prognosis analysis in stage III IMA patients showed that patients harboring alterations in EGFR (mDFS=30.3 vs. 16.0 months, HR=0.19, P=0.027) and PI3K pathway (mDFS=36.0 vs. 16.0 months, HR=0.12, P=0.023) achieved prolonged DFS, while patients with poorly differentiated tumors (mDFS=14.1 vs. 28.0 months, HR=3.75, p=0.037) or with KRAS mutations (mDFS=13.0 vs. 20.0 months, HR=6.95, p=0.027) had shorter DFS. Multivariate analysis showed that KRAS mutations, PI3K pathway alterations, and tumor differentiation status were independent factors that have statistically significant influences on clinical outcomes of IMA patients.

Conclusion

Our study provided genomic insights into Chinese surgically resected lung IMA. We also identified several genomic features that may serve as potential biomarkers on postoperative recurrence in IMA patients with stage III disease.