bluuebunny/crossref_metadata_2025 huggingface dataset:
Monoclonal Antibodies for Protozoan Infections: A Future Reality or a Utopic Idea?
Authors: Longoni Silvia Stefania , Tiberti Natalia , Bisoffi Zeno , Piubelli Chiara
Published: October 2021

Following the SARS-CoV-2 pandemic, several clinical trials have been approved for the investigation of the possible use of mAbs, supporting the potential of this technology as a therapeutic approach for infectious diseases. The first monoclonal antibody (mAb), Muromonab CD3, was introduced for the prevention of kidney transplant rejection more than 30 years ago; since then more than 100 mAbs have been approved for therapeutic purposes. Nonetheless, only four mAbs are currently employed for infectious diseases: Palivizumab, for the prevention of respiratory syncytial virus (RSV) infections, Raxibacumab and Obiltoxaximab, for the prophylaxis and treatment against anthrax toxin and Bezlotoxumab, for the prevention ofClostridium difficilerecurrence. Protozoan infections are often neglected diseases for which effective and safe chemotherapies are generally missing. In this context, drug resistance and drug toxicity are two crucial problems. The recent advances in bioinformatics, parasite genomics, and biochemistry methodologies are contributing to better understand parasite biology, which is essential to guide the development of new therapies. In this review, we present the efforts that are being made in the evaluation of mAbs for the prevention or treatment of leishmaniasis, Chagas disease, malaria, and toxoplasmosis. Particular emphasis will be placed on the potential strengths and weaknesses of biological treatments in the control of these protozoan diseases that are still affecting hundreds of thousands of people worldwide.
Mechanisms of Proteinuria in HIV
Authors: Hall Gentzon , Wyatt Christina M.
Published: October 2021

Proteinuria is common in the setting of HIV infection, and may reflect comorbid kidney disease, treatment-related nephrotoxicity, and HIV-related glomerular diseases. The mechanisms of podocyte and tubulointerstial injury in HIV-associated nephropathy (HIVAN) have been the subject of intense investigation over the past four decades. The pathologic contributions of viral gene expression, dysregulated innate immune signaling, and ancestry-driven genetic risk modifiers have been explored in sophisticated cellular and whole animal models of disease. These studies provide evidence that injury-induced podocyte dedifferentiation, hyperplasia, cytoskeletal dysregulation, and apoptosis may cause the loss of glomerular filtration barrier integrity and slit diaphragm performance that facilitates proteinuria and tuft collapse in HIVAN. Although the incidence of HIVAN has declined with the introduction of antiretroviral therapy, the collapsing FSGS lesion has been observed in the context of other viral infections and chronic autoimmune disorders, and with the use of interferon-based therapies in genetically susceptible populations. This highlights the fact that the lesion is not specific to HIVAN and that the role of the immune system in aggravating podocyte injury warrants further exploration. This review will summarize our progress in characterizing the molecular mechanisms of podocyte dysfunction in HIVAN and other forms of HIV-associated kidney disease.
En Bloc Resection of Primary Large Esophageal Mucosa-Associated Lymphoid Tissue Lymphoma by Endoscopic Submucosal Dissection: A Case Report
Authors: Xia Yujia , Wang Yu , Han Jian , Liu Mei
Published: October 2021

Treatment of mucosa-associated lymphoid tissue (MALT) lymphoma has recently received considerable attention. Here, we report a case of large esophageal MALT lymphoma that was successfully en bloc resected using endoscopic submucosal dissection (ESD). A 77-year-old woman was admitted to our hospital with progressive dysphagia for more than 2 months. Upper gastrointestinal endoscopy revealed a large rounded submucosal mass covered by normal mucosa, located at the lower esophagus. Endoscopic ultrasonography (EUS) showed a well-demarcated hypoechoic mass chiefly located in the esophageal wall, but the layers of the esophageal wall were not clear. ESD was performed for diagnostic and treatment purposes. No complications occurred during or after ESD. The resected specimen measured 4.3 cm × 2.8 cm × 1.5 cm. The histologic findings were diagnostic of esophageal MALT lymphoma. Infiltration of neoplastic cells in the lateral margins of the resected specimen was not observed. However, vertical margins showed an R1 situation and mild damage to the muscularis propria. After 3 months, her dysphagia disappeared. Additional radiation therapy was then administered. After 5 months, the patient was still under surveillance and free of recurrent disease. Resection with ESD of such a large mass of MALT in the esophageal region has rarely been reported before in the literature.
Effects of Long-Term Triclosan Exposure on Microbiota in Zebrafish
Authors: Tang Ning , Fan Pianpian , Yu Xiaogang , Ma Rui , Tao Yexuan , Wang Weiye , Ouyang Fengxiu
Published: October 2021

Background: Triclosan (TCS) is a widely used antibacterial agent in personal care products and is ubiquitous in the environment. We aimed to examine whether TCS exposure affects microbiota in the gastrointestinal tract of zebrafish.

Methods: After exposure to TCS 0 (Dimethyl Sulphoxide, DMSO control), 0.03, 0.3, 3, 30, 100, and 300ng/ml, respectively, from day 0 to 120days post fertilization (dpf), or for 7days in adult 4-month zebrafish, the long- and short-term impact of TCS exposure on the microbiome in the gastrointestinal tract was evaluated by analyzing 16S rRNA gene V3-V4 region sequencing.

Results: The top two most dominant microbiota phyla were Proteobacteria and Fusobacteria phylum in all zebrafish groups. In TCS exposure 0–120 dpf, compared with DMSO control, the mean number of microbial operational taxonomic units (OTUs) was 54.46 lower (p<0.0001), Chao indice 41.40 lower (p=0.0004), and Ace indice 34.10 lower (p=0.0044) in TCS 300ng/ml group, but no change was observed in most of the other TCS concentrations. PCoA diagram showed that the microbial community in the long-term TCS 300ng/ml exposure group clustered differently from those in the DMSO control and other TCS exposure groups. A shorter body length of the zebrafish was observed in the long-term TCS exposure at 0.03, 100, and 300ng/ml. For 7-day short-term exposure in adult zebrafish, no difference was observed in alpha or beta diversity of microbiota nor the relative abundance of Proteobacteria or Fusobacteria phylum among DMSO control and any TCS levels, but a minor difference in microbial composition was observed for TCS exposure.

Conclusions: Long-term exposure to high TCS concentration in a window from early embryonic life to early adulthood may reduce diversity and alter the composition of microbiota in the gastrointestinal tract. The effect of short-term TCS exposure was not observed on the diversity of microbiota but there was a minor change of microbial composition in adult zebrafish with TCS exposure.
Alfalfa Silage Treated With Sucrose Has an Improved Feed Quality and More Beneficial Bacterial Communities
Authors: Kang Jinhe , Tang Shaoxun , Zhong Rongzhen , Tan Zhiliang , Wu Duanqin
Published: October 2021

Alfalfa silage is one of the main roughages in the production of dairy cow, which can provide nutrition with high quality to improve milk quality and production. Sucrose additions have been widely used to improve the silage quality. In this study, the effects of sucrose on the fermentation quality and bacterial communities of alfalfa silage were investigated here using 0, 0.5, and 1% sucrose ensiling treatments for 15, 30, and 60 days. The ensiling time significantly decreased the crude fiber content and increased the ammonia nitrogen, acetic acid content, and the relative abundance of Enterococcus in the silages. The 1% sucrose-treated silage at 60 days had the lowest neutral detergent fiber acid, acid detergent fiber, and crude fiber content and the highest relative feed value. Moreover, sucrose-treated silage contained less acetic acid, propionic acid, and butyric acid, and had a lower pH than the controls for each duration. Enterobacteriaceae, Klebsiella, and Enterococcus were the dominant genera in all groups, and the relative abundance of Enterococcus and Lactobacillus was higher in the 1% sucrose-treated group than in the control. These results suggested that sucrose supplementation could improve alfalfa silage quality and increase its beneficial bacterial content.
Oral Microbiota Analysis of Tissue Pairs and Saliva Samples From Patients With Oral Squamous Cell Carcinoma – A Pilot Study
Authors: Yang Ke , Wang Yuezhu , Zhang Shizhou , Zhang Dongsheng , Hu Lihua , Zhao Tengda , Zheng Huajun
Published: October 2021

Oral microbiota dysbiosis is associated with the occurrence and progression of oral cancer. To investigate the association between the microbiota and risk of oral squamous cell carcinoma (OSCC), we identified the microbial composition of paired tumor (TT)/normal paracancerous tissues (NPT) and saliva (TS) samples in OSCC patients through 16S rRNA gene sequencing. A total of 22 phyla, 321 genera, and 869 species were identified in the oral samples. Paired comparisons revealed significant differences between TT, NPT, and TS groups, with the genus Filifactor significantly enriched in TT. The phylum Actinobacteria; genus Veillonella; and species Granulicatella adiacens, Streptococcus sanguinis, and Veillonella rogosae were significantly enriched in NPT, while the phylum Bacteroidetes; genera Capnocytophaga, Haemophilus, and Prevotella; and seven species, including Capnocytophaga sp., Haemophilus sp., and Neisseria sp., were significantly enriched in TS. In TTs, the abundance of Prevotella intermedia was profoundly higher in the gingiva, while Capnocytophaga gingivalis and Rothia mucilaginosa were enriched in the lining mucosa and tongue. Increasing in abundance from the early tumor stage to the late stage, Solobacterium moorei in TT and Campylobacter sp. strain HMT 044 in TS were positively correlated with OSCC development, suggesting that bacteria were selected by different microenvironments. The correlation between 11 microbial species and 17 pathway abundances was revealed, indicating the potential function of low-abundance bacteria. Overall, our analysis revealed that multiple oral bacterial taxa are associated with a subsequent risk of OSCC and may be used as biomarkers for risk prediction and intervention in oral cancers.
Anti-cancer Substances and Safety of Lactic Acid Bacteria in Clinical Treatment
Authors: Liu Chaoran , Zheng Jiaqi , Ou Xuan , Han Yuzhu
Published: October 2021

Lactic acid bacteria (LAB) are a kind of Gram-positive bacteria which can colonize in the biological gastrointestinal tract and play a variety of probiotic roles. LAB have a wide range of applications in industry, animal husbandry, planting, food safety, and medical science fields. Previous studies on LAB have typically concentrated on their effects on improving the digestion and absorption of the gastrointestinal tract, regulating the balance of the microflora, and inhibiting the production and accumulation of toxic substances. The resistance of LAB to cancer is a topic of growing interest and relevance. This paper provided a summary of bio-active substances of LAB when they act against cancer, as well as the safety of LAB in clinical cancer treatment. Moreover, this paper further discussed several possible directions for future research and the potential application of LAB as anti-cancer therapy.
Cryptococcus neoformans and Other Opportunistic Cryptococcus Species in Pigeon Dropping in Saudi Arabia: Identification and Characterization by DNA Sequencing
Authors: Sirag Bashir , Khidir El-Shiekh , Dumyati Mohammed , Sindi Basam , Alsinnari Mahir , Faidah Hani , Ahmed Abdalla
Published: October 2021

The prevalent variants of Cryptococcus neoformans, and other Cryptococcus species in pigeon excreta in Western Region of Saudi Arabia were studied. Ninety pigeon dropping samples were plated directly on Niger seed agar, and suspected colonies were sequenced using Illumina MiSeq. Species identification was determined using sequence read mapping to reference genomes of the two C. neoformans variants. In addition, sequence reads were identified using the KmerFinder tool. internal transcribed spacer 2 in the rDNA was also used for fungal barcoding of none of the C. neoformans species using two fungal identification databases. Phylogeny was studied using CSI Phylogeny (Center for Genomic Epidemiology, Denmark). The C. neoformans var. grubii mitochondrion and chromosome 1 reference sequences (accession numbers NC_004336.1 and CP022321.1, respectively) were used for sequence comparison and variant calling. Fifteen Cryptococcus isolates were isolated, 11 were identified as C. neoformans var. grubii, and 4 were found to be other opportunistic Cryptococcus species. Phylogeny analysis of C. neoformans var. grubii isolates showed a high degree of similarity between the C. neoformans isolates especially at the mitochondrial genome level. This study supports the fact that pathogenic and opportunistic Cryptococcus species are prevalent in domestic bird excreta which is an easy source of infection in the susceptible population.
Newer Horizon of Mesenchymal Stem Cell–Based Therapy in the Management of SARS-CoV-2–Associated Mucormycosis: A Safe Hope for Future Medicine
Authors: Raghav Alok , Ali Syed Ghazanfar , Jeong Goo-Bo , Gautam Kirti Amresh , Banday Shahid , Mateen Qazi Noorul , Tripathi Prashant , Giri Richa , Agarwal Saurabh , Singh Manish , Khan Haris M.
Published: October 2021

SARS-CoV-2–infected patients are reported to show immunocompromised behavior that gives rise to a wide variety of complications due to impaired innate immune response, cytokine storm, and thrombo-inflammation. Prolonged use of steroids, diabetes mellitus, and diabetic ketoacidosis (DKA) are some of the factors responsible for the growth of Mucorales in such immunocompromised patients and, thus, can lead to a life-threatening condition referred to as mucormycosis. Therefore, an early diagnosis and cell-based management cosis is the need of the hour to help affected patients overcome this severe condition. In addition, extended exposure to antifungal drugs/therapeutics is found to initiate hormonal and neurological complications. More recently, mesenchymal stem cells (MSCs) have been used to exhibit immunomodulatory function and proven to be beneficial in a clinical cell-based regenerative approach. The immunomodulation ability of MSCs in mucormycosis patient boosts the immunity by the release of chemotactic proteins. MSC-based therapy in mucormycosis along with the combination of short-term antifungal drugs can be utilized as a prospective approach for mucormycosis treatment with promising outcomes. However, preclinical and in mucormyIn mucormycosis, the hyphae of clinical trials are needed to establish the precise mechanism of MSCs in mucormycosis treatment.
Effect of Fiber and Fecal Microbiota Transplantation Donor on Recipient Mice Gut Microbiota
Authors: Zhong Yifan , Cao Jiahong , Deng Zhaoxi , Ma Yanfei , Liu Jianxin , Wang Haifeng
Published: October 2021

Both fecal microbiota transplantation (FMT) and dietary fiber intervention were verified as effective ways to manipulate the gut microbiota, whereas little is known about the influence of the combined methods on gut microbiota. Here, we constructed “non-industrialized” and “industrialized” gut microbiota models to investigate the donor effect of FMT and diet effect in shaping the gut microbiota. Mice were transplanted fecal microbiota from domestic pig and received a diet with low-fiber (D) or high-fiber (DF), whereas the other two groups were transplanted fecal microbiota from wild pig and then received a diet with low-fiber (W) or high-fiber (WF), respectively. Gut microbiota of WF mice showed a lower Shannon and Simpson index (P < 0.05), whereas gut microbiota of W mice showed no significant difference than that of D and DF mice. Random forest models revealed the major differential bacteria genera between four groups, including Anaeroplasma or unclassified_o_Desulfovibrionales, which were influenced by FMT or diet intervention, respectively. Besides, we found a lower out-of-bag rate in the random forest model constructed for dietary fiber (0.086) than that for FMT (0.114). Linear discriminant analysis effective size demonstrated that FMT combined with dietary fiber altered specific gut microbiota, including Alistipes, Clostridium XIVa, Clostridium XI, and Akkermansia, in D, DF, W, and WF mice, respectively. Our results revealed that FMT from different donors coupled with dietary fiber intervention could lead to different patterns of gut microbiota composition, and dietary fiber might play a more critical role in shaping gut microbiota than FMT donor. Strategies based on dietary fiber can influence the effectiveness of FMT in the recipient.
Induction of UPR Promotes Interferon Response to Inhibit PRRSV Replication via PKR and NF-κB Pathway
Authors: Zhu Zhenbang , Liu Panrao , Yuan Lili , Lian Zhengmin , Hu Danhe , Yao Xiaohui , Li Xiangdong
Published: October 2021

Porcine reproductive and respiratory syndrome virus (PRRSV) was previously shown to induce a certain level of cellular stress during viral replication. Unfolded protein response (UPR) is a cellular stress response responsible for coping with stress and cellular survival. However, the pathway leading to the induction of UPR that may influence PRRSV replication is still unknown. Here, we found that PRRSV infection induced UPR prior to interferon response. Induction of UPR significantly enhanced the expression of interferon and interferon-related genes, thus leading to the suppression of PRRSV infection. Next, we explored the underlying mechanisms of UPR-induced antiviral response. We found that induction of UPR promoted the expression of protein kinase R (PKR), and PKR was highly correlated with the reduction of PRRSV replication. Furthermore, tunicamycin stimulation and PKR overexpression activated NF-κB and interferon response at the early stage of PRRSV infection, thus reinforcing the expression of type I interferons and proinflammatory cytokines and leading to inhibition of PRRSV. In addition, PRRSV nsp4 was shown to reduce the expression of PKR. These findings might have implications for our understandings of the host’s immune mechanism against PRRSV and a new strategy of PRRSV to evade the host antiviral immunity.
Screening and Identification of a Novel Anti-tuberculosis Compound That Targets Deoxyuridine 5′-Triphosphate Nucleotidohydrolase
Authors: Zhang Yu , Zhang Hongjuan , Chen Ying , Qiao Luyao , Han Yanxing , Lin Yuan , Si Shuyi , Jiang Jian-Dong
Published: October 2021

Tuberculosis (TB) is still a threat to humans worldwide. The rise of drug-resistant TB strains has escalated the need for developing effective anti-TB agents. Deoxyuridine 5′-triphosphate nucleotidohydrolase (dUTPase) is essential for thymidylate biosynthesis to maintain the DNA integrity. In Mycobacterium tuberculosis, dUTPase provides the sole source for thymidylate biosynthesis, which also has the specific five-residue loop and the binding pockets absent in human dUTPase. Therefore, dUTPase has been regarded as a promising anti-TB drug target. Herein, we used a luminescence-based dUTPase assay to search for the inhibitors target M. tuberculosis dUTPase (Mt-dUTPase) and identified compound F0414 as a potent Mt-dUTPase inhibitor with an IC50 of 0.80 ± 0.09 μM. F0414 exhibited anti-TB activity with low cytotoxicity. Molecular docking model and site-directed mutation experiments revealed that P79 was the key residue in the interaction of Mt-dUTPase and F0414. Moreover, F0414 was shown to have stronger binding with Mt-dUTPase than with Mt-P79A-dUTPase by surface plasmon resonance (SPR) detection. Interestingly, F0414 exhibited insensitivity and weak directly binding on human dUTPase compared with that on Mt-dUTPase. All the results highlight that F0414 is the first compound reported to have anti-TB activity by inhibiting Mt-dUTPase, which indicates the potential application in anti-TB therapy.
Tumor Microenvironment Characterization in Breast Cancer Identifies Prognostic and Neoadjuvant Chemotherapy Relevant Signatures
Authors: Ji Fei , Yuan Jiao-Mei , Gao Hong-Fei , Xu Ai-Qi , Yang Zheng , Yang Ci-Qiu , Zhang Liu-Lu , Yang Mei , Li Jie-Qing , Zhu Teng , Cheng Min-Yi , Wu Si-Yan , Wang Kun
Published: October 2021

Immune response which involves distinct immune cells is associated with prognosis of breast cancer. Nonetheless, less study have determined the associations of different types of immune cells with patient survival and treatment response. In this study, A total of 1,502 estrogen receptor(ER)-negative breast cancers from public databases were used to infer the proportions of 22 subsets of immune cells. Another 320 ER-negative breast cancer patients from Guangdong Provincial People’s Hospital were also included and divided into the testing and validation cohorts. CD8+ T cells, CD4+ T cells, B cells, and M1 macrophages were associated with favourable outcome (all p <0.01), whereas Treg cells were strongly associated with poor outcome (p = 0.005). Using the LASSO model, we classified patients into the stromal immunotype A and B subgroups according to immunoscores. The 10 years OS and DFS rates were significantly higher in the immunotype A subgroup than immunotype B subgroup. Stromal immunotype was identified as an independent prognostic indicator in multivariate analysis in all cohorts and was also related to pathological complete response(pCR) after neoadjuvant chemotherapy. The nomogram that integrated the immunotype and clinicopathologic features showed good predictive accuracy for pCR and discriminatory power. The stromal immunotype A subgroup had higher expression levels of immune checkpoint molecules (PD-L1, PD-1, and CTLA-4) and cytokines (IL-2, INF-γ, and TGF-β). In addition, patients with immunotype A and B diseases had distinct mutation signatures. Therefore, The stromal immunotypes could predict survival and responses of ER-negative breast cancer patients to neoadjuvant chemotherapy.
Exosome-Mediated Crosstalk Between Tumor and Tumor-Associated Macrophages
Authors: Chen Qi , Li Yuefeng , Gao Wujiang , Chen Lu , Xu Wenlin , Zhu Xiaolan
Published: October 2021

Exosomes are nanosized vesicles, derived from the endolysosomal compartment of cells and can shuttle diverse biomolecules such as nucleic acids, proteins, lipids, amino acids, and metabolites, which can reflect their origin cells. Delivery of these cargoes to recipient cells enables exosomes to influence diverse cellular functions. As one of the most abundant immune cells in the tumor microenvironment, tumor-associated macrophages (TAMs) are educated by the tumor milieu, which is rich in cancer cells and stroma components, to exert functions such as the promotion of tumor growth, immunosuppression, angiogenesis, and cancer cell dissemination. Herein, we focus on exosomes-mediated intercellular communication between tumor cells and TAM in the tumor microenvironment, which may provide new targets for anti-tumor treatment. In this review, we highlight the most recent studies on the effect of tumor/macrophage-derived exosomes on macrophage/tumor function in different cancer types.
MicroRNAs as Potential Orchestrators of Alzheimer's Disease-Related Pathologies: Insights on Current Status and Future Possibilities
Authors: Abuelezz Nermeen Z. , Nasr Fayza Eid , AbdulKader Mohammad Ahmed , Bassiouny Ahmad R. , Zaky Amira
Published: October 2021

Alzheimer's disease (AD) is a progressive and deleterious neurodegenerative disease, strongly affecting the cognitive functions and memory of seniors worldwide. Around 58% of the affected patients live in low and middle-income countries, with estimates of increasing deaths caused by AD in the coming decade. AD is a multifactor pathology. Mitochondrial function declines in AD brain and is currently emerging as a hallmark of this disease. It has been considered as one of the intracellular processes severely compromised in AD. Many mitochondrial parameters decline already during aging; mitochondrial efficiency for energy production, reactive oxygen species (ROS) metabolism and the de novo synthesis of pyrimidines, to reach an extensive functional failure, concomitant with the onset of neurodegenerative conditions. Besides its impact on cognitive functions, AD is characterized by loss of synapses, extracellular amyloid plaques composed of the amyloid-β peptide (Aβ), and intracellular aggregates of hyperphosphorylated Tau protein, accompanied by drastic sleep disorders, sensory function alterations and pain sensitization. Unfortunately, till date, effective management of AD-related disorders and early, non-invasive AD diagnostic markers are yet to be found. MicroRNAs (miRNAs) are small non-coding nucleic acids that regulate key signaling pathway(s) in various disease conditions. About 70% of experimentally detectable miRNAs are expressed in the brain where they regulate neurite outgrowth, dendritic spine morphology, and synaptic plasticity. Increasing studies suggest that miRNAs are intimately involved in synaptic function and specific signals during memory formation. This has been the pivotal key for considering miRNAs crucial molecules to be studied in AD. MicroRNAs dysfunctions are increasingly acknowledged as a pivotal contributor in AD via deregulating genes involved in AD pathogenesis. Moreover, miRNAs have been proved to control pain sensitization processes and regulate circadian clock system that affects the sleep process. Interestingly, the differential expression of miRNA panels implies their emerging potential as diagnostic AD biomarkers. In this review, we will present an updated analysis of miRNAs role in regulating signaling processes that are involved in AD-related pathologies. We will discuss the current challenges against wider use of miRNAs and the future promising capabilities of miRNAs as diagnostic and therapeutic means for better management of AD.
SIRT6 Through the Brain Evolution, Development, and Aging
Authors: Garcia-Venzor Alfredo , Toiber Debra
Published: October 2021

During an organism’s lifespan, two main phenomena are critical for the organism’s survival. These are (1) a proper embryonic development, which permits the new organism to function with high fitness, grow and reproduce, and (2) the aging process, which will progressively undermine its competence and fitness for survival, leading to its death. Interestingly these processes present various similarities at the molecular level. Notably, as organisms became more complex, regulation of these processes became coordinated by the brain, and failure in brain activity is detrimental in both development and aging. One of the critical processes regulating brain health is the capacity to keep its genomic integrity and epigenetic regulation—deficiency in DNA repair results in neurodevelopmental and neurodegenerative diseases. As the brain becomes more complex, this effect becomes more evident. In this perspective, we will analyze how the brain evolved and became critical for human survival and the role Sirt6 plays in brain health. Sirt6 belongs to the Sirtuin family of histone deacetylases that control several cellular processes; among them, Sirt6 has been associated with the proper embryonic development and is associated with the aging process. In humans, Sirt6 has a pivotal role during brain aging, and its loss of function is correlated with the appearance of neurodegenerative diseases such as Alzheimer’s disease. However, Sirt6 roles during brain development and aging, especially the last one, are not observed in all species. It appears that during the brain organ evolution, Sirt6 has gained more relevance as the brain becomes bigger and more complex, observing the most detrimental effect in the brains of Homo sapiens. In this perspective, we part from the evolution of the brain in metazoans, the biological similarities between brain development and aging, and the relevant functions of Sirt6 in these similar phenomena to conclude with the evidence suggesting a more relevant role of Sirt6 gained in the brain evolution.
Evaluation of the Activity of Choline Acetyltransferase From Different Synaptosomal Fractions at the Distinct Stages of Spatial Learning in the Morris Water Maze
Authors: Storozheva Zinaida I. , Zakharova Elena I. , Proshin Andrey T.
Published: October 2021

Accumulated data have evidenced that brain cholinergic circuits play a crucial role in learning and memory; however, our knowledge about the participation of neocortical and hippocampal cholinergic systems in spatial learning needs to be refined. The aim of this study was to evaluate the association of the activity of membrane-bound and soluble choline acetyltransferase (ChAT) in the synaptosomal sub-fractions of the neocortex and hippocampus with performance of the spatial navigation task in the Morris water maze at different temporal stages of memory trace formation. To identify distinct stages of memory formation, rats were trained using a 5-day protocol with four trials per day. The mean escape latency for each trial was collected, and the entire dataset was subjected to principal component analysis. Based on the Morris water maze protocol, there were three relatively distinct stages of memory formation: days 1–2, day 3, and days 4–5. The remotely stored memory trace tested in repeated and reversal learning beginning on day 19 (14 days after the end of initial learning) was associated at the individual level mainly with performance during the second trial on day 21 (the third day or repeated or reversal learning). The ChAT activity data suggest the participation of cortical cholinergic projections mainly in the first stage of spatial learning (automatic sensory processing) and the involvement of hippocampal interneurons in the second stage (error-corrected learning). Cholinergic cortical interneurons participated mainly in the stage of asymptotic performance (days 4–5). It is advisable to evaluate other signalling pathways at the identified stages of memory formation.
insideOut: A Bio-Inspired Machine Learning Approach to Estimating Posture in Robots Driven by Compliant Tendons
Authors: Hagen Daniel A. , Marjaninejad Ali , Loeb Gerald E. , Valero-Cuevas Francisco J.
Published: October 2021

Estimates of limb posture are critical for controlling robotic systems. This is generally accomplished with angle sensors at individual joints that simplify control but can complicate mechanical design and robustness. Limb posture should be derivable from each joint's actuator shaft angle but this is problematic for compliant tendon-driven systems where (i) motors are not placed at the joints and (ii) nonlinear tendon stiffness decouples the relationship between motor and joint angles. Here we propose a novel machine learning algorithm to accurately estimate joint posture during dynamic tasks by limited training of an artificial neural network (ANN) receiving motor anglesandtendon tensions, analogous to biological muscle and tendon mechanoreceptors. Simulating an inverted pendulum—antagonistically-driven by motors and nonlinearly-elastic tendons—we compare how accurately ANNs estimate joint angles when trained with different sets of non-collocated sensory information generated via random motor-babbling. Cross-validating with new movements, we find that ANNs trained with motor anglesandtendon tension data predict joint angles more accurately than ANNs trained without tendon tension. Furthermore, these results are robust to changes in network/mechanical hyper-parameters. We conclude that regardless of the tendon properties, actuator behavior, or movement demands, tendon tension information invariably improves joint angle estimates from non-collocated sensory signals.
The Development of the Mesoprefrontal Dopaminergic System in Health and Disease
Authors: Islam K. Ushna S. , Meli Norisa , Blaess Sandra
Published: October 2021

Midbrain dopaminergic neurons located in the substantia nigra and the ventral tegmental area are the main source of dopamine in the brain. They send out projections to a variety of forebrain structures, including dorsal striatum, nucleus accumbens, and prefrontal cortex (PFC), establishing the nigrostriatal, mesolimbic, and mesoprefrontal pathways, respectively. The dopaminergic input to the PFC is essential for the performance of higher cognitive functions such as working memory, attention, planning, and decision making. The gradual maturation of these cognitive skills during postnatal development correlates with the maturation of PFC local circuits, which undergo a lengthy functional remodeling process during the neonatal and adolescence stage. During this period, the mesoprefrontal dopaminergic innervation also matures: the fibers are rather sparse at prenatal stages and slowly increase in density during postnatal development to finally reach a stable pattern in early adulthood. Despite the prominent role of dopamine in the regulation of PFC function, relatively little is known about how the dopaminergic innervation is established in the PFC, whether and how it influences the maturation of local circuits and how exactly it facilitates cognitive functions in the PFC. In this review, we provide an overview of the development of the mesoprefrontal dopaminergic system in rodents and primates and discuss the role of altered dopaminergic signaling in neuropsychiatric and neurodevelopmental disorders.
Magnetoencephalography STOUT Method Adapted to Radiofrequency Thermocoagulation for MR-Negative Insular Epilepsy: A Case Report
Authors: Ma Kaiqiang , Luan Guoming , Wang Xiongfei , Luo Shen , Qin Lang , Teng Pengfei , Guan Yuguang , Zhao Meng , Wang Jing , Wang Mengyang , Gao Jia-Hong
Published: October 2021

Epilepsy is one of the most challenging neurologic diseases confronted by human society. Approximately 30–40% of the worldwide epilepsy patients are diagnosed with drug-resistant epilepsy and require pre-surgery evaluation. Magnetoencephalography (MEG) is a unique technology that provides optimal spatial-temporal resolution and has become a powerful non-invasive imaging modality that can localize the interictal spikes and guide the implantation of intracranial electrodes. Currently, the most widely used MEG source estimation method for clinical applications is equivalent current dipoles (ECD). However, ECD has difficulties in precisely locating deep sources such as insular lobe. In contrast to ECD, another MEG source estimation method named spatio-temporal unifying tomography (STOUT) with spatial sparsity has particular advantages in locating deep sources. In this case study, we recruited a 5 year-old female patient with insular lobe epilepsy and her seizure recurred in 1 year after receiving the radiofrequency thermocoagulation (RF-TC) therapy. The STOUT method was adopted to locate deep sources for identifying the epileptic foci in epilepsy evaluation. MEG STOUT method strongly supported a stereo-electroencephalographic (SEEG)-guided RF-TC operation, and the patient reported a satisfactory therapeutic effect. This case raises the possibility that STOUT method can be used particularly for the localization of deep sources, and successfully conducted RF-TC under the guidance of MEG STOUT results.
Radiological and Laboratory Features of Multiple Sclerosis Patients With Immunosuppressive Therapy: A Multicenter Retrospective Study in Japan
Authors: Ashida Shinji , Ochi Hirofumi , Hamatani Mio , Fujii Chihiro , Nishigori Ryusei , Kawamura Kazuyuki , Matsumoto Sadayuki , Nakagawa Masanori , Takahashi Ryosuke , Mizuno Toshiki , Kondo Takayuki
Published: October 2021

Background: Multiple sclerosis (MS) is a relapsing, inflammatory, and demyelinating disease of central nervous system showing marked clinical heterogeneity. Many factors might influence the choice of relapse prevention drug, and treatment response varies among patients. Despite the enlargement of disease-modifying drugs for MS (MS-DMDs), some patients have been treated with corticosteroid and/or immunosuppressant (CS/IS).

Objective: To clarify the radiological and laboratory features of MS treated with CS/IS for relapse prevention.

Methods: Clinical records including radiological and laboratory findings, and drugs used for relapse prevention were reviewed retrospectively.

Results: Out of 92 consecutive MS patients, 25 (27%) were treated with CS/IS. The followings were observed less frequently in patients treated with CS/IS than in those with MS-DMDs: three or more periventricular lesions, ovoid lesions, subcortical lesions, typical contrast-enhancing lesions, negative for serum autoantibodies, and positive for oligoclonal bands in the cerebrospinal fluid. Multiple logistic regression analysis revealed that the absence of typical contrast-enhancing lesions and positivity for serum autoantibodies were independent factors associated with CS/IS prescription (odds ratio 25.027 and 14.537, respectively).

Conclusion: In this cohort of Japanese patients clinically diagnosed with MS, radiological and serological findings atypical of MS were observed more frequently in patients treated with CS/IS than in those with MS-DMDs as a part of MS therapy. The absence of contrast-enhancing lesions typical of MS and positivity for serum autoantibodies were independent factors strongly associated with CS/IS use.
The Genotype and Phenotype Features in a Large Chinese MFN2 Mutation Cohort
Authors: Ma Yan , Sun Aping , Zhang Yingshuang , Fan Dongsheng , Liu Xiaoxuan
Published: October 2021

Introduction:Charcot–Marie–Tooth disease type 2A (CMT2A) is a group of clinically and genetically heterogeneous disorders, which is mostly caused by mutations of themitofusin2(MFN2) gene. As the genotype–phenotype characteristics of CMT2A were still incompletely understood, we further explored the spectrum of CMT2A variants in China and demonstrated their phenotypic diversities.

Methods:A total of 402 index patients/families with CMT throughout Mainland China were enrolled in this study. Among them, we analyzed 20 unrelated index cases with CMT2A by Sanger sequencing, next-generation sequencing, or whole-exome sequencing. Detailed clinical and genetic features of CMT2A patients were collected and analyzed. Of note,de novomutations were not rare in MFN2 gene; we compared the clinical features of patients from thede novogroup with those from the non-de novogroup.

Results:We identified 20 MFN2 variants, occupying 5.0% of CMT. Most patients presented with early onset and moderate phenotype with abnormal gait and foot drop as the main complaints at onset. Pyramidal signs accounts for 31.6% (6/19) in all patients, which is not uncommon. Four novel variants (p.Tyr752*, c.475-2A>G, p.Val99Met, and p.Arg275_Gln276insArg) were identified in the cohort. Besides,de novovariants occupied 35.0% (7/20) in our study with a much earlier age at onset compared with those in the non-de novogroup (p= 0.021).

Conclusion:Chinese CMT2A is a predominant typical pure CMT2A, with early onset and mild to moderate phenotype. Given the high frequency ofde novoMFN2 mutations, genetic study should be considered for patients with early onset and severe idiopathic axonal neuropathy.
Time Course of Perceived Visual Distortion and Axial Length Growth in Myopic Children Undergoing Orthokeratology
Authors: Liu Guihua , Wu Yiyuan , Bi Hua , Wang Biying , Gu Tianpu , Du Bei , Tong Jianliang , Zhang Bin , Wei Ruihua
Published: October 2021

Purpose: To establish the time course of the subjective visual function changes during the first month of orthokeratology treatment in myopic children, and to investigate how the time course variations are associated with the objective optical quality changes and the axial length growth (ALG) after 1 year of treatment.

Methods: A total of 58 myopic children aged from 8 to 16 years participated in this self-controlled prospective study. All subjects were fitted with designed spherical four-zone orthokeratology lenses. Subjective visual function was evaluated with orientation discrimination threshold (ODT), and objective optical quality was quantified with the high-order aberration root-mean-square (HOA-RMS) and the changing speed of HOA. The measurements were done before the lens fitting and 1 day, 1-, 2-, and 4-weeks after lens wear. Axial length was obtained at baseline and 1-year follow-up, and ALG was defined as the difference. One-way ANOVA was conducted to compare the difference for statistical analysis.

Results: After lens fitting, the ODT time courses peaked on day 1 in 28 children, 1 week in 15 children, 2 weeks in 11 children, and 4 weeks in 4 children. In contrast, the HOA-RMS steadily rose during the first month, and the changing speed of HOA was only transiently elevated on day 1 after the initial lens wear. The ALG was 0.12 ± 0.20 mm in subjects whose ODT peaked at day 1, 0.08 ± 0.09 mm in subjects whose ODT peaked on 1-week, and 0.12 ± 0.15 mm in subjects whose ODT peaked on 2-week or later. There was no difference in axial growth among the subjects whose ODT peaked at different days (P = 0.734).

Conclusion: While half ODT time course resembled the changing speed of HOA with a transient elevation on day 1, about a quarter of the ODT time course resemble the steadily rising of HOA-RMS, and the rest was located in the middle. The ALGs in children with different types of ODT time courses were similar.
Assessing the Perceived Value of Neuroethics Questions and Policy to Neuro-Entrepreneurs
Authors: Moss Ankita U. , Li Zone R. , Rommelfanger Karen S.
Published: October 2021

Neuroscience and its findings have deep personal and cultural meaning, so the implications of brain science raise new flavors of ethical issues not covered by traditional bioethics. The field of neuroethics bridges this gap, addressing and responding to the ethical, legal, and social issues intimately related to the evolving landscape of neuroscience. Neuroethical concerns have registered at the highest levels of government. In 2018, an interdisciplinary global neuroethics group working with leading scientists from the International Brain Initiative, a consortium of seven large-scale national-level brain research projects around the globe, published “Neuroethics Questions to Guide Ethical Research in the International Brain Initiatives.” The document provides guiding questions to consider throughout the lifecycle of neuroscience research. These questions tackle issues such as identity, morality, cross-cultural differences, privacy, and potential stakeholder involvement in ethical decision-making. In our work with the International Brain Initiative, we noted the important role that the private sector will play in translating and scaling neuroscience for society. We also noticed a gap in communication and collaboration between government, academia and the private sector. These guiding questions were largely co-created with policy makers and academics, so it was unclear how these issues might be received by neuro-entrepreneurs and neuro-industry. We hoped to identify not only common concerns, but also a common language for discussing neuroethical issues with stakeholders outside of government and academia. We used empirical ethics methods to assess the perceived value and attitudes of neuro-entrepreneurs toward neuroethical issues and whether or not these issues align with the process of neuro-innovation. We conducted one-on-one structured interviews with 21 neuro-entrepreneurs in the private sector and used two independent reviewers to analyze for themes. From this preliminary research, we identified key neuroethical themes and processual pain points of neurotech entrepreneurs throughout the innovation process. We also provide a preliminary neuroethics needs assessment for neuro-industry and suggest avenues through which neuroethicists can work with neurotech leadership to build an ethically aligned future. Overall, we hope to raise awareness and provide actionable steps toward advancing and accelerating societally impactful neuroscience.
Electrophysiological Responses in the Human S3 Nerve During Sacral Neuromodulation for Fecal Incontinence
Authors: Gmel Gerrit E. , Vollebregt Paul F. , Thijssen Marjolein E. G. , Santos Escapa Rosana , McAlees Eleanor , Mugan Dave , Parker John L. , Knowles Charles H.
Published: October 2021

Intra-operative electrode placement for sacral neuromodulation (SNM) relies on visual observation of motor contractions alone, lacking complete information on neural activation from stimulation. This study aimed to determine whether electrophysiological responses can be recorded directly from the S3 sacral nerve during therapeutic SNM in patients with fecal incontinence, and to characterize such responses in order to better understand the mechanism of action (MOA) and whether stimulation is subject to changes in posture. Eleven patients undergoing SNM were prospectively recruited. A bespoke stimulating and recording system was connected (both intraoperatively and postoperatively) to externalized SNM leads, and electrophysiological responses to monopolar current sweeps on each electrode were recorded and analyzed. The nature and thresholds of muscle contractions (intraoperatively) and patient-reported stimulation perception were recorded. We identified both neural responses (evoked compound action potentials) as well as myoelectric responses (far-field potentials from muscle activation). We identified large myelinated fibers (conduction velocity: 36–60 m/s) in 5/11 patients, correlating with patient-reported stimulation perception, and smaller myelinated fibers (conduction velocity <15 m/s) in 4/11 patients (not associated with any sensation). Myoelectric responses (observed in 7/11 patients) were attributed to pelvic floor and/or anal sphincter contraction. Responses varied with changes in posture. We present the first direct electrophysiological responses recorded from the S3 nerve during ongoing SNM in humans, showing both neural and myoelectric responses. These recordings highlight heterogeneity of neural and myoelectric responses (relevant to understanding MOA of SNM) and confirm that electrode lead position can change with posture.
Disruption of Glucose Metabolism in Aged Octodon degus: A Sporadic Model of Alzheimer's Disease
Authors: Cisternas Pedro , Gherardelli Camila , Salazar Paulina , Inestrosa Nibaldo C.
Published: October 2021

Alzheimer's disease is a progressive neurodegenerative disorder and the most common cause of dementia. Although transgenic Alzheimer's disease (AD) animal models have greatly contributed to our understanding of the disease, therapies tested in these animals have resulted in a high rate of failure in preclinical trials for AD. A promising model is Octodon degus (degu), a Chilean rodent that spontaneously develops AD-like neuropathology. Previous studies have reported that, during aging, degus exhibit a progressive decline in cognitive function, reduced neuroinflammation, and concomitant increases in the number and size of amyloid β (Aβ) plaques in several brain regions. Importantly, in humans and several AD models, a correlation has been shown between brain dysfunction and neuronal glucose utilization impairment, a critical aspect considering the high-energy demand of the brain. However, whether degus develop alterations in glucose metabolism remains unknown. In the present work, we measured several markers of glucose metabolism, namely, glucose uptake, ATP production, and glycolysis and pentose phosphate pathway (PPP) flux, in hippocampal slices from degus of different ages. We found a significant decrease in hippocampal glucose metabolism in aged degus, caused mainly by a drop in glucose uptake, which in turn, reduced ATP synthesis. Moreover, we observed a negative correlation between age and PPP flux. Together, our data further support the use of degus as a model for studying the neuropathology involved in sporadic AD-like pathology and as a potentially valuable tool in the search for effective treatments against the disease.