bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation and Optimization of Microdrop Digital PCR for Detection of Serotype A and B Clostridium botulinum
Authors: Gao Pengya , Wu Changde , Zhang Jin , Wang Shuping , Huang Ying , Dong Yinping , Liu Tingting , Ye Changyun , Xu Xuefang , Xin Wenwen
Published: May 2022

Clostridium botulinum is the causative pathogen of botulism. Laboratory detection of C. botulinum is essential for clinical therapy treatment of botulism due to the difficulty in diagnosis, especially in infant botulism. The extreme toxicity of botulinum neurotoxin (BoNT) requires a sensitive detection method. Due to the detection limit of real-time quantitative PCR (q-PCR), a more sensitive detection method, micro-drop digital PCR (ddPCR) was applied in C. botulinum main serotypes A and B. The following performance criteria were evaluated by ddPCR: analytical sensitivity; repeatability; and diagnostic specificity. The limit of detection (LOD) was 0.84 and 0.88 copies/μl for BoNT A and B genes, respectively, by ddPCR with high specificity, compared to 5.04×102 and 6.91×102 copies/μl by q-PCR. It was increased 10 times compared with q-PCR in spiked stool samples. This improvement in sensitivity was especially important in clinical samples as more positive samples were detected by digital PCR compared with q-PCR. Meanwhile, enrichment time for low bacteria content samples was shortened by four hours both in serotypes A and B C. botulinum by ddPCR compared with q-PCR, which are important for laboratory diagnosis and epidemiology work.
Effects of Biochar on the Growth and Development of Tomato Seedlings and on the Response of Tomato Plants to the Infection of Systemic Viral Agents
Authors: Luigi Marta , Manglli Ariana , Dragone Immacolata , Antonelli Maria Grazia , Contarini Mario , Speranza Stefano , Bertin Sabrina , Tiberini Antonio , Gentili Andrea , Varvaro Leonardo , Tomassoli Laura , Faggioli Francesco
Published: May 2022

Biochar is a rich carbon product obtained by pyrolysis of biomass under a limited supply of oxygen. It is composed mainly of aromatic molecules, but its agronomic value is hard to evaluate and difficult to predict due to its great variable characteristics depending on the type of starting biomass and the conditions of pyrolysis. Anyway, it could be used as soil amendment because it increases the soil fertility of acidic soils, increases the agricultural productivity, and seems to provide protection against some foliar and soilborne diseases. In this study, the effects of biochar, obtained from olive pruning, have been evaluated on tomato seedlings growth and on their response to systemic agents' infection alone or added with beneficial microorganisms (Bacillus spp. and Trichoderma spp.). First, experimental data showed that biochar seems to promote the development of the tomato seedlings, especially at concentrations ranging from 1 to 20% (w/w with peat) without showing any antimicrobial effects on the beneficial soil bacteria at the tomato rhizosphere level and even improving their growth. Thus, those concentrations were used in growing tomato plants experimentally infected with tomato spotted wilt virus (TSWV) and potato spindle tuber viroid (PSTVd). The biochar effect was estimated by evaluating three parameters, namely, symptom expression, number of infected plants, and pathogen quantification, using RT-qPCR technique and −ΔΔCt analysis. Biochar at 10–15% and when added with Trichoderma spp. showed that it reduces the replication of PSTVd and the expression of symptoms even if it was not able to block the start of infection. The results obtained on TSWV-infected plants suggested that biochar could contribute to reducing both infection rate and virus replication. For systemic viral agents, such as PSTVd and TSWV, there are no curative control methods, and therefore, the use of prevention means, as can be assumed the use biochar, for example, in the nursery specialized in horticultural crops, can be of great help. These results can be an encouraging starting point to introduce complex biochar formulates among the sustainable managing strategies of plant systemic diseases.
Investigating Abiotic and Biotic Mechanisms of Pyrite Reduction
Authors: Spietz Rachel L. , Payne Devon , Kulkarni Gargi , Metcalf William W. , Roden Eric E. , Boyd Eric S.
Published: May 2022

Pyrite (FeS2) has a very low solubility and therefore has historically been considered a sink for iron (Fe) and sulfur (S) and unavailable to biology in the absence of oxygen and oxidative weathering. Anaerobic methanogens were recently shown to reduce FeS2 and assimilate Fe and S reduction products to meet nutrient demands. However, the mechanism of FeS2 mineral reduction and the forms of Fe and S assimilated by methanogens remained unclear. Thermodynamic calculations described herein indicate that H2 at aqueous concentrations as low as 10–10 M favors the reduction of FeS2, with sulfide (HS–) and pyrrhotite (Fe1–xS) as products; abiotic laboratory experiments confirmed the reduction of FeS2 with dissolved H2 concentrations greater than 1.98 × 10–4 M H2. Growth studies of Methanosarcina barkeri provided with FeS2 as the sole source of Fe and S resulted in H2 production but at concentrations too low to drive abiotic FeS2 reduction, based on abiotic laboratory experimental data. A strain of M. barkeri with deletions in all [NiFe]-hydrogenases maintained the ability to reduce FeS2 during growth, providing further evidence that extracellular electron transport (EET) to FeS2 does not involve H2 or [NiFe]-hydrogenases. Physical contact between cells and FeS2 was required for mineral reduction but was not required to obtain Fe and S from dissolution products. The addition of a synthetic electron shuttle, anthraquinone-2,6-disulfonate, allowed for biological reduction of FeS2 when physical contact between cells and FeS2 was prohibited, indicating that exogenous electron shuttles can mediate FeS2 reduction. Transcriptomics experiments revealed upregulation of several cytoplasmic oxidoreductases during growth of M. barkeri on FeS2, which may indicate involvement in provisioning low potential electrons for EET to FeS2. Collectively, the data presented herein indicate that reduction of insoluble FeS2 by M. barkeri occurred via electron transfer from the cell surface to the mineral surface resulting in the generation of soluble HS– and mineral-associated Fe1–xS. Solubilized Fe(II), but not HS–, from mineral-associated Fe1–xS reacts with aqueous HS– yielding aqueous iron sulfur clusters (FeSaq) that likely serve as the Fe and S source for methanogen growth and activity. FeSaq nucleation and subsequent precipitation on the surface of cells may result in accelerated EET to FeS2, resulting in positive feedback between cell activity and FeS2 reduction.
Metabolite Profile, Ruminal Methane Reduction, and Microbiome Modulating Potential of Seeds of Pharbitis nil
Authors: Bharanidharan Rajaraman , Thirugnanasambantham Krishnaraj , Ibidhi Ridha , Baik Myunggi , Kim Tae Hoon , Lee Yookyung , Kim Kyoung Hoon
Published: May 2022

We identified metabolites in the seeds of Pharbitis nil (PA) and evaluated their effects on rumen methanogenesis, fiber digestibility, and the rumen microbiome in vitro and in sacco. Four rumen-cannulated Holstein steers (mean body weight 507 ± 32 kg) were used as inoculum donor for in vitro trial and live continuous culture system for in sacco trial. PA was tested in vitro at doses ranging from 4.5 to 45.2% dry matter (DM) substrate. The in sacco trial was divided into three phases: a control phase of 10 days without nylon bags containing PA in the rumen, a treatment phase of 11 days in which nylon bags containing PA (180 g) were placed in the rumen, and a recovery phase of 10 days after removing the PA-containing bags from the rumen. Rumen headspace gas and rumen fluid samples were collected directly from the rumen. PA is enriched in polyunsaturated fatty acids dominated by linoleic acid (C18:2) and flavonoids such as chlorogenate, quercetin, quercetin-3-O-glucoside, and quinic acid derivatives. PA decreased (p < 0.001) methane (CH4) production linearly in vitro with a reduction of 24% at doses as low as 4.5% DM substrate. A quadratic increase (p = 0.078) in neutral detergent fiber digestibility was also noted, demonstrating that doses < 9% DM were optimal for simultaneously enhancing digestibility and CH4 reduction. In sacco, a 50% decrease (p = 0.087) in CH4 coupled with an increase in propionate suggested increased biohydrogenation in the treatment phase. A decrease (p < 0.005) in ruminal ammonia nitrogen (NH3-N) was also noted with PA in the rumen. Analysis of the rumen microbiome revealed a decrease (p < 0.001) in the Bacteroidetes-to-Firmicutes ratio, suggesting PA to have antiprotozoal potential. At the genus level, a 78% decrease in Prevotella spp. and a moderate increase in fibrolytic Ruminococcus spp. were noted in the treatment phase. In silico binding of PA metabolites to cyclic GMP-dependent protein kinase of Entodinium caudatum supported the antiprotozoal effect of PA. Overall, based on its high nutrient value and antiprotozoal activity, PA could probably replace the ionophores used for CH4 abatement in the livestock industry.
Present Impact of AlphaFold2 Revolution on Structural Biology, and an Illustration With the Structure Prediction of the Bacteriophage J-1 Host Adhesion Device
Authors: Goulet Adeline , Cambillau Christian
Published: May 2022

In 2021, the release of AlphaFold2 - the DeepMind’s machine-learning protein structure prediction program - revolutionized structural biology. Results of the CASP14 contest were an immense surprise as AlphaFold2 successfully predicted 3D structures of nearly all submitted protein sequences. The AlphaFold2 craze has rapidly spread the life science community since structural biologists as well as untrained biologists have now the possibility to obtain high-confidence protein structures. This revolution is opening new avenues to address challenging biological questions. Moreover, AlphaFold2 is imposing itself as an essential step of any structural biology project, and requires us to revisit our structural biology workflows. On one hand, AlphaFold2 synergizes with experimental methods including X-ray crystallography and cryo-electron microscopy. On the other hand, it is, to date, the only method enabling structural analyses of large and flexible assemblies resistant to experimental approaches. We illustrate this valuable application of AlphaFold2 with the structure prediction of the whole host adhesion device from the Lactobacillus casei bacteriophage J-1. With the ongoing improvement of AlphaFold2 algorithms and notebooks, there is no doubt that AlphaFold2-driven biological stories will increasingly be reported, which questions the future directions of experimental structural biology.
HIV-1 gp120 Impairs Spatial Memory Through Cyclic AMP Response Element-Binding Protein
Authors: Shrestha Jenny , Santerre Maryline , Allen Charles N. S. , Arjona Sterling P. , Merali Carmen , Mukerjee Ruma , Chitrala Kumaraswamy Naidu , Park Jin , Bagashev Asen , Bui Viet , Eugenin Eliseo A. , Merali Salim , Kaul Marcus , Chin Jeannie , Sawaya Bassel E.
Published: May 2022

HIV-associated neurocognitive disorders (HAND) remain an unsolved problem that persists despite using antiretroviral therapy. We have obtained data showing that HIV-gp120 protein contributes to neurodegeneration through metabolic reprogramming. This led to decreased ATP levels, lower mitochondrial DNA copy numbers, and loss of mitochondria cristae, all-important for mitochondrial biogenesis. gp120 protein also disrupted mitochondrial movement and synaptic plasticity. Searching for the mechanisms involved, we found that gp120 alters the cyclic AMP response element-binding protein (CREB) phosphorylation on serine residue 133 necessary for its function as a transcription factor. Since CREB regulates the promoters of PGC1α and BDNF genes, we found that CREB dephosphorylation causes PGC1α and BDNF loss of functions. The data was validated in vitro and in vivo. The negative effect of gp120 was alleviated in cells and animals in the presence of rolipram, an inhibitor of phosphodiesterase protein 4 (PDE4), restoring CREB phosphorylation. We concluded that HIV-gp120 protein contributes to HAND via inhibition of CREB protein function.
Serum sTREM2: A Potential Biomarker for Mild Cognitive Impairment in Patients With Obstructive Sleep Apnea
Authors: Jiahuan Xu , Ying Zou , Hongyu Jin , Zhijing Wei , Shibo Guan , Chengyue Deng , Liangyu Fu , Fan Liu , Wei Wang
Published: May 2022

Objective

Cognitive impairment is a common comorbidity in patients with obstructive sleep apnea (OSA) that leads to poor quality of life and a heavier medical burden. However, the assessment and longitudinal tracking of cognitive impairment in OSA is challenging. This study aimed to examine the alternation and related factors of serum soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in patients with OSA, and to explore whether serum sTREM2 could be a biomarker for mild cognitive impairment in OSA patients.

Methods

A total of 94 OSA patients and 13 snoring subjects were enrolled in this cross-sectional study. Demographic information, questionnaires, and polysomnography results were collected. Serum sTREM2 levels were quantified using an enzyme-linked immunosorbent assay. Multivariate linear regression was used to analyze the factors influencing sTREM2, and the receiver operating characteristic curve was used to assess the predictive value of serum sTREM2 for mild cognitive impairment in patients with OSA.

Results

Patients with OSA had higher serum sTREM2 levels than the controls. Multivariate linear regression analysis showed that serum sTREM2 levels in patients with OSA were associated with the Montreal Cognitive Assessment score and oxygen depletion index levels. Additionally, serum sTREM2 levels were higher in OSA patients with mild cognitive impairment (MCI) than in those without. The receiver operating characteristic curve showed that at a cutoff value of >18,437 pg/ml, the sensitivity of serum sTREM2 to predict MCI in OSA was 64.62%, the specificity was 68.97%, and the area under the curve was 0.70 (95% CI: 0.58–0.81).

Conclusion

Serum sTREM2 levels were elevated in patients with OSA, particularly in those with MCI. It therefore has the potential to be a biomarker for MCI in OSA patients.
NLRP3/Caspase-1-Mediated Pyroptosis of Astrocytes Induced by Antipsychotics Is Inhibited by a Histamine H1 Receptor-Selective Agonist
Authors: He Meng , Fan Jun , Zhou Ruqin , Gao Guanbin , Li Ruoxi , Zuo YuFeng , Li Benben , Li Yanmei , Sun Taolei
Published: May 2022

Emerging data indicate that antipsychotic treatment causes brain volume loss and astrocyte death, but the mechanisms remain elusive. Pyroptosis, inflammatory cell death characterized by the formation of inflammatory bodies, increased expression of nod-like receptor proteins (NLRPs) such as NLRP3, and activation of caspases and gasdermin D (GSDMD) are largely associated with innate immunity, inflammation, and cell injury/death. However, the main effect of antipsychotics on astrocyte pyroptotic signaling and the molecular mechanisms remain obscure. In the present study, 72-h treatment with olanzapine, quetiapine, risperidone, or haloperidol significantly decreased the viability of astrocytes. Twenty-four hour treatment with olanzapine, quetiapine, risperidone, or haloperidol dose-dependently increased the protein expression of astrocytic NLRP3, NLRP6, caspase-1, caspase-4, and GSDMD. Co-treatment with a histamine H1 receptor agonist, 2-(3-trifluoromethylphenyl) histamine (FMPH), dose-dependently reduced the increased expression of NLRP3, caspase-1 and GSDMD induced by olanzapine, quetiapine, risperidone, or haloperidol. Moreover, olanzapine, quetiapine, risperidone, or haloperidol treatment induced pore formation in the membranes of astrocytes, and these effects were inhibited by FMPH co-treatment. Taken together, antipsychotic treatment activated astrocyte pyroptotic signaling, and these effects may be related to antipsychotic-induced astrocyte death. H1 receptor activation is an effective treatment strategy to suppress antipsychotic-induced astrocyte pyroptosis and inflammation.
Analyzing Corin–BNP–NEP Protein Pathway Revealing Differential Mechanisms in AF-Related Ischemic Stroke and No AF-Related Ischemic Stroke
Authors: Shen Xiaozhu , Dong Nan , Xu Yiwen , Han Lin , Yang Rui , Liao Juan , Zhang Xianxian , Xie Tao , Wang Yugang , Chen Chen , Liu Mengqian , Jiang Yi , Yu Liqiang , Fang Qi
Published: May 2022

Background

The incidence of atrial fibrillation (AF)-related stroke increases with aging. Natriuretic peptides (NPs) family, including Corin-B type natriuretic peptide (BNP)-neprilysin (NEP) protein levels increased with age and are risk markers of cardiovascular and cerebrovascular diseases, such as AF and cardioembolic stroke. Aging is also linked to epigenetics, specifically DNA methylation. However, only a few studies have investigated the effect of DNA methylation on the NP system. Thus, the present study aimed to investigate whether the Corin-BNP-NEP protein pathway is involved in the pathogenesis of AF-stroke and CpG methylation in the promoter region of the Corin protein gene has an effect on AF-related ischemic stroke.

Methods

A total of 82 patients hospitalized with acute ischemic strokes were enrolled in this study. The differences in clinical information were compared between the AF-stroke (n = 37) and no AF-stroke groups (n = 45). Plasma-soluble Corin and NEP were detected using an ELISA kit. CpG methylation in the promoter region of the gene was assessed by a next-generation sequencing-based bisulfite sequencing polymerase chain reaction (BSP).

Results

(1) Patients in AF-stroke were older, had higher initial NIHSS score, 90-day mRs, higher D2-dimer, INR, and APTT, and low TG, TC, and HbA1c (all p < 0.05). (2) Serum levels of Corin and BNP in the AF-stroke group were significantly higher than that in the no AF-stroke group (p < 0.05). No significant difference was detected in the serum levels of NEP between the two groups. (3) The levels of CpG methylation in the promoter region of the Corin protein gene in the AF-stroke group was significantly lower than that in the no AF-stroke group (p < 0.05). The CpG sites with maximal methylation differences between the two groups were CORIN:678, CORIN:682, CORIN:694, and CORIN:700.

Conclusion

The current findings raise the possibility that the Corin–BNP–NEP protein pathway may be involved in the pathogenesis of AF-related ischemic stroke. Deficient CpG methylation in the promoter region of the Corin protein gene is associated with AF-related ischemic stroke.
Brain Activity in Age-Related Macular Degeneration Patients From the Perspective of Regional Homogeneity: A Resting-State Functional Magnetic Resonance Imaging Study
Authors: Liu Qi-Ying , Pan Yi-Cong , Shu Hui-Ye , Zhang Li-Juan , Li Qiu-Yu , Ge Qian-Min , Shao Yi , Zhou Qiong
Published: May 2022

Objective

In this study, the regional homogeneity (ReHo) method was used to investigate levels of cerebral homogeneity in individuals with age-related macular degeneration (AMD), with the aim of exploring whether these measures are associated with clinical characteristics.

Materials and Methods

Patients with AMD and healthy controls attending the First Affiliated Hospital of Nanchang University were invited to participate. Resting state functional magnetic resonance images were recorded in each participant and levels of synchronous neural activity were evaluated using ReHo. Receiver operating characteristic (ROC) curves were used to evaluate the sensitivity and specificity of this method.

Results

Eighteen patients with AMD (9 males and 9 females) and 15 healthy controls (HCs) were recruited. The two groups were approximately matched in age, gender and weight. Compared with controls, the ReHo values were significantly higher in the AMD group at the limbic lobe and parahippocampal gyrus, and were significantly reduced at the cingulate gyrus, superior frontal gyrus, middle frontal gyrus, inferior parietal lobule, and precentral gyrus. Mean ReHo values at the cingulate gyrus and the superior frontal gyrus were negatively correlated with clinical symptoms.

Conclusion

Brain neural homogeneity dysfunction is a manifestation of visual pathways in AMD patients, and may be one of the pathological mechanisms of chronic vision loss, anxiety and depression in AMD patients. In addition, the ReHo data may be useful for early screening for AMD.
Relationships Between Traditional Chinese Medicine Constitution and Age-Related Cognitive Decline in Chinese Centenarians
Authors: Sun Zhigao , Ping Ping , Li Yulong , Feng Long , Liu Fan , Zhao Yali , Yao Yao , Zhang Pei , Fu Shihui
Published: May 2022

Background

Age-related cognitive decline (ARCD) is a common condition among older adults, affecting 100 million people worldwide. Traditional Chinese Medicine’s (TCM) constitution is closely related to the occurrence and development of diseases in the elderly population. However, little is known about the relationships between TCM constitution and ARCD in the super-aged population. The present study aimed to investigate the relationships between the TCM constitution and ARCD in Chinese centenarians and to explore the application of the constitution to prevent ARCD in the elderly population.

Methods

Each participant underwent a standardized epidemiological investigation and physical examination, based on the China Hainan Centenarian Cohort Study. Data on the demographic characteristics and TCM constitution were collected using structured questionnaires.

Results

The present study included 636 centenarians aged 100–116 years. The prevalence of ARCD was 87.7% (n = 558 centenarians). In multiple linear regression analysis, an inverse relationship between Qi depression and Mini-Mental State Examination scales was significant after controlling for a wide range of other factors (P < 0.05). In multiple logistic regression analysis, Qi depression was positively associated with ARCD after full adjustment (P < 0.05).

Conclusion

As the first study in the world, the present study provides strong epidemiological evidence that Qi depression has a significant relationship with ARCD in Chinese centenarians, and regulating Qi depression may be a valuable method to prevent and treat ARCD in the elderly population.
Activation of Estrogen Receptor β in the Lateral Habenula Improves Ovariectomy-Induced Anxiety-Like Behavior in Rats
Authors: Liu Xiaofeng , Song Meiying , Chen Xiaowei , Sun Yanfei , Fan Renfei , Wang Liping , Lin Weihong , Hu Zheng , Zhao Hua
Published: May 2022

Background

Loss of estrogen due to menopause or ovarian resection is involved in the development of anxiety, which negatively impacts work productivity and quality of life. Estrogen modulates mood by binding to estrogen receptors in the brain. Estrogen receptor beta (ERβ) is highly expressed in the lateral habenula (LHb), a key site for controlling the activities of dopaminergic neurons in the ventral tegmental area (VTA) and serotoninergic neurons in the dorsal raphe nucleus (DRN) that are known to be involved in anxiety.

Methods

In this study, we examined the role of LHb in the anxiolytic-like effect of estrogen in ovariectomized (OVX) rats. The establishment of OVX anxiety model was validated in behavioral tests, including elevated plus maze (EPM) and mirror chamber maze (MCM) tasks. The expression of c-Fos in the LHb neurons was analyzed by immunohistochemistry, and monoamine neurotransmitter levels in related nuclei were analyzed using high-performance liquid chromatography (HPLC).

Results

Estrogen-treated OVX rats showed a lower degree of anxiety-like behavior than OVX rats. OVX rats showed anxiety-like behavior and low monoamine levels in the DRN and VTA compared with sham operated and estrogen-treated OVX rats. c-Fos expression in the LHb was higher than that in the sham operated and estrogen-treated OVX rats. Intra-LHb injection of the ERβ-selective agonist diarylprepionitrile (DPN) reduced expression of c-Fos (a neuronal activity marker) and anxiety-like behavior in OVX rats, but not in normal rats, as evidenced by increased time spent in EPM open areas and the MCM mirror chamber. These changes coincided with higher levels of serotonin and dopamine in the DRN and higher dopamine levels in the VTA in OVX rats receiving intra-LHb DPN compared with those receiving vehicle injection.

Conclusion

These results suggest that OVX-induced anxiety-like behavior may be associated with increased LHb activity. DPN may inhibit LHb activity to improve anxiety-like behavior in OVX rats by increasing monoamine neurotransmitter levels in the DRN and VTA.
Design of a Bio-Inspired Gait Phase Decoder Based on Temporal Convolution Network Architecture With Contralateral Surface Electromyography Toward Hip Prosthesis Control
Authors: Chen Yixi , Li Xinwei , Su Hao , Zhang Dingguo , Yu Hongliu
Published: May 2022

Inter-leg coordination is of great importance to guarantee the safety of the prostheses wearers, especially for the subjects at high amputation levels. The mainstream of current controllers for lower-limb prostheses is based on the next motion state estimation by the past motion signals at the prosthetic side, which lacks immediate responses and increases falling risks. A bio-inspired gait pattern generation architecture was proposed to provide a possible solution to the bilateral coordination issue. The artificial movement pattern generator (MPG) based on the temporal convolution network, fusing with the motion intention decoded from the surface electromyography (sEMG) measured at the impaired leg and the motion status from the kinematic modality of the prosthetic leg, can predict four sub gait phases. Experiment results suggested that the gait phase decoder exhibited a relatively high intra-subject consistency in the gait phase inference, adapted to various walking speeds with mean decoding accuracy ranging from 89.27 to 91.16% across subjects, and achieved an accuracy of 90.30% in estimating the gait phase of the prosthetic leg in the hip disarticulation amputee at the self-selected pace. With the proof of concept and the offline experiment results, the proposed architecture improves the walking coordination with prostheses for the amputees at hip level amputation.
The Cystine/Glutamate Antiporter, System xc–, Contributes to Cortical Infarction After Moderate but Not Severe Focal Cerebral Ischemia in Mice
Authors: He Yan , Hewett Sandra J.
Published: May 2022

Understanding the mechanisms underlying ischemic brain injury is of importance to the goal of devising novel therapeutics for protection and/or recovery. Previous work in our laboratory and in others has shown that activation of cystine/glutamate antiporter, system xc– (Sxc–), facilitates neuronal injury in several in vitro models of energy deprivation. However, studies on the contribution of this antiporter to ischemic brain damage in vivo are more limited. Since embolic or thrombotic transient or permanent occlusion of a cerebral blood vessel eventually leads to brain infarction in most stroke cases, we evaluated the contribution of Sxc– to cerebral ischemic damage by comparing brain infarction between mice naturally null for SLC7a11 (SLC7a11sut/sut mice) – the gene the encodes for the substrate specific light chain for system xc– – with their wild type (SLC7a11 + ⁣/ +) littermates following photothrombotic ischemic stroke of the middle cerebral artery (PTI) and permanent middle cerebral artery occlusion (pMCAo) rendered by cauterization. In the PTI model, we found a time-dependent reduction in cerebral blood flow that reached 50% from baseline in both genotypes 47–48 h post-illumination. Despite this, a remarkable reduction in incidence and total infarct volume of SLC7a11sut/sut mice was revealed 48 h following PTI as compared to SLC7a11+/+ mice. No difference in injury markers and/or infarct volume was measured between genotypes when occlusion of the MCA was permanent, however. Present data demonstrate a model-dependent differential role for Sxc– in focal cerebral ischemic damage, further highlighting that ischemic severity activates heterogeneous biochemical events that lead to damage engendered by stroke.
Structure-Activity Relationships of Dopamine Transporter Pharmacological Chaperones
Authors: Sutton Charles , Williams Erin Q. , Homsi Hoomam , Beerepoot Pieter , Nazari Reza , Han Dong , Ramsey Amy J. , Mash Deborah C. , Olson David E. , Blough Bruce , Salahpour Ali
Published: May 2022

Mutations in the dopamine transporter gene (SLC6A3) have been implicated in many human diseases. Among these is the infantile parkinsonism-dystonia known as Dopamine Transporter Deficiency Syndrome (DTDS). Afflicted individuals have minimal to no functional dopamine transporter protein. This is primarily due to retention of misfolded disease-causing dopamine transporter variants. This results in a variety of severe motor symptoms in patients and the disease ultimately leads to death in adolescence or young adulthood. Though no treatment is currently available, pharmacological chaperones targeting the dopamine transporter have been shown to rescue select DTDS disease-causing variants. Previous work has identified two DAT pharmacological chaperones with moderate potency and efficacy: bupropion and ibogaine. In this study, we carried out structure-activity relationships (SARs) for bupropion and ibogaine with the goal of identifying the chemical features required for pharmacological chaperone activity. Our results show that the isoquinuclidine substituent of ibogaine and its analogs is an important feature for pharmacological chaperone efficacy. For bupropion, the secondary amine group is essential for pharmacological chaperone activity. Lastly, we describe additional ibogaine and bupropion analogs with varying chemical modifications and variable pharmacological chaperone efficacies at the dopamine transporter. Our results contribute to the design and refinement of future dopamine transporter pharmacological chaperones with improved efficacies and potencies.
The Mesencephalic Locomotor Region: Beyond Locomotor Control
Authors: Noga Brian R. , Whelan Patrick J.
Published: May 2022

The mesencephalic locomotor region (MLR) was discovered several decades ago in the cat. It was functionally defined based on the ability of low threshold electrical stimuli within a region comprising the cuneiform and pedunculopontine nucleus to evoke locomotion. Since then, similar regions have been found in diverse vertebrate species, including the lamprey, skate, rodent, pig, monkey, and human. The MLR, while often viewed under the lens of locomotion, is involved in diverse processes involving the autonomic nervous system, respiratory system, and the state-dependent activation of motor systems. This review will discuss the pedunculopontine nucleus and cuneiform nucleus that comprises the MLR and examine their respective connectomes from both an anatomical and functional angle. From a functional perspective, the MLR primes the cardiovascular and respiratory systems before the locomotor activity occurs. Inputs from a variety of higher structures, and direct outputs to the monoaminergic nuclei, allow the MLR to be able to respond appropriately to state-dependent locomotion. These state-dependent effects are roughly divided into escape and exploratory behavior, and the MLR also can reinforce the selection of these locomotor behaviors through projections to adjacent structures such as the periaqueductal gray or to limbic and cortical regions. Findings from the rat, mouse, pig, and cat will be discussed to highlight similarities and differences among diverse species.
Cerebrovascular Events in Suspected Sepsis: Retrospective Prevalence Study in Critically Ill Patients Undergoing Full-Body Computed Tomography
Authors: Pohlan Julian , Nawabi Jawed , Witham Denis , Schroth Luna , Krause Finn , Schulze Jan , Gelen Simon , Ahlborn Robert , Rubarth Kerstin , Dewey Marc
Published: May 2022

Purpose

This study aimed at retrospectively evaluating full-body computed tomography (CT) examinations for the prevalence of cerebrovascular events in patients with suspected sepsis treated in the intensive care unit (ICU).

Methods

All full-body CT examinations, i.e., both cranial CT (cCT) and body CT including chest, abdomen and pelvis, for focus search in septic patients over a 12-months period were identified from three ICUs, using full-text search. From this retrospective cohort, we fully analyzed 278 cCT examinations for the occurrence of acute cerebral findings. All acute cerebrovascular events were independently reviewed by two blinded readers. Clinical and laboratory findings were extracted. The data were statistically analyzed using contingency tests.

Results

In our population of patients with suspected sepsis, 10.8% (n = 30/278) were identified to have major cerebral events, including 7.2% (n = 20/278) major cerebrovascular events and 4.3% (n = 12/278) generalized parenchymal damage. 13.4% (n = 22/163) of patients with a severe coma as compared with non-severe coma, 4.4% (n = 3/68), showed a major cerebral event (p = 0.04). Patients referred from the cardiology/nephrology ICU ward showed major cerebral events in 16.3% (n = 22/135), as compared with 4.9% (n = 3/61) in patients from pulmonary ICU and 6.1% (n = 5/82) major cerebral events with surgical referral (p = 0.02).

Conclusion

Our study provides further evidence that septic patients may suffer from cerebral events with relevance to their prognosis. Severe coma and the referring ward were associated with acute cerebral conditions. Full-body CT has the advantage of both detecting of septic foci and possibly identifying ischemic or hemorrhagic stroke in this vulnerable patient population.
Clinical Characteristics and Outcomes of Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorder With Brainstem Lesions as Heralding Prodrome
Authors: Ji Qiling , Dong Huiqing , Lee Hangil , Liu Zheng , Tong Yanna , Elkin Kenneth , Haddad Yazeed , Geng Xiaokun , Ding Yuchuan
Published: May 2022

Objective

The present study sought to differentiate multiple sclerosis and neuromyelitis optica spectrum disorder patients at their first attack by describing and distinguishing their clinical features, radiographic characteristics, and immunologic characteristics of serum and cerebrospinal fluid.

Methods

We retrospectively studied 58 patients with multiple sclerosis (MS) and 52 patients with neuromyelitis optica spectrum disorder (NMOSD) by referencing brainstem lesions as the prodromal events. Their demographics and presentation at the time of the first attack was evaluated including their gender, age, clinical features of the first attack, the expanded disability status scale (EDSS), brainstem lesion(s) by head MRI, and immunological indices of serum and cerebrospinal fluid.

Results

The NMOSD group had more female patients (4.8 vs. 1.9, p < 0.05), and was older than the MS group (37.81 ± 16.60 vs. 27.57 ± 11.17, p <0.001). NMOSD patients also had a significantly higher association with autoimmune diseases or positive autoimmune antibodies (p < 0.01). There was no significant difference in the EDSS scores between the two groups (p = 0.420). Central hiccups, vomiting, and pyramidal tract signs were more common in the NMOSD group than the MS group (p < 0.001, p < 0.001, p < 0.01), while eye movement abnormalities were more common with MS (p < 0.01). There were no significant differences in other clinical manifestations such as vertigo, diplopia, limb weakness, numbness, and eating difficulty. MS patients were more likely to have midbrain and pons imaging lesions (p < 0.001, p < 0.001), while NMOSD patients had more lesions in the medulla oblongata (p < 0.001). The lesions in the MS group were mostly located in the periphery, while those in the NMOSD group were centrally located (p < 0.001, p < 0.001). Patchy lesions were more common in MS patients (p < 0.001), while large lesions were more common in the NMOSD group (p < 0.001). Finally, serum AQP4 Ab was found only in the NMOSD group (p < 0.001).

Conclusion

Patients with MS and NMOSD have differentiating clinical manifestations at the time of their first brainstem lesions which include central hiccups, vomiting, pyramidal tract signs, and abnormal eye movements. Additionally, distinct imaging manifestations such as lesion location(s) and morphology may also aid in the development of pathognomonic criteria leading to timely initial diagnosis of MS and NMOSD.
Mobile Stroke Unit Operational Metrics: Institutional Experience, Systematic Review and Meta-Analysis
Authors: Ellens Nathaniel R. , Schartz Derrek , Rahmani Redi , Akkipeddi Sajal Medha K. , Kelly Adam G. , Benesch Curtis G. , Parker Stephanie A. , Burgett Jason L. , Proper Diana , Pilcher Webster H. , Mattingly Thomas K. , Grotta James C. , Bhalla Tarun , Bender Matthew T.
Published: May 2022

Background

The available literature on mobile stroke units (MSU) has focused on clinical outcomes, rather than operational performance. Our objective was to establish normalized metrics and to conduct a meta-analysis of the current literature on MSU performance.

Methods

Our MSU in upstate New York serves 741,000 people. We present prospectively collected, retrospectively analyzed data from the inception of our MSU in October of 2018, through March of 2021. Rates of transportation/dispatch and MSU utilization were reported. We also performed a meta-analysis using MEDLINE, SCOPUS, and Cochrane Library databases, calculating rates of tPA/dispatch, tPA-per-24-operational-hours (“per day”), mechanical thrombectomy (MT)/dispatch and MT/day.

Results

Our MSU was dispatched 1,719 times in 606 days (8.5 dispatches/24-operational-hours) and transported 324 patients (18.8%) to the hospital. Intravenous tPA was administered in 64 patients (3.7% of dispatches) and the rate of tPA/day was 0.317 (95% CI 0.150–0.567). MT was performed in 24 patients (1.4% of dispatches) for a MT/day rate of 0.119 (95% CI 0.074–0.163). The MSU was in use for 38,742 minutes out of 290,760 total available minutes (13.3% utilization rate). Our meta-analysis included 14 articles. Eight studies were included in the analysis of tPA/dispatch (342/5,862) for a rate of 7.2% (95% CI 4.8–9.5%, I2 = 92%) and 11 were included in the analysis of tPA/day (1,858/4,961) for a rate of 0.358 (95% CI 0.215–0.502, I2 = 99%). Seven studies were included for MT/dispatch (102/5,335) for a rate of 2.0% (95% CI 1.2–2.8%, I2 = 67%) and MT/day (103/1,249) for a rate of 0.092 (95% CI 0.046–0.138, I2 = 91%).

Conclusions

In this single institution retrospective study and meta-analysis, we outline the following operational metrics: tPA/dispatch, tPA/day, MT/dispatch, MT/day, and utilization rate. These metrics are useful for internal and external comparison for institutions with or considering developing mobile stroke programs.
Clinical Characteristics and Prognosis of Anti-AChR Positive Myasthenia Gravis Combined With Anti-LRP4 or Anti-Titin Antibody
Authors: Chen Yuping , Tao Xiaoyong , Wang Yan , Xu Shengjie , Yang Yanhua , Han Jinming , Qiu Feng
Published: May 2022

Objective

This study aimed to summarize the clinical characteristics and prognosis of patients with anti- acetylcholine receptor (AChR) positive myasthenia gravis (MG) with a combination of anti-LRP4 or Titin antibodies.

Methods

A total of 188 patients with generalized MG before immunotherapy were retrospectively collected and then divided into three groups: single anti-AChR positive-MG (AChR-MG, 101 cases), anti-AChR combined with anti-low-density lipoprotein receptor-related protein four-positive MG (AChR+LRP4-MG, 29 cases), and anti-AChR combined with anti-Titin-positive MG (AChR+Titin-MG, 58 cases). Clinical manifestations, therapeutic responses to immunotherapy, and follow-up information were analyzed.

Results

Of the 188 seropositive MG patients, 29 (15.4%) were positive for both AChR and LRP4 antibodies, and 58 (30.9%) were positive for both AChR and Titin antibodies. The mean disease onset ages in the three groups were 47.41 ± 7.0, 49.81 ± 9.2, and 48.11 ± 6.5 years, respectively. AChR+LRP4-MG showed female predominance (27.6% were males and 72.4% were females), with mild overall clinical symptoms. The AChR+Titin-MG group showed shorter times for conversion to generalized MG (5.14 ± 0.0 months) than the AChR-MG group (11.69 ± 0.0 months) and the AChR+LRP4-MG group (13.08 ± 0.5 months; P < 0.001 in both cases). Furthermore, AChR+Titin-MG group had increased bulbar dysfunction, higher incidences of thymoma (32.8 vs. 19.8% and 3.4%, P=0.035), more severe quantitative MG scores, as assessed by both QMG scores [15.5 (11.75–22.5) vs. 13 (8–19), P = 0.005; and 9 (6–14) P < 0.001], and MG-ADL scores [10 (8–13) vs. 8 (5–13), P = 0.018; and 6 (4–8), P < 0.001]. Treatment for AChR+Titin-MG was largely dependent on corticosteroids and immunosuppressive agents (56.7 vs. 19.2% and 16.7%, p = 0.028). The rates of achieving s(MMS) or better within 2 years following immunotherapy in the three groups were 51.5, 62.1, and 51.7%, respectively (P = 0.581).

Conclusion

Clinical symptoms of anti-AChR positive MG combined with Titin antibody were more severe and progressed faster than those in the AChR + LRP4 and AChR groups. Regardless of antibody status, all patients responded well to immunotherapy and had relatively good prognoses.
Fatigue Across the Lifespan in Men and Women: State vs. Trait
Authors: Wylie Glenn R. , Pra Sisto Amanda J. , Genova Helen M. , DeLuca John
Published: May 2022

Objective

Fatigue is commonly thought to worsen with age, but the literature is mixed: some studies show that older individuals experience more fatigue, others report the reverse. Some inconsistencies in the literature may be related to gender differences in fatigue while others may be due to differences in the instruments used to study fatigue, since the correlation between state (in the moment) and trait (over an extended period of time) measures of fatigue has been shown to be weak. The purpose of the current study was to examine both state and trait fatigue across age and gender using neuroimaging and self-report data.

Methods

We investigated the effects of age and gender in 43 healthy individuals on self-reported fatigue using the Modified Fatigue Impact Scale (MFIS), a measure of trait fatigue. We also conducted fMRI scans on these individuals and collected self-reported measures of state fatigue using the visual analog scale of fatigue (VAS-F) during a fatiguing task.

Results

There was no correlation between age and total MFIS score (trait fatigue) (r= –0.029,p= 0.873), nor was there an effect of gender [F(1,31)< 1]. However, for state fatigue, increasing age was associated with less fatigue [F(1,35)= 9.19,p< 0.01, coefficient = –0.4]. In the neuroimaging data, age interacted with VAS-F in the middle frontal gyrus. In younger individuals (20–32), more activation was associated with less fatigue, for individuals aged 33–48 there was no relationship, and for older individuals (55+) more activation was associated with more fatigue. Gender also interacted with VAS-F in several areas including the orbital, middle, and inferior frontal gyri. For women, more activation was associated with less fatigue while for men, more activation was associated with more fatigue.

Conclusion

Older individuals reported less fatigue during task performance (state measures). The neuroimaging data indicate that the role of middle frontal areas change across age: younger individuals may use these areas to combat fatigue, but this is not the case with older individuals. Moreover, these results may suggest greater resilience in females than males when faced with a fatiguing task.
The Association of Obesity and Cardiorespiratory Fitness in Relation to Cognitive Flexibility: An Event-Related Potential Study
Authors: Song Tai-Fen , Chu Chien-Heng , Nien Jui-Ti , Li Ruei-Hong , Wang Hsin-Yi , Chen Ai-Guo , Chang Yi-Chieh , Yang Kao-Teng , Chang Yu-Kai
Published: May 2022

This study investigates an association between obesity and cardiorespiratory fitness concerning their potential effects on cognitive flexibility in young adults from behavioral and neuroelectrical perspectives. Eligible young adults (N = 140, 18–25 years) were assigned into one of four groups, according to their status of obesity (i.e., body mass index) and cardiorespiratory fitness levels (i.e., estimated maximal oxygen uptake), namely, normal weight with high cardiorespiratory fitness (NH), obese with high cardiorespiratory fitness (OH), normal weight with low cardiorespiratory fitness (NL), and obese with low cardiorespiratory fitness (OL). The task-switching test was utilized, and its induced endogenous (P3) and exogenous (N1) event-related potential components were recorded. Concerning behavioral indices, the NH demonstrated superior behavioral performance across global switching and local switching of the task-switching test compared to individuals with lower cardiorespiratory fitness and obesity (i.e., NL, OH, and OL). Additionally, the OH demonstrated better performance than the OL during the heterogeneous condition. For neuroelectrical indices, the NH had larger mean P3 amplitudes during global and local switching than the other three groups. A larger N1 amplitude was also observed in the NH during local switching than in the OH group. The findings suggest that cardiorespiratory fitness has beneficial effects on cognitive flexibility, attentional resource allocation, and sensory evaluation in young adults. Furthermore, our research provided novel evidence showing that cardiorespiratory fitness might potentially alleviate the adverse effects of obesity on cognitive flexibility in young adults.
Altered Variability and Concordance of Dynamic Resting-State Functional Magnetic Resonance Imaging Indices in Patients With Major Depressive Disorder and Childhood Trauma
Authors: Luo Qianyi , Yu Huiwen , Chen Juran , Lin Xinyi , Wu Zhiyao , Yao Jiazheng , Li Yuhong , Wu Huawang , Peng Hongjun
Published: May 2022

Childhood trauma is a non-specific risk factor for major depressive disorder (MDD). resting-state functional magnetic resonance imaging (R-fMRI) studies have demonstrated changes in regional brain activity in patients with MDD who experienced childhood trauma. However, previous studies have mainly focused on static characteristics of regional brain activity. This study aimed to determine the specific brain regions associated with MDD with childhood trauma by performing temporal dynamic analysis of R-fMRI data in three groups of patients: patients with childhood trauma-associated MDD (n = 48), patients without childhood trauma-associated MDD (n = 30), and healthy controls (n = 103). Dynamics and concordance of R-fMRI indices were calculated and analyzed. In patients with childhood trauma-associated MDD, a lower dynamic amplitude of low-frequency fluctuations was found in the left lingual gyrus, whereas a lower dynamic degree of centrality was observed in the right lingual gyrus and right calcarine cortex. Patients with childhood trauma-associated MDD showed a lower voxel-wise concordance in the left middle temporal and bilateral calcarine cortices. Moreover, group differences (depressed or not) significantly moderated the relationship between voxel-wise concordance in the right calcarine cortex and childhood trauma history. Overall, patients with childhood trauma-associated MDD demonstrated aberrant variability and concordance in intrinsic brain activity. These aberrances may be an underlying neurobiological mechanism that explains MDD from the perspective of temporal dynamics.