bluuebunny/crossref_metadata_2025 huggingface dataset:
Soluble Receptor Isoform of IFN-Beta (sIFNAR2) in Multiple Sclerosis Patients and Their Association With the Clinical Response to IFN-Beta Treatment
Authors: Aliaga-Gaspar Pablo , Hurtado-Guerrero Isaac , Ciano-Petersen Nicolas Lundahl , Urbaneja Patricia , Brichette-Mieg Isabel , Reyes Virginia , Rodriguez-Bada Jose Luis , Alvarez-Lafuente Roberto , Arroyo Rafael , Quintana Ester , Ramió-Torrentà Lluis , Alonso Ana , Leyva Laura , Fernández Oscar , Oliver-Martos Begoña
Published: December 2021

Purpose

Interferon beta receptor 2 subunit (IFNAR2) can be produced as a transmembrane protein, but also as a soluble form (sIFNAR2) generated by alternative splicing or proteolytic cleavage, which has both agonist and antagonist activities for IFN-β. However, its role regarding the clinical response to IFN-β for relapsing-remitting multiple sclerosis (RRMS) is unknown. We aim to evaluate the in vitro short-term effects and after 6 and 12 months of IFN-β therapy on sIFNAR2 production and their association with the clinical response in MS patients.

Methods

Ninety-four RRMS patients were included and evaluated at baseline, 6 and 12 months from treatment onset. A subset of 41 patients were classified as responders and non-responders to IFN-β therapy. sIFNAR2 serum levels were measured by ELISA. mRNA expression for IFNAR1, IFNAR2 splice variants, MxA and proteases were assessed by RT-PCR. The short-term effect was evaluated in PBMC from RRMS patients after IFN-β stimulation in vitro.

Results

Protein and mRNA levels of sIFNAR2 increased after IFN-β treatment. According to the clinical response, only non-responders increased sIFNAR2 significantly at both protein and mRNA levels. sIFNAR2 gene expression correlated with the transmembrane isoform expression and was 2.3-fold higher. While MxA gene expression increased significantly after treatment, IFNAR1 and IFNAR2 only slightly increased. After short-term IFN-β in vitro induction of PBMC, 6/7 patients increased the sIFNAR2 expression.

Conclusions

IFN-β administration induces the production of sIFNAR2 in RRMS and higher levels might be associated to the reduction of therapeutic response. Thus, levels of sIFNAR2 could be monitored to optimize an effective response to IFN-β therapy.
The Role of Immune Cells in Post-Stroke Angiogenesis and Neuronal Remodeling: The Known and the Unknown
Authors: Ma Yinzhong , Yang Shilun , He Qianyan , Zhang Dianhui , Chang Junlei
Published: December 2021

Following a cerebral ischemic event, substantial alterations in both cellular and molecular activities occur due to ischemia-induced cerebral pathology. Mounting evidence indicates that the robust recruitment of immune cells plays a central role in the acute stage of stroke. Infiltrating peripheral immune cells and resident microglia mediate neuronal cell death and blood-brain barrier disruption by releasing inflammation-associated molecules. Nevertheless, profound immunological effects in the context of the subacute and chronic recovery phase of stroke have received little attention. Early attempts to curtail the infiltration of immune cells were effective in mitigating brain injury in experimental stroke studies but failed to exert beneficial effects in clinical trials. Neural tissue damage repair processes include angiogenesis, neurogenesis, and synaptic remodeling, etc. Post-stroke inflammatory cells can adopt divergent phenotypes that influence the aforementioned biological processes in both endothelial and neural stem cells by either alleviating acute inflammatory responses or secreting a variety of growth factors, which are substantially involved in the process of angiogenesis and neurogenesis. To better understand the multiple roles of immune cells in neural tissue repair processes post stroke, we review what is known and unknown regarding the role of immune cells in angiogenesis, neurogenesis, and neuronal remodeling. A comprehensive understanding of these inflammatory mechanisms may help identify potential targets for the development of novel immunoregulatory therapeutic strategies that ameliorate complications and improve functional rehabilitation after stroke.
Active or Autoclaved Akkermansia muciniphila Relieves TNF-α-Induced Inflammation in Intestinal Epithelial Cells Through Distinct Pathways
Authors: Luo Yuheng , Lan Cong , Xie Kunhong , Li Hua , Devillard Estelle , He Jun , Liu Li , Cai Jingyi , Tian Gang , Wu Aimin , Ren Zhihua , Chen Daiwen , Yu Bing , Huang Zhiqing , Zheng Ping , Mao Xiangbing , Yu Jie , Luo Junqiu , Yan Hui , Wang Quyuan , Wang Huifen , Tang Jiayong
Published: December 2021

Intestinal inflammation is a major threat to the health and growth of young animals such as piglets. As a next-generation probiotics, limited studies have shown that Akkermansia muciniphila could alleviate inflammation of intestinal epithelial cells (IECs). In this study, a TNF-α-induced inflammatory model of IPEC-J2 cells, the intestinal porcine enterocytes, was built to evaluate the effects of active or inactive A. muciniphila on the inflammation of IECs. The viability of IPEC-J2 cells was the highest when treated with active (108 copies/mL) or inactive (109 copies/mL) A. muciniphila for 7.5 h (P < 0.01). Treated with 20 ng/mL of TNF-α and followed by a treatment of A. muciniphila, the mRNA level of proinflammatory cytokines (IL-8, IL-1β, IL-6 and TNF-α) was remarkably reduced (P < 0.05) along with the increased mRNA level of tight junction proteins (ZO-1 and Occludin, P < 0.05). Flow cytometry analysis showed that active or inactive A. muciniphila significantly suppressed the rate of the early and total apoptotic of the inflammatory IPEC-J2 cells (P < 0.05). According to results of transcriptome sequencing, active and inactive A. muciniphila may decline cell apoptosis by down-regulating the expression of key genes in calcium signaling pathway, or up-regulating the expression of key genes in cell cycle signaling pathway. And the bacterium may alleviate the inflammation of IECs by down-regulating the expression of PI3K upstream receptor genes. Our results indicate that A. muciniphila may be a promising NGP targeting intestinal inflammation.
Treatment With CD52 Antibody Protects Neurons in Experimental Autoimmune Encephalomyelitis Mice During the Recovering Phase
Authors: Hao Wenlin , Luo Qinghua , Menger Michael D. , Fassbender Klaus , Liu Yang
Published: December 2021

Multiple sclerosis (MS) is a chronic autoimmune disease driven by T and B lymphocytes. The remyelination failure and neurodegeneration results in permanent clinical disability in MS patients. A desirable therapy should not only modulate the immune system, but also promote neuroprotection and remyelination. To investigate the neuroprotective effect of CD52 antibody in MS, both C57BL/6J and SJL mice with experimental autoimmune encephalomyelitis (EAE) were treated with CD52 antibody at the peak of disease. Treatment with CD52 antibody depleted T but not B lymphocytes in the blood, reduced the infiltration of T lymphocytes and microglia/macrophages in the spinal cord. Anti-CD52 therapy attenuated EAE scores during the recovery phase. It protected neurons immediately after treatment (within 4 days) as shown by reducing the accumulation of amyloid precursor proteins. It potentially promoted remyelination as it increased the number of olig2/CC-1-positive mature oligodendrocytes and prevented myelin loss in the following days (e.g., 14 days post treatment). In further experiments, EAE mice with a conditional knockout of BDNF in neurons were administered with CD52 antibodies. Neuronal deficiency of BDNF attenuated the effect of anti-CD52 treatment on reducing EAE scores and inflammatory infiltration but did not affect anti-CD52 treatment-induced improvement of myelin coverage in the spinal cord. In summary, anti-CD52 therapy depletes CD4-positive T lymphocytes, prevents myelin loss and protects neurons in EAE mice. Neuronal BDNF regulates neuroprotective and anti-inflammatory effect of CD52 antibody in EAE mice.
Spatial Point Pattern Analysis Identifies Mechanisms Shaping the Skin Parasite Landscape in Leishmania donovani Infection
Authors: Doehl Johannes S. P. , Ashwin Helen , Brown Najmeeyah , Romano Audrey , Carmichael Samuel , Pitchford Jon W. , Kaye Paul M.
Published: December 2021

Increasing evidence suggests that in hosts infected with parasites of the Leishmania donovani complex, transmission of infection to the sand fly vector is linked to parasite repositories in the host skin. However, a detailed understanding of the dispersal (the mechanism of spread) and dispersion (the observed state of spread) of these obligatory-intracellular parasites and their host phagocytes in the skin is lacking. Using endogenously fluorescent parasites as a proxy, we apply image analysis combined with spatial point pattern models borrowed from ecology to characterize dispersion of parasitized myeloid cells (including ManR+ and CD11c+ cells) and predict dispersal mechanisms in a previously described immunodeficient model of L. donovani infection. Our results suggest that after initial seeding of infection in the skin, heavily parasite-infected myeloid cells are found in patches that resemble innate granulomas. Spread of parasites from these initial patches subsequently occurs through infection of recruited myeloid cells, ultimately leading to self-propagating networks of patch clusters. This combination of imaging and ecological pattern analysis to identify mechanisms driving the skin parasite landscape offers new perspectives on myeloid cell behavior following parasitism by L. donovani and may also be applicable to elucidating the behavior of other intracellular tissue-resident pathogens and their host cells.
Global Climate Services: A Typology of Global Decisions Influenced by Climate Risk
Authors: Bisaro Alexander , Hinkel Jochen , Le Cozannet Gonéri , van der Pol Thomas , Haas Armin
Published: December 2021

Climate services are ideally co-developed by scientists and stakeholders working together to identify decisions and user needs. Yet, while climate services have been developed at regional to local scales, relatively little attention has been paid to the global scale. Global climate services involve decisions that rely on climate information from many locations in different world regions, and are increasingly salient. Increasing interconnections in the global financial system and supply chains expose private companies and financial institutions to climate risk in multiple locations in different world regions. Further, multilateral decisions on greenhouse gas emission reduction targets, disaster risk finance or international migration should make use of global scale climate risk assessments. In order to advance global climate service development, we present a typology of decisions relying on global (i.e., non-local) climate risk information. We illustrate each decision type through examples of current practice from the coastal domain drawn from the literature and stakeholder interviews. We identify 8 types of decisions making use of global climate information. At a top-level, we distinguish between “multilateral climate policy decisions,” and “portfolio decisions involving multiple locations.” Multilateral climate policy decisions regard either “mitigation targets” or “multilateral adaptation” decisions. Portfolio decisions regard either “choice of location” or “choice of financial asset” decisions. Choice of location decisions can be further distinguished as to whether they involve “direct climate risks,” “supply chain risks” or “financial network risks.” Our survey of examples shows that global climate service development is more advanced for portfolio decisions taken by companies with experience in climate risk assessment, i.e., (re-)insurers, whereas many multilateral climate policy decisions are at an earlier stage of decision-making. Our typology thus provides an entry-point for global climate service development by pointing to promising research directions for supporting global (non-local) decisions that account for climate risks.
Ichthyoplankton Species Composition and Assemblages From the Estuary to the Hukou Section of the Changjiang River
Authors: Fang Di-an , Xue Xiang-ping , Xu Dong-po , Wang Xiao-hao , Sun Ning-ze , Zhang Bai-dong , Ren Peng
Published: December 2021

Estuary river–lake (ERL) complex is critical for the development of ichthyoplankton, which plays an essential role in the breeding, nursing, and recruitment of freshwater fish species. In this study, different ERL sections were selected to investigate the ichthyoplankton assemblage from the Changjiang River estuary to its Hukou section between May 2018 and August 2020. During the study period, fish larvae of 40, 35, 54, and 46 fish species were sampled in the Rugao (RG), Nanjing (NJ) (nearby estuary), Anqing (AQ), and Hukou (HK) (connected river–lake) sections in the Changjiang River, respectively. Results on ichthyoplankton surveys revealed fluctuating assemblage patterns in the different river sections; larval fish species composition presented ecological habitat-dependent characteristics, which supported the importance of ERL complex for ichthyoplankton development. Furthermore, the density of fish larvae was negatively correlated with water transparency but positively correlated with water temperature, the daily rate of water level increase, and runoff in the limitative range. A generalized additive model analysis indicated that the hydrological factors significantly affecting larval fish abundance are water temperature, transparency, the daily rate of water level increase, and runoff (p < 0.05). These results also indicated that river estuaries and river–lake connected complexes are essential for ichthyoplankton recruitment and migration. In combination with the historical record, ichthyoplankton assemblage’s patterns in the Changjiang River lower reaches were preliminarily elucidated, although additional works are needed such as assessing effects on their survival and recruitment.
Artificial Intelligence in Prenatal Ultrasound Diagnosis
Authors: He Fujiao , Wang Yaqin , Xiu Yun , Zhang Yixin , Chen Lizhu
Published: December 2021

The application of artificial intelligence (AI) technology to medical imaging has resulted in great breakthroughs. Given the unique position of ultrasound (US) in prenatal screening, the research on AI in prenatal US has practical significance with its application to prenatal US diagnosis improving work efficiency, providing quantitative assessments, standardizing measurements, improving diagnostic accuracy, and automating image quality control. This review provides an overview of recent studies that have applied AI technology to prenatal US diagnosis and explains the challenges encountered in these applications.
Interaction Between Arousals and Ventilation During Cheyne-Stokes Respiration in Heart Failure Patients: Insights From Breath-by-Breath Analysis
Authors: Pinna Gian Domenico , Robbi Elena , Bruschi Claudio , La Rovere Maria Teresa , Maestri Roberto
Published: December 2021

Study Objectives: Arousals from sleep during the hyperpneic phases of Cheyne-Stokes respiration with central sleep apnea (CSR-CSA) in patients with heart failure are thought to cause ventilatory overshoot and a consequent longer apnea, thereby sustaining and exacerbating ventilatory instability. However, data supporting this model are lacking. We investigated the relationship between arousals, hyperpnea and post-hyperpnea apnea length during CSR-CSA.

Methods: Breath-by-breath changes in ventilation associated with the occurrence of arousal were evaluated in 18 heart failure patients with CSR-CSA, apnea-hypopnea index ≥15/h and central apnea index ≥5/h. The change in apnea length associated with the presence of arousal during the previous hyperpnea was also evaluated. Potential confounding variables (chemical drive, sleep stage) were controlled for.

Results: Arousals were associated with a large increase in ventilation at the beginning of the hyperpnea (+76 ± 35%, p < 0.0001), that rapidly declined during its crescendo phase. Around peak hyperpnea, the change in ventilation was −8 ± 26% (p = 0.14). The presence of arousal during the hyperpnea was associated with a median increase in the length of the subsequent apnea of +4.6% (Q1, Q2: −0.7%, 20.5%; range: −8.5%, 36.2%) (p = 0.021). The incidence of arousals occurring at the beginning of hyperpnea and mean ventilation in the region around its peak were independent predictors of the change in apnea length (p = 0.004 and p = 0.015, respectively; R2 = 0.78).

Conclusions: Arousals from sleep during CSR-CSA in heart failure patients are associated with a rapidly decreasing ventilatory overshoot at the beginning of the hyperpnea, followed by a tendency toward a slight ventilatory undershoot around its peak. On average, arousals are also associated with a modest increase in post-hyperpnea apnea length; however, large increases in apnea length (>20%) occur in about a quarter of the patients.
Sonographic Tophi and Inflammation Are Associated With Carotid Atheroma Plaques in Gout
Authors: Calabuig Irene , Martínez-Sanchis Agustín , Andrés Mariano
Published: December 2021

Objective: Gout and cardiovascular disease are closely related, but the mechanism connecting them remains unknown. This study aims to explore whether urate crystal deposits and inflammation (assessed by ultrasound) are associated with carotid atherosclerosis.

Methods: We included consecutive patients with crystal-proven gout newly presenting to a tertiary rheumatology unit. Patients under urate-lowering treatment were excluded. Ultrasound assessment was performed during intercritical periods. Musculoskeletal scans evaluated six joints and four tendons for urate crystal deposits (double contour, aggregates, and tophi), and power Doppler (PD) signal (graded 0–3) as a marker of local inflammation. The sum of locations showing deposits or a positive PD signal (≥1) was registered. Carotids were scanned for increased intima-media thickness (IMT) and atheroma plaques, according to the Mannheim consensus. Associations were analyzed using logistic regression.

Results: The study included 103 patients showing sonographic crystal deposits at the examined locations (mean sum 9.9, minimum 2); tophi were the most frequent. Two-thirds of participants presented a positive PD signal (30.1% grade 2–3). In the carotid scans, 59.2% of participants showed atheroma plaques, and 33.0% increased IMT. Tophi (odds ratio [OR] 1.24; 95% confidence interval [CI] 1.03–1.50) and a positive PD signal (OR 1.67; 95% CI 1.09–2.56) were significantly associated with atheroma plaques, while an increased IMT showed no sonographic association.

Conclusion: Sonographic crystal deposits and subclinical inflammation were consistently observed in patients with intercritical gout. Tophi and a positive PD signal were linked to carotid atherosclerosis. Our findings may contribute to understanding the complex relationship between gout and atherosclerosis.
Follow-Up of Blood Pressure, Arterial Stiffness, and GFR in Pediatric Kidney Transplant Recipients
Authors: Végh Anna , Bárczi Adrienn , Cseprekál Orsolya , Kis Éva , Kelen Kata , Török Szilárd , Szabó Attila J. , Reusz György S.
Published: December 2021

Pediatric renal transplant recipients (RTx) were studied for longitudinal changes in blood pressure (BP), arterial stiffness by pulse wave velocity (PWV), and graft function.

Patients and Methods: 52 RTx patients (22 males) were included; office BP (OBP) and 24 h BP monitoring (ABPM) as well as PWV were assessed together with glycemic and lipid parameters and glomerular filtration rate (GFR) at 2.4[1.0–4.7] (T1) and 9.3[6.3–11.8] years (T2) after transplantation (median [range]).

Results: Hypertension was present in 67 and 75% of patients at T1 and T2, respectively. Controlled hypertension was documented in 37 and 44% by OBP and 40 and 43% by ABPM. Nocturnal hypertension was present in 35 and 30% at T1 and T2; 24 and 32% of the patients had masked hypertension, while white coat hypertension was present in 16 and 21% at T1 and T2, respectively. Blood pressure by ABPM correlated significantly with GFR and PWV at T2, while PWV also correlated significantly with T2 cholesterol levels. Patients with uncontrolled hypertension by ABPM had a significant decrease in GFR, although not significant with OBP. Anemia and increased HOMAi were present in ~20% of patients at T1 and T2.

Conclusion: Pediatric RTx patients harbor risk factors that may affect their cardiovascular health. While we were unable to predict the evolution of renal function based on PWV and ABPM at T1, these risk factors correlated closely with GFR at follow-up suggesting that control of hypertension may have an impact on the evolution of GFR.
Enzymatic Disruption of Biofilms During Cheese Manufacturing: A Mini Review
Authors: Kumar Murali , Tierney Joseph , Wilkinson Martin
Published: December 2021

Bacteria are capable of colonizing industrial processing surfaces creating biofilms on them which may adversely affect the quality and safety of products. Traditional cleaning-in-place (CIP) treatments using caustic and nitric acid solutions have been known to exhibit variable efficiency in eliminating biofilm bacteria. Here, we introduce enzymes as an alternative to traditional CIP treatments and discuss their mechanism of action against bacterial biofilms in cheese manufacturing. In addition, we discuss research gaps namely thermal stability, substrate specificity and residual activity of enzymes that may play a vital role in the selection of enzymes with optimal effectiveness against multi species biofilms. The outcome of this mini review will aid in the development of a novel and sustainable enzyme-based CIP treatment during cheese manufacturing in the future.
Tobacco curly shoot virus Down-Regulated the Expression of nbe-miR167b-3p to Facilitate Its Infection in Nicotiana benthamiana
Authors: Wu Rui , Wu Gentu , Wang Lyuxin , Wang Xu , Liu Zhuoying , Li Mingjun , Tan Wanzhong , Qing Ling
Published: December 2021

Tobacco curly shoot virus (TbCSV) belongs to the genus Begomovirus of the family Geminiviridae, and causes leaf curling and curly shoot symptoms in tobacco and tomato crops. MicroRNAs (miRNAs) are pivotal modulators of plant development and host-virus interactions. However, the relationship between TbCSV infection and miRNAs accumulation has not been well investigated. The present study was conducted to analyze different expressions of miRNAs in Nicotiana benthamiana in response to the infection of TbCSV via small RNAs sequencing. The results showed that 15 up-regulated miRNAs and 12 down-regulated miRNAs were differentially expressed in TbCSV infected N. benthamiana, and nbe-miR167b-3p was down-regulated. To decipher the relationship between nbe-miR167b-3p expression and the accumulations of TbCSV DNA, pCVA mediation of miRNA overexpression and PVX based short tandem target mimic (STTM) were used in this study. It was found that overexpression of nbe-miR167b-3p attenuated leaf curling symptom of TbCSV and decreased viral DNA accumulation, but suppression of nbe-miR167b-3p expression enhanced the symptoms and accumulation of TbCSV. PRCP, the target gene of nbe-miR167b-3p, was silenced in plants using VIGS and this weakened the viral symptoms and DNA accumulation of TbCSV in the plants. Overall, this study clarified the effect of nbe-miR167b-3p on plant defense during TbCSV infection, and provided a framework to reveal the molecular mechanisms of miRNAs between plants and viruses.
Genoarchitectonic Compartmentalization of the Embryonic Telencephalon: Insights From the Domestic Cat
Authors: Siskos Nikistratos , Ververidis Charalampos , Skavdis George , Grigoriou Maria E.
Published: December 2021

The telencephalon develops from the alar plate of the secondary prosencephalon and is subdivided into two distinct divisions, the pallium, which derives solely from prosomere hp1, and the subpallium which derives from both hp1 and hp2 prosomeres. In this first systematic analysis of the feline telencephalon genoarchitecture, we apply the prosomeric model to compare the expression of a battery of genes, including Tbr1, Tbr2, Pax6, Mash1, Dlx2, Nkx2-1, Lhx6, Lhx7, Lhx2, and Emx1, the orthologs of which alone or in combination, demarcate molecularly distinct territories in other species. We characterize, within the pallium and the subpallium, domains and subdomains topologically equivalent to those previously described in other vertebrate species and we show that the overall genoarchitectural map of the E26/27 feline brain is highly similar to that of the E13.5/E14 mouse. In addition, using the same approach at the earlier (E22/23 and E24/25) or later (E28/29 and E34/35) stages we further analyze neurogenesis, define the timing and duration of several developmental events, and compare our data with those from similar mouse studies; our results point to a complex pattern of heterochronies and show that, compared with the mouse, developmental events in the feline telencephalon span over extended periods suggesting that cats may provide a useful animal model to study brain patterning in ontogenesis and evolution.
Decreased Phase–Amplitude Coupling Between the mPFC and BLA During Exploratory Behaviour in Chronic Unpredictable Mild Stress-Induced Depression Model of Rats
Authors: Wang Zihe , Cao Qingying , Bai Wenwen , Zheng Xuyuan , Liu Tiaotiao
Published: December 2021

Depression is a common neuropsychiatric illness observed worldwide, and reduced interest in exploration is one of its symptoms. The control of dysregulated medial prefrontal cortex (mPFC) over the basolateral amygdala (BLA) is related to depression. However, the oscillation interaction in the mPFC-BLA circuit has remained elusive. Therefore, this study used phase–amplitude coupling (PAC), which provides complicated forms of information transmission by the phase of low-frequency rhythm, modulating the amplitude of high-frequency rhythm, and has a potential application for the treatment of neurological disease. The chronic unpredictable mild stress (CUMS) was used to prepare the rat models of depression. Moreover, multichannel in vivo recording was applied to obtain the local field potentials (LFPs) of the mPFC, the BLA in rats in control, and CUMS groups, while they explored the open field. The results showed prominent coupling between the phase of theta oscillation (4–12 Hz) in the mPFC and the amplitude of high-gamma oscillation (70–120 Hz) in the BLA. Compared to the control group, this theta–gamma PAC was significantly decreased in the CUMS group, which was accompanied by the diminished exploratory behaviour. The results indicate that the coupling between the phase of theta in the mPFC and the amplitude of gamma in the BLA is involved in exploratory behaviour, and this decreased coupling may inhibit exploratory behaviour of rats exposed to CUMS.
Krabbe Disease Associated With Mitochondrial Dysfunction in a Chinese Family
Authors: Wu Liwen , Liao Xiangfu , Yang Sai , Gan Siyi
Published: December 2021

Background: Krabbe disease is caused by biallelic mutations of GALC gene. NDUFAF1 gene mutations are related to mitochondrial encephalopathy. To date, there has been no report on the co-pathogenesis of these two gene mutations. There were three children in a family who presented with global developmental retardation. MRI showed lesions in the white matter and dentate nucleus of the cerebellum.

Methods: Clinical data of the proband and her family members were gathered in a retrospective manner. Karyotype, FISH, whole exome sequencing was performed using genomic DNAs extracted from peripheral blood samples. Enzyme activities of galactosylceramidase (GALC) and mitochondria were determined to verify gene functions.

Results: This study reported a pedigree of leukoencephalopathy, in which 3 of the 4 children showed phenotypes of developmental delay, hearing/visual impairment, and peripheral neuropathy. Mutations of NDUFAF1 (c.278A>G; p. His93Arg, c.247G> A; p. Asp83Asn) and GALC (c.599C>A; p.Ser200*) were identified in all three cases. The proband's parents carried these mutations as a heterozygous state. Clinical features, MRI changes, enzyme activity of GALC, and mitochondrial function analysis demonstrated that this pedigree was caused by GALC and NDUFAF1 gene mutations working together.

Conclusion: We first report a pedigree of Krabbe disease with biallelic mitochondrial gene NDUFAF1 mutations. For multiple gene mutations found in genetic testing, clinical phenotypes, gene functions, and family history should be comprehensively analyzed. Gene panel examination may miss pathogenic mutations, and prenatal diagnosis of patients with polygenic inheritance needs careful consideration.
Neuropathic Pain in Multiple Sclerosis and Its Animal Models: Focus on Mechanisms, Knowledge Gaps and Future Directions
Authors: Mirabelli Ersilia , Elkabes Stella
Published: December 2021

Multiple sclerosis (MS) is a multifaceted, complex and chronic neurological disease that leads to motor, sensory and cognitive deficits. MS symptoms are unpredictable and exceedingly variable. Pain is a frequent symptom of MS and manifests as nociceptive or neuropathic pain, even at early disease stages. Neuropathic pain is one of the most debilitating symptoms that reduces quality of life and interferes with daily activities, particularly because conventional pharmacotherapies do not adequately alleviate neuropathic pain. Despite advances, the mechanisms underlying neuropathic pain in MS remain elusive. The majority of the studies investigating the pathophysiology of MS-associated neuropathic pain have been performed in animal models that replicate some of the clinical and neuropathological features of MS. Experimental autoimmune encephalomyelitis (EAE) is one of the best-characterized and most commonly used animal models of MS. As in the case of individuals with MS, rodents affected by EAE manifest increased sensitivity to pain which can be assessed by well-established assays. Investigations on EAE provided valuable insights into the pathophysiology of neuropathic pain. Nevertheless, additional investigations are warranted to better understand the events that lead to the onset and maintenance of neuropathic pain in order to identify targets that can facilitate the development of more effective therapeutic interventions. The goal of the present review is to provide an overview of several mechanisms implicated in neuropathic pain in EAE by summarizing published reports. We discuss current knowledge gaps and future research directions, especially based on information obtained by use of other animal models of neuropathic pain such as nerve injury.
Figure-Eight Coils for Magnetic Stimulation: From Focal Stimulation to Deep Stimulation
Authors: Ueno Shoogo , Sekino Masaki
Published: December 2021

This article reviews the evolution and recent developments of transcranial magnetic brain stimulation using figure-eight coils to stimulate localized areas in the human brain. Geometric variations of figure-eight coils and their characteristics are reviewed and discussed for applications in neuroscience and medicine. Recent topics of figure-eight coils, such as focality of figure-eight coils, tradeoff between depth and focality, and approaches for extending depth, are discussed.
Co-optimization Learning Network for MRI Segmentation of Ischemic Penumbra Tissues
Authors: Liu Liangliang , Zhang Jing , Wang Jin-xiang , Xiong Shufeng , Zhang Hui
Published: December 2021

Convolutional neural networks (CNNs) have brought hope for the medical image auxiliary diagnosis. However, the shortfall of labeled medical image data is the bottleneck that limits the performance improvement of supervised CNN methods. In addition, annotating a large number of labeled medical image data is often expensive and time-consuming. In this study, we propose a co-optimization learning network (COL-Net) for Magnetic Resonance Imaging (MRI) segmentation of ischemic penumbra tissues. COL-Net base on the limited labeled samples and consists of an unsupervised reconstruction network (R), a supervised segmentation network (S), and a transfer block (T). The reconstruction network extracts the robust features from reconstructing pseudo unlabeled samples, which is the auxiliary branch of the segmentation network. The segmentation network is used to segment the target lesions under the limited labeled samples and the auxiliary of the reconstruction network. The transfer block is used to co-optimization the feature maps between the bottlenecks of the reconstruction network and segmentation network. We propose a mix loss function to optimize COL-Net. COL-Net is verified on the public ischemic penumbra segmentation challenge (SPES) with two dozen labeled samples. Results demonstrate that COL-Net has high predictive accuracy and generalization with the Dice coefficient of 0.79. The extended experiment also shows COL-Net outperforms most supervised segmentation methods. COL-Net is a meaningful attempt to alleviate the limited labeled sample problem in medical image segmentation.
Practical Closed-Loop Strategies for Deep Brain Stimulation: Lessons From Chronic Pain
Authors: Prosky Jordan , Cagle Jackson , Sellers Kristin K. , Gilron Ro’ee , de Hemptinne Cora , Schmitgen Ashlyn , Starr Philip A. , Chang Edward F. , Shirvalkar Prasad
Published: December 2021

Deep brain stimulation (DBS) is a plausible therapy for various neuropsychiatric disorders, though continuous tonic stimulation without regard to underlying physiology (open-loop) has had variable success. Recently available DBS devices can sense neural signals which, in turn, can be used to control stimulation in a closed-loop mode. Closed-loop DBS strategies may mitigate many drawbacks of open-loop stimulation and provide more personalized therapy. These devices contain many adjustable parameters that control how the closed-loop system operates, which need to be optimized using a combination of empirically and clinically informed decision making. We offer a practical guide for the implementation of a closed-loop DBS system, using examples from patients with chronic pain. Focusing on two research devices from Medtronic, the Activa PC+S and Summit RC+S, we provide pragmatic details on implementing closed- loop programming from a clinician’s perspective. Specifically, by combining our understanding of chronic pain with data-driven heuristics, we describe how to tune key parameters to handle feature selection, state thresholding, and stimulation artifacts. Finally, we discuss logistical and practical considerations that clinicians must be aware of when programming closed-loop devices.
Silencing of Activity During Hypoxia Improves Functional Outcomes in Motor Neuron Networks in vitro
Authors: Fiskum Vegard , Sandvig Axel , Sandvig Ioanna
Published: December 2021

The effects of hypoxia, or reduced oxygen supply, to brain tissue can be disastrous, leading to extensive loss of function. Deoxygenated tissue becomes unable to maintain healthy metabolism, which leads to increased production of reactive oxygen species (ROS) and loss of calcium homoeostasis, with damaging downstream effects. Neurons are a highly energy demanding cell type, and as such they are highly sensitive to reductions in oxygenation and some types of neurons such as motor neurons are even more susceptible to hypoxic damage. In addition to the immediate deleterious effects hypoxia can have on neurons, there can be delayed effects which lead to increased risk of developing neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), even if no immediate consequences are apparent. Furthermore, impairment of the function of various hypoxia-responsive factors has been shown to increase the risk of developing several neurodegenerative disorders. Longitudinal assessment of electrophysiological network activity is underutilised in assessing the effects of hypoxia on neurons and how their activity and communication change over time following a hypoxic challenge. This study utilised multielectrode arrays and motor neuron networks to study the response to hypoxia and the subsequent development of the neuronal activity over time, as well as the effect of silencing network activity during the hypoxic challenge. We found that motor neuron networks exposed to hypoxic challenge exhibited a delayed fluctuation in multiple network activity parameters compared to normoxic networks. Silencing of activity during the hypoxic challenge leads to maintained bursting activity, suggesting that functional outcomes are better maintained in these networks and that there are activity-dependent mechanisms involved in the network damage following hypoxia.
DNA Damage and Repair Deficiency in ALS/FTD-Associated Neurodegeneration: From Molecular Mechanisms to Therapeutic Implication
Authors: Wang Haibo , Kodavati Manohar , Britz Gavin W. , Hegde Muralidhar L.
Published: December 2021

Emerging studies reveal that neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), are commonly linked to DNA damage accumulation and repair deficiency. Neurons are particularly vulnerable to DNA damage due to their high metabolic activity, relying primarily on oxidative phosphorylation, which leads to increased reactive oxygen species (ROS) generation and subsequent DNA damage. Efficient and timely repair of such damage is critical for guarding the integrity of genomic DNA and for cell survival. Several genes predominantly associated with RNA/DNA metabolism have been implicated in both ALS and FTD, suggesting that the two diseases share a common underlying pathology with varied clinical manifestations. Recent studies reveal that many of the gene products, including RNA/DNA binding proteins (RBPs) TDP-43 and FUS are involved in diverse DNA repair pathways. A key question in the etiology of the ALS/FTD spectrum of neurodegeneration is the mechanisms and pathways involved in genome instability caused by dysfunctions/mutations of those RBP genes and their consequences in the central nervous system. The understanding of such converging molecular mechanisms provides insights into the underlying etiology of the rapidly progressing neurodegeneration in ALS/FTD, while also revealing novel DNA repair target avenues for therapeutic development. In this review, we summarize the common mechanisms of neurodegeneration in ALS and FTD, with a particular emphasis on the DNA repair defects induced by ALS/FTD causative genes. We also highlight the consequences of DNA repair defects in ALS/FTD and the therapeutic potential of DNA damage repair-targeted amelioration of neurodegeneration.
Intraoperative Radiotherapy Is Not a Better Alternative to Whole Breast Radiotherapy as a Therapeutic Option for Early-Stage Breast Cancer
Authors: Wang Linwei , Sun Min , Yang Shuailong , Chen Yuanyuan , Li Tian
Published: December 2021

Objective

Intraoperative radiotherapy (IORT) in early-stage breast cancer has been studied over the years. However, it has not been demonstrated whether IORT is more suitable as a therapeutic option for early-stage breast cancer than whole breast radiotherapy (WBRT). Therefore, we performed a meta-analysis to compare the efficacy and safety of IORT to those of WBRT as therapeutic options for early-stage breast cancer patients receiving breast-conserving surgery (INPLASY2020120008).

Methods

PubMed, Embase, and Cochrane Library databases were searched from inception to October 2021. Computerized and manual searches were adopted to identify eligible randomized control trials from online databases. Risk ratio (RR) and 95% confidence intervals (CI) were calculated by random-effect models to assess the relative risk. Potential publication bias was quantified by Begg’s and Egger’s tests.

Results

Based on our inclusion criteria, 10 randomized control trials involving 5,698 patients were included in this meta-analysis. This meta-analysis showed that the IORT group was associated with a higher local recurrence risk (RR = 2.111, 95% CI, 1.130–3.943, p = 0.0191), especially in the long-term follow-up subgroup or published after 2020 subgroup or Caucasian subgroup (RR = 2.404, 95% CI, 1.183–4.885, p = 0.0154). Subgroup analysis showed that the IORT group had a higher recurrence risk than the WBRT group in the polycentric randomized controlled trial subgroup (RR = 1.213, 95% CI, 1.030–1.428, p = 0.0204). Pooled analysis showed that there was no statistically significant difference in overall survival, recurrence-free survival, distant metastasis-free survival, and cancer-specific survival between IORT and WBRT groups. Additionally, the risk of skin toxicity was reduced, but the incidences of fat toxicity, edema, and scar calcification were significantly increased in the patients who underwent IORT in comparison to those who underwent WBRT.

Conclusion

This meta-analysis revealed that IORT was not a better alternative to WBRT. More large-scale and well-designed clinical trials with longer follow-up periods are encouraged to further investigate the value of IORT.

Systematic Review Registration

https://inplasy.com/inplasy-2020-12-0008/.
Case Report: Vasculitis Triggered by SIRT in a Patient With Previously Untreated Cholangiocarcinoma
Authors: Stamatiou Antonia , Jankovic Jeremy , Szturz Petr , Fasquelle Francois , Duran Rafael , Schaefer Niklaus , Diciolla Antonella , Digklia Antonia
Published: December 2021

Arising from the biliary tract, cholangiocarcinoma is a rare and aggressive epithelial cancer. According to the primary site, it can be further classified into intrahepatic, perihilar and distal types. Due to the lack of symptoms early in the disease course, most patients are diagnosed at advanced stages. Being not candidates for curative surgical management, these patients are treated with palliative systemic chemotherapy, and their prognosis remains poor. Using radioisotopes like yttrium-90 -labeled microspheres (90Y), radioembolization represents a local approach to treat primary and secondary liver tumors. In the case of intrahepatic cholangiocarcinoma, radioembolization can be used as a primary treatment, as an adjunct to chemotherapy or after failing chemotherapy. An 88-year-old man underwent radioembolization for a previously untreated stage II intrahepatic cholangiocarcinoma. One week later, he presented to our clinic with a non-pruritic maculopapular rash of the lower extremities and abdomen, worsening fatigue and low-grade fever. Laboratory exams, including hepatitis screening, were within normal limits. Showing positive immunofluorescence staining for immunoglobulin M (IgM) and complement 3 (C3) in vessel walls without IgA involvement, the skin biopsy results were compatible with leukocytoclastic vasculitis. Apart from the anticancer intervention, there have been no recent medication changes which could explain this complication. Notably, we did not observe any side effects during or after the perfusion scan with technetium-99m macroaggregated albumin (MAA) performed prior to radioembolization. The symptoms resolved quickly after a short course of colchicine and did not reappear at cholangiocarcinoma progression. In the absence of other evident causes, we conclude that the onset of leukocytoclastic vasculitis in our patient was directly linked to the administration of yttrium-90 -labeled microspheres. Our report therefore demonstrates that this condition can be a rare but manageable complication of 90Y liver radioembolization.
Identification of an Aging-Related Gene Signature in Predicting Prognosis and Indicating Tumor Immune Microenvironment in Breast Cancer
Authors: Lv Wenchang , Zhao Chongru , Tan Yufang , Hu Weijie , Yu Honghao , Zeng Ning , Zhang Qi , Wu Yiping
Published: December 2021

Breast cancer (BC) is the most commonly diagnosed malignancy accompanied by high invasion and metastasis features. Importantly, emerging studies have supported that aging is a key clue that participates in the immune state and development of BC. Nevertheless, there are no studies concerning the aging-related genes (AGs) in constructing the prognosis signature of BC. Here, to address this issue, we initially performed a systematic investigation of the associations between AGs and BC prognosis and accordingly constructed a prognosis risk model with 10 AGs including PLAU, JUND, IL2RG, PCMT1, PTK2, HSPA8, NFKBIA, GCLC, PIK3CA, and DGAT1 by using the least absolute shrinkage and selection operator (LASSO) regression and Cox regression analysis. Meanwhile, our analysis further confirmed that the nomogram possessed a robust performance signature for predicting prognosis compared to clinical characteristics of BC patients, including age, clinical stage, and TNM staging. Moreover, the risk score was confirmed as an independent prognostic index of BC patients and was potentially correlated with immune scores, estimate score, immune cell infiltration level, tumor microenvironment, immunotherapy effect, and drug sensitivity. Furthermore, in the external clinical sample validation, AGs were expressed differentially in patients from different risk groups, and tumor-associated macrophage markers were elevated in high-risk BC tissues with more co-localization of AGs. In addition, the proliferation, transwell, and wound healing assays also confirmed the promoting effect of DGAT1 in BC cell proliferation and migration. Therefore, this well-established risk model could be used for predicting prognosis and immunotherapy in BC, thus providing a powerful instrument for combating BC.
Treatment of AML Relapse After Allo-HCT
Authors: Webster Jonathan A. , Luznik Leo , Gojo Ivana
Published: December 2021

With advances in allogeneic hematopoietic stem cell transplant (allo-HCT), disease relapse has replaced transplant-related mortality as the primary cause of treatment failure for patients with acute myeloid leukemia (AML). The efficacy of allo-HCT in AML is a consequence of a graft-versus-leukemia (GVL) effect that is mediated by T lymphocytes, and unique mechanisms of immune evasion underlying post-allo-HCT AML relapses have recently been characterized. Relapsed AML following allo-HCT presents a particularly vexing clinical challenge because transplant-related toxicities, such as graft-versus-host (GVHD) and infections, increase the risk of treatment-related morbidity and mortality. In general, the prognosis of relapsed AML following allo-HCT is poor with most patients failing to achieve a subsequent remission and 2-year survival consistently <15%. The two factors that have been found to predict a better prognosis are a longer duration of post-transplant remission prior to relapse and a lower disease burden at the time of relapse. When considered in combination with a patient’s age; co-morbidities; and performance status, these factors can help to inform the appropriate therapy for the treatment of post-transplant relapse. This review discusses the options for the treatment of post-transplant AML relapse with a focus on the options to achieve a subsequent remission and consolidation with cellular immunotherapy, such as a second transplant or donor lymphocyte infusion (DLI). While intensive reinduction therapy and less intensive approaches with hypomethylating agents have long represented the two primary options for the initial treatment of post-transplant relapse, molecularly targeted therapies and immunotherapy are emerging as potential alternative options to achieve remission. Herein, we highlight response and survival outcomes achieved specifically in the post-transplant setting using each of these approaches and discuss how some therapies may overcome the immunologic mechanisms that have been implicated in post-transplant relapse. As long-term survival in post-transplant relapse necessarily involves consolidation with cellular immunotherapy, we present data on the efficacy and toxicity of both DLI and second allo-HCT including when such therapies are integrated with reinduction. Finally, we provide our general approach to the treatment of post-transplant relapse, integrating both novel therapies and our improved understanding of the mechanisms underlying post-transplant relapse.