bluuebunny/crossref_metadata_2025 huggingface dataset:
Nlrx1-Regulated Defense and Metabolic Responses to Aspergillus fumigatus Are Morphotype and Cell Type Specific
Authors: Kastelberg Bridget , Ayubi Tariq , Tubau-Juni Nuria , Leber Andrew , Hontecillas Raquel , Bassaganya-Riera Josep , Kale Shiv D.
Published: November 2021

The Nlr family member X1 (Nlrx1) is an immuno-metabolic hub involved in mediating effective responses to virus, bacteria, fungi, cancer, and auto-immune diseases. We have previously shown that Nlrx1 is a critical regulator of immune signaling and mortality in several models of pulmonary fungal infection using the clinically relevant fungus Aspergillus fumigatus. In the absence of Nlrx1, hosts produce an enhanced Th2 response primarily by CD103+ dendritic cell populations resulting in enhanced mortality via immunopathogenesis as well as enhanced fungal burden. Here, we present our subsequent efforts showcasing loss of Nlrx1 resulting in a decreased ability of host cells to process A. fumigatus conidia in a cell-type-specific manner by BEAS-2B airway epithelial cells, alveolar macrophages, bone marrow-derived macrophages, but not bone marrow-derived neutrophils. Furthermore, loss of Nlrx1 results in a diminished ability to generate superoxide and/or generic reactive oxygen species during specific responses to fungal PAMPs, conidia, and hyphae. Analysis of glycolysis and mitochondrial function suggests that Nlrx1 is needed to appropriately shut down glycolysis in response to A. fumigatus conidia and increase glycolysis in response to hyphae in BEAS-2B cells. Blocking glycolysis and pentose phosphate pathway (PPP) via 2-DG and NADPH production through glucose-6-phosphate dehydrogenase inhibitor resulted in significantly diminished conidial processing in wild-type BEAS-2B cells to the levels of Nlrx1-deficient BEAS-2B cells. Our findings suggest a need for airway epithelial cells to generate NADPH for reactive oxygen species production in response to conidia via PPP. In context to fungal pulmonary infections, our results show that Nlrx1 plays significant roles in host defense via PPP modulation of several aspects of metabolism, particularly glycolysis, to facilitate conidia processing in addition to its critical role in regulating immune signaling.
Effects of a Single Cell Protein (Methylococcus capsulatus, Bath) in Pacific White Shrimp (Penaeus vannamei) Diet on Growth Performance, Survival Rate and Resistance to Vibrio parahaemolyticus, the Causative Agent of Acute Hepatopancreatic Necrosis Disease
Authors: Jintasataporn Orapint , Chumkam Srinoy , Triwutanon Supawit , LeBlanc Allan , Sawanboonchun Jarin
Published: November 2021

The efficacy of a single cell protein (SCP) methanotroph (Methylococcus capsulatus, Bath) bacteria meal (FeedKind®, Calysta, Menlo Park, CA, United States), in Pacific white shrimp (Penaeus vannamei) diets was studied to determine growth performance, survival rate and disease resistance against Vibrio parahaemolyticus causing Acute Hepatopancreatic Necrosis Disease (AHPND). The growth trial was assigned in a completely randomized design (CRD) with four treatments and 5 replicates of each, T1: a fishmeal-based control containing 15% fish meal and 3 diets with graded levels of methanotroph bacteria meal, namely T2: 5% methanotroph bacteria meal, T3: 10% methanotroph bacteria meal, and T4: 15% methanotroph bacteria meal. Shrimp were fed ad libitum for 6 weeks on trial diets to assess growth. Subsequent to the growth trial, three replicates of the same groups were exposed to V. parahaemolyticus by a single bath challenge and held for a further 15 days on the same diets as the growth study to assess survival and resistance. No significant differences (p > 0.05) in survival or in growth performance, including final weight, weight gain, specific growth rate, feed consumption or feed conversion ratio of white shrimp fed feeds containing methanotroph bacteria meal or control diets for 6 weeks. Immune markers such as hemocyte counts, phenoloxidase, superoxide dismutase and lysozyme activity were similar across all groups after the 6-week feeding trial. In a V. parahaemolyticus challenge, methanotroph bacteria meal in the diet significantly promoted the survival rate, and the reduction of Vibrio sp. in the hepatopancreas of white shrimp. Hemocyte count and phenoloxidase activity showed no significant differences (p > 0.05) between diet treatment groups, but hemolymph protein was significantly higher (p < 0.05) in shrimp fed diets containing 15% methanotroph bacteria meal after challenge. The Vibrio colony counts from hepatopancreas in the treatment groups were all significantly lower than the control (p < 0.05). The findings show that methanotroph bacteria meal can entirely replace fishmeal in white shrimp diets and the 15% inclusion of methanotroph bacteria meal in shrimp diet shows no adverse effects on growth performance, feed utilization and survival rate. In addition, shrimp fed methanotroph bacteria meal diets exhibited improved survival rates to an AHPND challenge.
The Cortical Motor System in the Domestic Pig: Origin and Termination of the Corticospinal Tract and Cortico-Brainstem Projections
Authors: del Cerro Patricia , Rodríguez-De-Lope Ángel , Collazos-Castro Jorge E.
Published: November 2021

The anatomy of the cortical motor system and its relationship to motor repertoire in artiodactyls is for the most part unknown. We studied the origin and termination of the corticospinal tract (CST) and cortico-brainstem projections in domestic pigs. Pyramidal neurons were retrogradely labeled by injecting aminostilbamidine in the spinal segment C1. After identifying the dual origin of the porcine CST in the primary motor cortex (M1) and premotor cortex (PM), the axons descending from those regions to the spinal cord and brainstem were anterogradely labeled by unilateral injections of dextran alexa-594 in M1 and dextran alexa-488 in PM. Numerous corticospinal projections from M1 and PM were detected up to T6 spinal segment and showed a similar pattern of decussation and distribution in the white matter funiculi and the gray matter laminae. They terminated mostly on dendrites of the lateral intermediate laminae and the internal basilar nucleus, and some innervated the ventromedial laminae, but were essentially absent in lateral laminae IX. Corticofugal axons terminated predominantly ipsilaterally in the midbrain and bilaterally in the medulla oblongata. Most corticorubral projections arose from M1, whereas the mesencephalic reticular formation, superior colliculus, lateral reticular nucleus, gigantocellular reticular nucleus, and raphe received abundant axonal contacts from both M1 and PM. Our data suggest that the porcine cortical motor system has some common features with that of primates and humans and may control posture and movement through parallel motor descending pathways. However, less cortical regions project to the spinal cord in pigs, and the CST neither seems to reach the lumbar enlargement nor to have a significant direct innervation of cervical, foreleg motoneurons.
Neonatal Isoflurane Does Not Affect Sleep Architecture and Minimally Alters Neuronal Beta Oscillations in Adolescent Rats
Authors: Manzella Francesca M. , Gulvezan Bethany F. , Maksimovic Stefan , Useinovic Nemanja , Raol Yogendra H. , Joksimovic Srdjan M. , Jevtovic-Todorovic Vesna , Todorovic Slobodan M.
Published: November 2021

General anesthetics are neurotoxic to the developing rodent and primate brains leading to neurocognitive and socio-affective impairment later in life. In addition, sleep patterns are important predictors of cognitive outcomes. Yet, little is known about how anesthetics affect sleep-wake behaviors and their corresponding oscillations. Here we examine how neonatal general anesthesia affects sleep and wake behavior and associated neuronal oscillations. We exposed male and female rat pups to either 6 h of continuous isoflurane or sham anesthesia (compressed air) at the peak of their brain development (postnatal day 7). One cohort of animals was used to examine neurotoxic insult 2 h post-anesthesia exposure. At weaning age, a second cohort of rats was implanted with cortical electroencephalogram electrodes and allowed to recover. During adolescence, we measured sleep architecture (divided into wake, non-rapid eye movement, and rapid eye movement sleep) and electroencephalogram power spectra over a 24 h period. We found that exposure to neonatal isoflurane caused extensive neurotoxicity but did not disrupt sleep architecture in adolescent rats. However, these animals had a small but significant reduction in beta oscillations, specifically in the 12–20 Hz beta 1 range, associated with wake behavior. Furthermore, beta oscillations play a critical role in cortical development, cognitive processing, and homeostatic sleep drive. We speculate that dysregulation of beta oscillations may be implicated in cognitive and socio-affective outcomes associated with neonatal anesthesia.
Targeting CDK5 in Astrocytes Promotes Calcium Homeostasis Under Excitotoxic Conditions
Authors: Toro-Fernández Luisa Fernanda , Zuluaga-Monares Juan Camilo , Saldarriaga-Cartagena Ana María , Cardona-Gómez Gloria Patricia , Posada-Duque Rafael
Published: November 2021

Glutamate excitotoxicity triggers overactivation of CDK5 and increases calcium influx in neural cells, which promotes dendritic retraction, spine loss, increased mitochondrial calcium from the endoplasmic reticulum, and neuronal death. Our previous studies showed that CDK5 knockdown (KD) in astrocytes improves neurovascular integrity and cognitive functions and exerts neuroprotective effects. However, how CDK5-targeted astrocytes affect calcium regulation and whether this phenomenon is associated with changes in neuronal plasticity have not yet been analyzed. In this study, CDK5 KD astrocytes transplanted in CA3 remained at the injection site without proliferation, regulated calcium in the CA1 hippocampal region after excitotoxicity by glutamate in ex vivo hippocampal slices, improving synapsin and PSD95 clustering. These CDK5 KD astrocytes induced astrocyte stellation and neuroprotection after excitotoxicity induced by glutamate in vitro. Also, these effects were supported by CDK5 inhibition (CDK5i) in vitro through intracellular stabilization of calcium levels in astrocytes. Additionally, these cells in cocultures restored calcium homeostasis in neurons, redistributing calcium from somas to dendrites, accompanied by dendrite branching, higher dendritic spines and synapsin-PSD95 clustering. In summary, induction of calcium homeostasis at the CA1 hippocampal area by CDK5 KD astrocytes transplanted in the CA3 area highlights the role of astrocytes as a cell therapy target due to CDK5-KD astrocyte-mediated synaptic clustering, calcium spreading regulation between both areas, and recovery of the intracellular astrocyte-neuron calcium imbalance and plasticity impairment generated by glutamate excitotoxicity.
Spontaneous Intracranial Hypotension Without CSF Leakage—Concept of a Pathological Cranial to Spinal Fluid Shift
Authors: Goldberg Johannes , Häni Levin , Jesse Christopher Marvin , Zubak Irena , Piechowiak Eike I. , Gralla Jan , Dobrocky Tomas , Beck Jürgen , Raabe Andreas
Published: November 2021

Objective: Spontaneous intracranial hypotension (SIH) is typically caused by CSF leakage from a spinal dural tear, a meningeal diverticulum, or a CSF venous fistula. However, some patients present with classic orthostatic symptoms and typical intracranial imaging findings without evidence of CSF leakage despite repeated diagnostic work-up. This article aims to elaborate a hypothesis that would explain a pathologically increased orthostatic shift of CSF from the cranial to the spinal compartment in the absence of a CSF leak.

Medical Hypothesis: The symptoms of SIH are caused by a decrease in intracranial CSF volume, intracranial hypotension, and downward displacement of intracranial structures. A combination of pathologically increased spinal compliance, decreased intracranial CSF volume, low CSF outflow resistance, and decreased venous pressure might result in a pathological orthostatic cranial-to-spinal CSF shift. Thus, in rare cases, intracranial hypotension may occur in the absence of CSF leakage from the dural sac.

Conclusion: We propose a pathophysiological concept for the subgroup of SIH patients with typical cranial imaging findings and no evidence of CSF leakage. In these patients, reducing the compliance or the volume of the spinal compartment seems to be the appropriate therapeutic strategy.
Interaction of the Left–Right Somatosensory Pathways in Patients With Thalamic Hemorrhage: A Case Report
Authors: Ishii Daisuke , Ishibashi Kiyoshige , Takeda Kotaro , Yuine Hiroshi , Yamamoto Satoshi , Kaku Yuki , Yozu Arito , Kohno Yutaka
Published: November 2021

Neural plasticity compensates for the loss of motor function after stroke. However, whether neural plasticity occurs in the somatosensory pathways after stroke is unknown. We investigated the left–right somatosensory interaction in two hemorrhagic patients using a paired somatosensory evoked potentials (p-SEPs) recorded at CP3 and CP4, which was defined as an amplitude difference between the SEPs of paired median nerve stimulations to both sides and that of single stimulation to the affected side. Patient 1 (61-year-old, left thalamic hemorrhage) has a moderate motor impairment, severe sensory deficit, and complained of pain in the affected right upper limb. Patient 2 (72-year-old, right thalamic hemorrhage) had slight motor and sensory impairments with no complaints of pain. Single SEPs (s-SEPs) were obtained by stimulation of the right and left median nerves, respectively. For paired stimulations, 1 ms after the first stimulation to the non-affected side, followed by a second stimulation to the affected side. In patient 1, a s-SEP with stimulation to the non-affected side and a p-SEP were observed in CP4. However, a s-SEP was not observed in either hemisphere with stimulation to the affected side. On the other hand, in patient 2, a s-SEP in CP3 with stimulation to the non-affected side and in CP4 with stimulation to the affected side were observed; however, a p-SEP was not observed. In addition, to investigate the mechanism by which ipsilateral median nerve stimulation enhances contralateral p-SEP in patient 1, we compared the SEP averaged over the first 250 epochs with the SEP averaged over the second 250 epochs (total number of epochs recorded: 500). The results showed that in the patient 1, when the bilateral median nerve was stimulated continuously, the habituation did not occur and the response was larger than that of the s-SEP with unilateral median nerve stimulation. In the current case report, the damage to the thalamus may cause neuroplasticity in terms of the left–right interaction (e.g., left and right S1). The somatosensory input from the affected side may interfere with the habituation of the contralateral somatosensory system and conversely increase the response.
Autistic Traits and Attention-Deficit Hyperactivity Disorder Symptoms Associated With Greater Pain Interference and Depression, and Reduced Health-Related Quality of Life in Children With Chronic Pain
Authors: Wiwe Lipsker Camilla , Hirvikoski Tatja , Balter Leonie J. T. , Bölte Sven , Lekander Mats , Holmström Linda , Wicksell Rikard K.
Published: November 2021

Previous research indicates elevated levels of clinically significant traits and symptoms of autism spectrum disorder and attention-deficit hyperactivity disorder (ADHD) in children with chronic pain, but associations with functioning and depression are yet unclear. The current study examined the relationships of autistic traits and ADHD symptoms with pain interference, depression, and health-related quality of life, as well as the mediating roles of insomnia and psychological inflexibility, in children with chronic pain (n = 146, 8–17 years, 102 girls) presenting at a tertiary pain clinic. Children completed measures of pain intensity, depression, pain interference, health-related quality of life, insomnia, and psychological inflexibility. Parents (n = 146, 111 mothers) completed measures to assess autistic traits and ADHD symptoms in their children. Children with clinically significant autistic traits and ADHD symptoms presented with significantly higher levels of depressive symptoms and pain interference, and significantly lower health-related quality of life, than did the other children. Autistic traits and ADHD symptoms contributed significantly to the prediction of pain interference and depressive symptoms, as well as health-related quality of life. Psychological inflexibility mediated the relationships between ADHD symptoms and autistic traits on the one hand and depression, pain interference, and health-related quality of life on the other, while insomnia mediated the relationships between ADHD symptoms and depression, pain interference, and health-related quality of life. All analyses were adjusted for demographics and pain intensity. Results suggest the utility of screening for neurodevelopmental disorders in children with chronic pain. Furthermore, the findings may indicate insomnia and skills related to psychological flexibility as potential treatment targets in interventions aiming at improving functioning and health-related quality of life in children with chronic pain and co-occurring symptoms of neurodevelopmental disorders.
Implication of Vestibular Hair Cell Loss of Planar Polarity for the Canal and Otolith-Dependent Vestibulo-Ocular Reflexes in Celsr1–/– Mice
Authors: Simon François , Tissir Fadel , Michel Vincent , Lahlou Ghizlene , Deans Michael , Beraneck Mathieu
Published: November 2021

Introduction: Vestibular sensory hair cells are precisely orientated according to planar cell polarity (PCP) and are key to enable mechanic-electrical transduction and normal vestibular function. PCP is found on different scales in the vestibular organs, ranging from correct hair bundle orientation, coordination of hair cell orientation with neighboring hair cells, and orientation around the striola in otolithic organs. Celsr1 is a PCP protein and a Celsr1 KO mouse model showed hair cell disorganization in all vestibular organs, especially in the canalar ampullae. The objective of this work was to assess to what extent the different vestibulo-ocular reflexes were impaired in Celsr1 KO mice.

Methods: Vestibular function was analyzed using non-invasive video-oculography. Semicircular canal function was assessed during sinusoidal rotation and during angular velocity steps. Otolithic function (mainly utricular) was assessed during off-vertical axis rotation (OVAR) and during static and dynamic head tilts.

Results: The vestibulo-ocular reflex of 10 Celsr1 KO and 10 control littermates was analyzed. All KO mice presented with spontaneous nystagmus or gaze instability in dark. Canalar function was reduced almost by half in KO mice. Compared to control mice, KO mice had reduced angular VOR gain in all tested frequencies (0.2–1.5 Hz), and abnormal phase at 0.2 and 0.5 Hz. Concerning horizontal steps, KO mice had reduced responses. Otolithic function was reduced by about a third in KO mice. Static ocular-counter roll gain and OVAR bias were both significantly reduced. These results demonstrate that canal- and otolith-dependent vestibulo-ocular reflexes are impaired in KO mice.

Conclusion: The major ampullar disorganization led to an important reduction but not to a complete loss of angular coding capacities. Mildly disorganized otolithic hair cells were associated with a significant loss of otolith-dependent function. These results suggest that the highly organized polarization of otolithic hair cells is a critical factor for the accurate encoding of the head movement and that the loss of a small fraction of the otolithic hair cells in pathological conditions is likely to have major functional consequences. Altogether, these results shed light on how partial loss of vestibular information encoding, as often encountered in pathological situations, translates into functional deficits.
Glyoxalase 1 Confers Susceptibility to Schizophrenia: From Genetic Variants to Phenotypes of Neural Function
Authors: Yin Jingwen , Ma Guoda , Luo Shucun , Luo Xudong , He Bin , Liang Chunmei , Zuo Xiang , Xu Xusan , Chen Qing , Xiong Susu , Tan Zhi , Fu Jiawu , Lv Dong , Dai Zhun , Wen Xia , Zhu Dongjian , Ye Xiaoqing , Lin Zhixiong , Lin Juda , Li You , Chen Wubiao , Luo Zebin , Li Keshen , Wang Yajun
Published: November 2021

This research aimed to investigate the role of glyoxalase 1 (Glo-1) polymorphisms in the susceptibility of schizophrenia. Using the real-time polymerase chain reaction (PCR) and spectrophotometric assays technology, significant differences in Glo-1 messenger ribonucleic acid (mRNA) expression (P = 3.98 × 10−5) and enzymatic activity (P = 1.40 × 10−6) were found in peripheral blood of first-onset antipsychotic-naïve patients with schizophrenia and controls. The following receiver operating characteristic (ROC) curves analysis showed that Glo-1 could predict the schizophrenia risk (P = 4.75 × 10−6 in mRNA, P = 1.43 × 10−7 in enzymatic activity, respectively). To identify the genetic source of Glo-1 risk in schizophrenia, Glo-1 polymorphisms (rs1781735, rs1130534, rs4746, and rs9470916) were genotyped with SNaPshot technology in 1,069 patients with schizophrenia and 1,023 healthy individuals. Then, the impact of risk polymorphism on the promoter activity, mRNA expression, and enzymatic activity was analyzed. The results revealed significant differences in the distributions of genotype (P = 0.020, false discovery rate (FDR) correction) and allele (P = 0.020, FDR correction) in rs1781735, in which G > T mutation significantly showed reduction in the promoter activity (P = 0.016), mRNA expression, and enzymatic activity (P = 0.001 and P = 0.015, respectively, GG vs. TT, in peripheral blood of patients with schizophrenia) of Glo-1. The expression quantitative trait locus (eQTL) findings were followed up with the resting-state functional magnetic resonance imaging (fMRI) analysis. The TT genotype of rs1781735, associated with lower RNA expression in the brain (P < 0.05), showed decreased neuronal activation in the left middle frontal gyrus in schizophrenia (P < 0.001). In aggregate, this study for the first time demonstrates how the genetic and biochemical basis of Glo-1 polymorphism culminates in the brain function changes associated with increased schizophrenia risk. Thus, establishing a combination of multiple levels of changes ranging from genetic variants, transcription, protein function, and brain function changes is a better predictor of schizophrenia risk.
Transient Receptor Potential Channel 4 Small-Molecule Inhibition Alleviates Migraine-Like Behavior in Mice
Authors: Cohen Cinder Faith , Prudente Arthur Silveira , Berta Temugin , Lee Sang Hoon
Published: November 2021

Migraine is a common neurological disorder with few available treatment options. Recently, we have demonstrated the role of transient receptor potential cation channel subfamily C member 4 (TRPC4) in itch and the modulation of the calcitonin gene-related peptide (CGRP), a biomarker and emerging therapeutic target for migraine. In this study, we characterized the role of TRPC4 in pain and evaluated its inhibition as anti-migraine pain therapy in preclinical mouse models. First, we found that TRPC4 is highly expressed in trigeminal ganglia and its activation not only mediates itch but also pain. Second, we demonstrated that the small-molecule inhibitor ML204, a specific TRPC4 antagonist, significantly reduced episodic and chronic migraine-like behaviors in male and female mice after injection of nitroglycerin (NTG), a well-known migraine inducer in rodents and humans. Third, we found a significant decrease in CGRP protein levels in the plasma of both male and female mice treated with ML-204, which largely prevented the development of chronic migraine-like behavior. Using sensory neuron cultures, we confirmed that activation of TRPC4 elicited release of CGRP, which was significantly diminished by ML-204. Collectively, our findings identify TRPC4 in peripheral sensory neurons as a mediator of CGRP release and NTG-evoked migraine. Since a TRPC4 antagonist is already in clinical trials, we expect that this study will rapidly lead to novel and effective clinical treatments for migraineurs.
Long Chain Polyunsaturated Fatty Acids Docosahexaenoic Acid and Arachidonic Acid Supplementation in the Suckling and the Post-weaning Diet Influences the Immune System Development of T Helper Type-2 Bias Brown Norway Rat Offspring
Authors: Patel Dhruvesh , Newell Marnie , Goruk Susan , Richard Caroline , Field Catherine J.
Published: November 2021

Background:Dietary long chain polyunsaturated fatty acids (LCPUFA) such as arachidonic acid (ARA) and docosahexaenoic acid (DHA) play an important role in the development of the infant immune system. The role of LCPUFA in the T helper type 2 (Th2) biased immune system is unknown. We aimed to understand the effect of feeding LCPUFA during suckling and post-weaning on immune system development in Th2 bias Brown Norway rat offspring.

Methods:Brown Norway dams were randomly assigned to nutritionally adequate maternal diet throughout the suckling period (0–3 weeks), namely, control diet (0% ARA, 0% DHA;n= 8) or ARA + DHA (0.45% ARA, 0.8% DHA;n= 10). At 3 weeks, offspring from each maternal diet group were randomized to either a control (0% ARA, 0% DHA;n= 19) or ARA+DHA post-weaning (0.5% ARA, 0.5% DHA;n= 18) diet. At 8 weeks, offspring were killed, and tissues were collected for immune cell function and fatty acid composition analyses.

Results:ARA + DHA maternal diet resulted in higher (p< 0.05) DHA composition in breast milk (4×) without changing ARA levels. This resulted in more mature adaptive immune cells in spleen [T regulatory (Treg) cells and B cells], mesenteric lymph nodes (MLN, lower CD45RA+), and Peyer's patches (PP; higher IgG+, B cells) in the ARA+DHA group offspring at 8 weeks. ARA+DHA post-weaning diet (3–8 weeks) resulted in 2 × higher DHA in splenocyte phospholipids compared to control. This also resulted in higher Th1 cytokines, ~50% higher TNF-α and IFNγ, by PMAi stimulated splenocytesex vivo, with no differences in Th2 cytokines (IL-4, IL-13, and IL-10) compared to controls.

Conclusion:Feeding dams a diet higher in DHA during the suckling period resulted in adaptive immune cell maturation in offspring at 8 weeks. Providing ARA and DHA during the post-weaning period in a Th2 biased Brown Norway offspring model may support Th1 biased immune response development, which could be associated with a lower risk of developing atopic diseases.
The Ferroptosis-Related Noncoding RNA Signature as a Novel Prognostic Biomarker in the Tumor Microenvironment, Immunotherapy, and Drug Screening of Gastric Adenocarcinoma
Authors: Chen Xinming , Zhu Zheng , Li Xiaoling , Yao Xinyue , Luo Lianxiang
Published: November 2021

Background

Ferroptosis is a new type of cell death different from apoptosis, necrosis, autophagy, and pyroptosis. This study aimed to explore the relationship between ferroptosis-related noncoding RNA (ncRNA) and gastric adenocarcinoma with regard to immunity and prognosis.

Methods

Ferroptosis-related ncRNA expression profiles and clinical pathology and overall survival information were collected from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus database. The ferroptosis-related ncRNA signature was identified by Cox regression analysis and the least absolute shrinkage and selection operator analysis. The survival analysis, receiver operating characteristic (ROC) analysis, and decision curve analysis were adopted to evaluate the prognostic prediction performance of the signature. The correlation between risk and multiple clinical characteristics was analyzed using the chi-square test. The Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and gene set enrichment analysis were used for mining functions and pathways. The CIBERSORT, ssGSEA, and ESTIMATE algorithms were used to assess immune infiltration and the tumor microenvironment. The response of immunotherapy was predicted using the Submap algorithm, and the Connectivity Map and the ridge regression model were used to screen and evaluate drugs.

Results

A carcinogenic risk signature was constructed using five ferroptosis-related ncRNAs. It showed an extraordinary ability to predict the prognoses of patients with gastric adenocarcinoma [area under the ROC curve (AUC) after 6 years = 0.689; GSE84426, AUC after 6 years = 0.747]. The lower ferroptosis potential level and lower tumor mutation burden were related to the poor prognoses of patients. The high-risk group had more immune cell recruitment, and the overall effect of the anti-immune checkpoint immunotherapy was not as good as that of the low-risk group. The high- and low-risk groups were enriched in tumor- and immune-related pathways, respectively. The screened antitumor drugs, such as genistein, guanabenz, and betulinic acid, improved the survival of the patients.

Conclusions

The ferroptosis-related ncRNA signature is a potential carcinogenic prognostic biomarker of gastric adenocarcinoma.
Axial Length Changes Following Surgical Intervention in Children With Primary Congenital Glaucoma
Authors: Al Dalgan Hind A. , Al Obaida Ibrahim A. , Al Owaifeer Adi M. , Ahmad Khabir , Malik Rizwan
Published: November 2021

Background

Primary congenital glaucoma (PCG) is a challenging condition to diagnose, treat and effectively monitor. Serial assessment of intraocular pressure (IOP), optic disc cupping, refraction, and axial length (AxL) after surgery are useful to assess disease control. This study aimed to evaluate AxL changes in relation to IOP changes following glaucoma surgery in children with PCG.

Methods

We retrospectively studied AxL changes in children with PCG undergoing surgery. Eyes of children aged ≤ 4 years that did not have prior ocular surgery and that underwent at least one glaucoma surgery during the course of follow-up between June 2014 and July 2018, were included. The effect of change in IOP on change in AxL was estimated using linear mixed effects models.

Results

A total of 105 eyes (of 72 children) with PCG underwent glaucoma surgery representing 26.4% (105/397) eyes. The mean ± SD age of children at baseline was 3.53 ± 4.04 months. At baseline, the mean IOP and AxL were 26.63 ± 9.57 mmHg and 21.67 ± 1.82 mm, respectively. During the course of follow-up post-surgery, the IOP decreased by a mean of 7.25 ± 12.08 mmHg while the AxL increased by a mean of 0.70 ± 1.40 mm. A multivariable mixed effects linear regression revealed that change in AxL was significantly associated with change in IOP (p=0.030) and time since first surgery (p<0.001). A substantial reduction in IOP (≥35 mmHg) was needed at 3 months post-surgery, for AxL to regress.

Conclusion

In children with PCG who undergo glaucoma surgery, change in IOP significantly influences change in AxL. For AxL to regress, a substantial reduction in IOP is needed post-surgery.
Segmental Chiropractic Spinal Manipulation Does not Reduce Pain Amplification and the Associated Pain-Related Brain Activity in a Capsaicin-Heat Pain Model
Authors: Provencher Benjamin , Northon Stéphane , Piché Mathieu
Published: November 2021

Musculoskeletal injuries lead to sensitization of nociceptors and primary hyperalgesia (hypersensitivity to painful stimuli). This occurs with back injuries, which are associated with acute pain and increased pain sensitivity at the site of injury. In some cases, back pain persists and leads to central sensitization and chronic pain. Thus, reducing primary hyperalgesia to prevent central sensitization may limit the transition from acute to chronic back pain. It has been shown that spinal manipulation (SM) reduces experimental and clinical pain, but the effect of SM on primary hyperalgesia and hypersensitivity to painful stimuli remains unclear. The goal of the present study was to investigate the effect of SM on pain hypersensitivity using a capsaicin-heat pain model. Laser stimulation was used to evoke heat pain and the associated brain activity, which were measured to assess their modulation by SM. Eighty healthy participants were recruited and randomly assigned to one of the four experimental groups: inert cream and no intervention; capsaicin cream and no intervention; capsaicin cream and SM at T7; capsaicin cream and placebo. Inert or capsaicin cream (1%) was applied to the T9 area. SM or placebo were performed 25 min after cream application. A series of laser stimuli were delivered on the area of cream application (1) before cream application, (2) after cream application but before SM or placebo, and (3) after SM or placebo. Capsaicin cream induced a significant increase in laser pain (p < 0.001) and laser-evoked potential amplitude (p < 0.001). However, SM did not decrease the amplification of laser pain or laser-evoked potentials by capsaicin. These results indicate that segmental SM does not reduce pain hypersensitivity and the associated pain-related brain activity in a capsaicin-heat pain model.
Myotonia Congenita: Clinical Characteristic and Mutation Spectrum of CLCN1 in Chinese Patients
Authors: Hu Chaoping , Shi Yiyun , Zhao Lei , Zhou Shuizhen , Li Xihua
Published: November 2021

Background:CLCN1-related myotonia congenita (MC) is one of the most common forms of non-dystrophic myotonia, in which muscle relaxation is delayed after voluntary or evoked contraction. However, there is limited data of clinical and molecular spectrum of MC patients in China.

Patients and Methods: Five patients with myotonia congenita due to mutations in CLCN1 gene were enrolled, which were identified through trio-whole-exome sequencing or panel-based next-generation sequencing test. The clinical presentation, laboratory data, electrophysiological tests, muscular pathology feature, and genetic results were collected and reviewed. We also searched all previously reported cases of MC patients with genetic diagnosis in Chinese populations, and their data were reviewed.

Results: The median onset age of five patients was 3.0 years old, ranging from 1.0 to 5.0 years old, while the median age of admit was 5.0 years old, ranging from 3.5 to 8.8 years old. Five patients complained of muscle stiffness when rising from chairs or starting to climb stairs (5/5, 100.0%), four patients complained of delayed relaxation of their hands after forceful grip (4/5, 80.0%), all of which improved with exercise (warm-up phenomenon) (5/5, 100%). Electromyogram was conducted in five patients, which all revealed myotonic change (100%). Genetic tests revealed nine potential disease-causing variants in CLCN1 gene, including two novel variants: c.962T>A (p.V321E) and c.1250A>T (p.E417V). Literature review showed that 43 MC Chinese patients with genetic diagnosis have been reported till now (including our five patients). Forty-seven variants in CLCN1 gene were found, which consisted of 33 missense variants, 6 nonsense variants, 5 frame-shift variants, and 3 splicing variants. Variants in exon 8, 15, 12, and 16 were most prevalent, while the most common variants were c.892G>A (p.A298T) (n = 9), c.139C>T (p.R47W) (n = 3), c.1205C>T(p.A402V) (n = 3), c.1657A>T (p.I553F) (n = 3), c.1679T>C (p.M560T) (n = 3), c.350A>G (p.D117G) (n = 2), c.762C>G (p.C254W) (n = 2), c.782A>G (P.Y261C) (n = 2), and c.1277C>A (p.T426N) (n = 2).

Conclusion: Our results reported five CLCN1-related MC patients, which expanded the clinical and genetic spectrum of MC patients in China. Based on literature review, 43MC Chinese patients with genetic diagnosis have been reported till now, and variants in exon eight were most prevalent in Chinese MC patients while c.892G>A (p.A298T) was probably a founder mutation.
Targeting Wnt Signaling in the Tumor Immune Microenvironment to Enhancing EpCAM CAR T-Cell therapy
Authors: Li Weizhen , Zhou Yang , Wu Zhongen , Shi Yaoping , Tian Enming , Zhu Yingqi , Wang Tao , Dou Wei , Meng Xiangjing , Chen Ming , Zhai Bo , Zhu Di
Published: November 2021

Colorectal cancer (CRC) patients are still lacking viable treatments. Chimeric antigen receptor (CAR) T cells have shown promise in hematologic malignancies, but their efficacy in solid tumors has been limited due to the immunosuppressive tumor microenvironment. We found that cancer antigen- EpCAM expression increased in the metastatic stage compared with the primary stage in cancers and the activation of Wnt and TGFβ pathways was positively correlated with EpCAM expression in multiple cancers, including colorectal cancer. We constructed CAR T cells targeting EpCAM that successfully showed selective cytotoxicity in highly EpCAM-expressing cancer cell lines. The combination of EpCAM CAR-T with the Wnt inhibitor-hsBCL9CT-24 displayed synergetic effect against EpCAM-positive colon cellsin vitroand alsoin vivo. A mechanistic study showed that hsBCL9CT-24 treatment could modulate the tumor environment and improve infiltration of T cells, while possibly promoting the effector T cells at the early stages and postponing the exhaustion of CAR T cells at advanced stages. Overall, these results demonstrated that the combination of EpCAM CAR T-cell therapy with the Wnt inhibitor can overcome the limitations of CAR T cells in treating solid tumors.
Contribution of Character Strengths to Psychology Stress, Sleep Quality, and Subjective Health Status in a Sample of Chinese Nurses
Authors: Zhang Shu-e , Yang Li-bin , Zhao Chen-xi , Shi Yu , Wang Hong-ni , Zhao Xin , Wang Xiao-he , Sun Tao , Cao De-pin
Published: November 2021

Objectives: The main objectives of this study were to describe the current state of character strengths (CSs) of nurses; explain how they affect stress, sleep quality, and subjective health status; and reveal the mediating role of stress for the subject matter on the association between CSs, sleep quality, and subjective health status.

Methods: A cross-sectional online survey was conducted from September to October 2020 in China. A multistage stratified sampling method was used, and 1,221 valid questionnaires across 100 cities in 31 provinces were collected.

Results: For the participants in this survey, the three dimensions of CSs ranging from high to low were caring (4.20 ± 0.640), self-control (3.53 ± 0.763), and inquisitiveness (3.37 ± 0.787). There was difference in CSs scores across age (F = 8.171, P < 0.01), professional categories (F = 5.545, P < 0.01), and job tenure (F = 9.470, P < 0.01). The results showed that CSs significantly affected the psychological stress (β = −0.365, P< 0.01), sleep quality (β = 0.312, P< 0.01), and subjective health (β = 0.398, P< 0.01) of nurses. Moreover, psychological stress partially mediated the association between CSs and both types of health outcomes.

Conclusion: In China, the CSs of nurses are at high levels. We find that nurses with high-level CSs are likely to experience less psychological stress and exhibit healthy psycho–physiological responses, which contribute to positive health outcomes. Finally, our study argues that strength-based interventions of positive psychology in hospitals should be provided to minimize threats to the physical and psychological health of health professionals, which is a beneficial choice for future hospital reforms in the domain of occupational health management.
Proof of Concept: A Brief Psycho-Educational Training Program to Increase the Use of Positive Emotion Regulation Strategies in Individuals With Autism Spectrum Disorder
Authors: Zaharia Alexandra , Noir-Kahlo Katharina , Bressoud Nicolas , Sander David , Dukes Daniel , Samson Andrea C.
Published: November 2021

Attenuated positive emotions and difficulties in regulating emotions are frequently observed in individuals with autism spectrum disorders (ASD) and are linked to increased risk of affective disorders, problematic behaviors, and impaired socio-emotional functioning. As such, interventions specifically focused on positive emotion regulation (ER) skills could be very valuable for individuals with ASD, their caregivers, and therapists. However, the field of positive ER in ASD is under-researched. The present study aimed at testing the practical potential and the preliminary effects of a brief novel psycho-educational training program on positive ER for individuals with ASD. Thirty male participants with ASD (aged 10–35years; Ntraining=14, Nwaitlist=16) underwent a three-session program on the use of adaptive positive ER strategies (i.e., attentional deployment, cognitive change, and response modulation). Participants rated the program as easy to understand, interesting, pleasant, and likable. No dropouts or adverse effects were observed. The training group showed a significant increase in the self-reported use of the ER strategies compared to the waitlist group. The increase in the use of ER strategies maintained up to 7 weeks in the overall sample. Having reached high satisfaction rates and the intended effects in this proof of concept study, this novel program represents a promising tool to support ER. Future research should next investigate the efficacy of the intervention on day-to-day emotional experience and wellbeing.

Clinical Trial Registration:ClinicalTrials.gov # NCT02898298
Post-Traumatic Stress Disorder, Mobile Phone Dependence, and Academic Boredom in Adolescents During the COVID-19 Pandemic
Authors: Shen Lingyan , Wu Xinyue , Zhen Rui , Zhou Xiao
Published: November 2021

Background: The coronavirus disease (COVID-19) pandemic has threatened adolescents’ mental health and even elicited their academic problems. Post-traumatic stress disorder (PTSD) is one of the most common negative psychological reactions, and academic boredom is a typical academic problem to the pandemic. PTSD might be related to academic boredom, but the underlying mechanism of this potential relation in the context of the COVID-19 pandemic remains unclear.

Aims: Under the framework of the job demands–resources model and the model of compensatory internet use, this study aims to examine the mediating role of mobile phone dependency in the relation between PTSD and academic boredom.

Methods: Six hundred and thirty-one middle school students in Hubei Province were investigated using self-report questionnaires. SPSS19.0 and Mplus7.0 were used for data analysis.

Results: PTSD symptoms were associated positively with academic boredom, and mobile phone dependence played a mediating role in the relation between PTSD and academic boredom. Specifically, adolescents with severe PTSD symptoms tended to report greater dependency on mobile phones, and hence show higher levels of boredom in learning.

Conclusion: PTSD symptoms of adolescents directly aggravated their academic boredom, and indirectly affected academic boredom by increasing their dependence on mobile phones.
Fear of COVID-19 and Life Satisfaction: The Role of the Health-Related Hardiness and Sense of Coherence
Authors: Dymecka Joanna , Gerymski Rafał , Machnik-Czerwik Anna , Derbis Romuald , Bidzan Mariola
Published: November 2021

Introduction: The COVID-19 pandemic is contributing to increased fear and anxiety throughout society, which may affect life satisfaction. Health-related hardiness and sense of coherence (SOC) are personal resources that help people adapt to difficult circumstances. The purpose of this study was to investigate the relationship between fear of COVID-19, SOC, health-related hardiness, and life satisfaction.

Methods: A total of 907 Polish people (522 women and 385 men) participated in this study. The Fear of COVID-19 Scale (FOC-6), the Health-Related Hardiness Scale, the Sense of Coherence Scale (SOC-29), and the Satisfaction with Life Scale were used.

Results: Correlation showed that fear of COVID-19 was negatively related to health-related hardiness, SOC, and life satisfaction. Health-related hardiness and SOC were positively related to life satisfaction. Both SOC and hardiness were mediators between fear of COVID-19 and life satisfaction during the current pandemic.

Conclusion: SOC and health-related hardiness are personal resources that are important for dealing with the effects of the COVID-19 pandemic. According to our study, SOC and hardiness can mediate between fear of COVID-19 and life satisfaction. Presented cross-sectional results have to be verified in future longitudinal studies in order to strengthen the conclusions presented in this manuscript. This study verified the role of only two personal resources, so more research is needed on the role of other personal resources during COVID-19 pandemic.
Brain Functional and Structural Changes in Alzheimer's Disease With Sleep Disorders: A Systematic Review
Authors: Liu Yong-shou , Wang Yong-ming , Zha Ding-jun
Published: November 2021

Introduction: Sleep disorders (SLD) are supposed to be associated with increased risk and development of Alzheimer's disease (AD), and patients with AD are more likely to show SLD. However, neurobiological performance of patients with both AD and SLD in previous studies is inconsistent, and identifying specific patterns of the brain functional network and structural characteristics in this kind of comorbidity is warranted for understanding how AD and SLD symptoms interact with each other as well as finding effective clinical intervention. Thus, the aims of this systematic review were to summarize the relevant findings and their limitations and provide future research directions.

Methods: A systematic search on brain functional and structural changes in patients with both AD and SLD was conducted from PubMed, Web of Science, and EMBASE databases.

Results: Nine original articles published between 2009 and 2021 were included with a total of 328 patients with comorbid AD and SLD, 367 patients with only AD, and 294 healthy controls. One single-photon emission computed tomography study and one multislice spiral computed tomography perfusion imaging study investigated changes of cerebral blood flow; four structural magnetic resonance imaging (MRI) studies investigated brain structural changes, two of them used whole brain analysis, and another two used regions of interest; two resting-state functional MRI studies investigated brain functional changes, and one 2-deoxy-2-(18F)fluoro-d-glucose positron emission tomography (18F-FDG-PET) investigated 18F-FDG-PET uptake in patients with comorbid AD and SLD. Findings were inconsistent, ranging from default mode network to sensorimotor cortex, hippocampus, brain stem, and pineal gland, which may be due to different imaging techniques, measurements of sleep disorder and subtypes of AD and SLD.

Conclusions: Our review provides a systematic summary and promising implication of specific neuroimaging dysfunction underlying co-occurrence of AD and SLD. However, limited and inconsistent findings still restrict its neurobiological explanation. Further studies should use unified standards and comprehensive brain indices to investigate the pathophysiological basis of interaction between AD and SLD symptoms in the development of the disease spectrums.