bluuebunny/crossref_metadata_2025 huggingface dataset:
Robot-Based Last-Mile Deliveries With Pedestrian Zones
Authors: Bakach Iurii , Campbell Ann Melissa , Ehmke Jan Fabian
Published: January 2022

Since delivery robots share sidewalks with pedestrians, it may be beneficial to choose paths for them that avoid zones with high pedestrian density. In this paper, we investigate a robot-based last-mile delivery problem considering path flexibility given the presence of zones with varying pedestrian level of service (LOS). Pedestrian LOS is a measure of pedestrian flow density. We model this new problem with stochastic travel times and soft customer time windows. The model includes an objective that reflects customer service quality based on early and late arrivals. The heuristic solution approach uses the minimum travel time paths from different LOS zones (path flexibility). We demonstrate that the presence of pedestrian zones leads to alternative path choices in 30% of all cases. In addition, we find that extended time windows may help increase service quality in zones with high pedestrian density by up to 40%.
circTAF8 Regulates Myoblast Development and Associated Carcass Traits in Chicken
Authors: Li Kan , Huang Weichen , Wang Zhijun , Chen Yangfeng , Cai Danfeng , Nie Qinghua
Published: January 2022

Recent studies have shown that circular RNAs (circRNAs) play important roles in skeletal muscle development. CircRNA biogenesis is dependent on the genetic context. Single-nucleotide polymorphisms in the introns flanking circRNAs may be intermediate-inducible factors between circRNA expression and phenotypic traits. Our previous study showed that circTAF8 is an abundantly and differentially expressed circRNA in leg muscle during chicken embryonic development. Here, we aimed to investigate circTAF8 function in muscle development and the association of the SNPs in the circTAF8 flanking introns with carcass traits. In this study, we observed that overexpression of circTAF8 could promote the proliferation of chicken primary myoblasts and inhibit their differentiation. In addition, the SNPs in the introns flanking the circTAF8 locus and those associated with chicken carcass traits were analyzed in 335 partridge chickens. A total of eight SNPs were found associated with carcass traits such as leg muscle weight, live weight, and half and full-bore weight. The association analysis results of haplotype combinations were consistent with the association analysis of a single SNP. These results suggest that circTAF8 plays a regulatory role in muscle development. These identified SNPs were found correlated with traits to muscle development and carcass muscle weight in chickens.
Genomic Analysis of Visceral Fat Accumulation in Holstein Cows
Authors: Novo Larissa C. , Cavani Ligia , Pinedo Pablo , Melendez Pedro , Peñagaricano Francisco
Published: January 2022

Visceral fat is related to important metabolic processes, including insulin sensitivity and lipid mobilization. The goal of this study was to identify individual genes, pathways, and molecular processes implicated in visceral fat deposition in dairy cows. Data from 172 genotyped Holstein cows classified at slaughterhouse as having low (n = 77; omental fold <5 mm in thickness and minimum fat deposition in omentum) or high (n = 95; omental fold ≥20 mm in thickness and marked fat deposition in omentum) omental fat were analyzed. The identification of regions with significant additive and non-additive genetic effects was performed using a two-step mixed model-based approach. Genomic scans were followed by gene-set analyses in order to reveal the genetic mechanisms controlling abdominal obesity. The association mapping revealed four regions located on BTA19, BTA20 and BTA24 with significant additive effects. These regions harbor genes, such as SMAD7, ANKRD55, and the HOXB family, that are implicated in lipolysis and insulin tolerance. Three regions located on BTA1, BTA13, and BTA24 showed marked non-additive effects. These regions harbor genes MRAP, MIS18A, PRNP and TSHZ1, that are directly implicated in adipocyte differentiation, lipid metabolism, and insulin sensitivity. The gene-set analysis revealed functional terms related to cell arrangement, cell metabolism, cell proliferation, cell signaling, immune response, lipid metabolism, and membrane permeability, among other functions. We further evaluated the genetic link between visceral fat and two metabolic disorders, ketosis, and displaced abomasum. For this, we analyzed 28k records of incidence of metabolic disorders from 14k cows across lactations using a single-step genomic BLUP approach. Notably, the region on BTA20 significantly associated with visceral fat deposition was also associated with the incidence of displaced abomasum. Overall, our findings suggest that visceral fat deposition in dairy cows is controlled by both additive and non-additive effects. We detected at least one region with marked pleiotropic effects affecting both visceral fat accumulation and displaced abomasum.
A Targeted In-Fusion Expression System for Recombinant Protein Production in Bombyx mori
Authors: Li Zhiqian , You Lang , Zhang Qichao , Yu Ye , Tan Anjiang
Published: January 2022

The domesticated silkworm, Bombyx mori, is an economically important insect that synthesizes large amounts of silk proteins in its silk gland to make cocoons. In recent years, germline transformation strategies advanced the bioengineering of the silk gland as an ideal bioreactor for mass production of recombinant proteins. However, the yield of exogenous proteins varied largely due to the random insertion and gene drift caused by canonical transposon-based transformation, calling for site-specific and stable expression systems. In the current study, we established a targeted in-fusion expression system by using the transcription activator-like effector nuclease (TALEN)-mediated targeted insertion to target genomic locus of sericin, one of the major silk proteins. We successfully generated chimeric Sericin1-EGFP (Ser-2A-EGFP) transformant, producing up to 3.1% (w/w) of EGFP protein in the cocoon shell. With this strategy, we further expressed the medically important human epidermal growth factor (hEGF) and the protein yield in both middle silk glands, and cocoon shells reached to more than 15-fold higher than the canonical piggyBac-based transgenesis. This natural Sericin1 expression system provides a new strategy for producing recombinant proteins by using the silkworm silk gland as the bioreactor.
Roles of Epithelial and Mesenchymal TRP Channels in Mediating Inflammatory Fibrosis
Authors: Okada Yuka , Sumioka Takayoshi , Reinach Peter S. , Miyajima Masayasu , Saika Shizuya
Published: January 2022

The maintenance of normal vision is dependent on preserving corneal transparency. For this to occur, this tissue must remain avascular and its stromal architecture needs to be retained. Epithelial transparency is maintained provided the uppermost stratified layers of this tissue are composed of terminally differentiated non-keratinizing cells. In addition, it is essential that the underlying stromal connective tissue remains avascular and scar-free. Keratocytes are the source of fibroblasts that are interspersed within the collagenous framework and the extracellular matrix. In addition, there are sensory nerve fibers whose lineage is possibly either neural crest or mesenchymal. Corneal wound healing studies have been undertaken to delineate the underlying pathogenic responses that result in the development of opacification following chemical injury. An alkali burn is one type of injury that can result in severe and long- lasting losses in ocular transparency. During the subsequent wound healing process, numerous different proinflammatory cytokines and proteolytic enzymes undergo upregulation. Such increases in their expression levels induce maladaptive expression of sustained stromal inflammatory fibrosis, neovascularization, and losses in the smooth optical properties of the corneal outer surface. It is becoming apparent that different transient receptor potential channel (TRP) isoforms are important players in mediating these different events underlying the wound healing process since injury upregulates both their expression levels and functional involvement. In this review, we focus on the involvement of TRPV1, TRPA1 and TRPV4 in mediating some of the responses that underlie the control of anterior ocular tissue homeostasis under normal and pathological conditions. They are expressed on both different cell types throughout this tissue and also on corneal sensory nerve endings. Their roles have been extensively studied as sensors and transducers of environmental stimuli resulting from exposure to intrinsic modulators and extrinsic ligands. These triggers include alteration of the ambient temperature and mechanical stress, etc., that can induce pathophysiological responses underlying losses in tissue transparency activated by wound healing in mice losses in tissue transparency. In this article, experimental findings are reviewed about the role of injury-induced TRP channel activation in mediating inflammatory fibrotic responses during wound healing in mice.
High Complete Response Rate in Patients With Metastatic Renal Cell Carcinoma Receiving Autologous Cytokine-Induced Killer Cell Therapy Plus Anti-Programmed Death-1 Agent: A Single-Center Study
Authors: Zhao Lingdi , Li Tiepeng , Song Yongping , Yang Yonghao , Ma Baozhen , Zhang Yong , Shang Yiman , Xu Benling , Guo Jindong , Qin Peng , Han Lu , Fu Xiaomin , Lin Hongwei , Liu Liang , Ren Xiubao , Wang Zibing , Gao Quanli
Published: January 2022

Background and Objective

The results of the CheckMate 025 trial established the status of nivolumab in the second-line treatment of metastatic renal cell carcinoma (mRCC), with an objective response rate (ORR) of 25% and a complete response (CR) rate of 1%. Thus, the efficacy of anti-programmed death (PD)-1 antibodies in the second-line treatment of mRCC requires improvement. The purpose of this study was to explore the clinical efficacy and safety of anti-PD-1 agents combined with cytokine-induced killer (CIK) cell therapy for refractory mRCC.

Patients and Methods

Patients with mRCC refractory to previous targeted therapy were included in this study. All patients received anti-PD-1 plus CIK cell therapy. The ORR and CR rate, progression-free survival (PFS), overall survival (OS), and safety were assessed.

Results

CR was observed in seven of the 29 patients, and partial response was observed in five patients. The ORR was 41.4% and the median PFS was 15.0 months. Up to the last follow-up, 15 patients died with an average survival time of 37 months. Among the patients who achieved a CR, one experienced cerebellar metastasis 18.8 months after discontinuation, but achieved CR again after localized gamma knife and 1-month axitinib treatment. This regimen was tolerated well and there was no treatment-related death.

Conclusions

Combination therapy with anti-PD-1 and CIK cell therapy is safe and effective in patients with mRCC refractory to previous targeted therapy. The high CR rate and long disease-free survival even after long-term discontinued therapy suggest that this combination treatment may represent a potential curative regimen for this type of malignancy.
Hypozincemia in COVID-19 Patients Correlates With Stronger Antibody Response
Authors: Xu Wenye , Liu Yingzhi , Zou Xuan , Luo Huanle , Wu Weihua , Xia Junjie , Chan Matthew T. V. , Fang Shisong , Shu Yuelong , Wu William K. K. , Zhang Lin
Published: January 2022

Zinc ion as an enzyme cofactor exhibits antiviral and anti-inflammatory activity during infection, but circulating zinc ion level during Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection is unclear. This study aimed to evaluate serum zinc ion level in Coronavirus Disease 2019 (COVID-19) patients and healthy subjects, as well as its correlation with antibodies against SARS-CoV-2. 114 COVID-19 patients and 48 healthy subjects (38 healthy volunteers and 10 close contacts of patients with COVID-19) were included. Zinc ion concentration and levels of antibodies against SARS-CoV-2 Spike 1 + Spike 2 proteins, nucleocapsid protein, and receptor-binding domain in serum were measured. Results showed that the concentration of zinc ion in serum from COVID-19 patients [median: 6.4 nmol/mL (IQR 1.5 – 12.0 nmol/mL)] were significantly lower than that from the healthy subjects [median: 15.0 nmol/mL (IQR 11.9 – 18.8 nmol/mL)] (p < 0.001) and the difference remained significant after age stratification (p < 0.001) or when the patients were at the recovery stage (p < 0.001). Furthermore, COVID-19 patients with more severe hypozincemia showed higher levels of IgG against the receptor-binding domain of SARS-CoV-2 spike protein. Further studies to confirm the effect of zinc supplementation on improving the outcomes of COVID-19, including antibody response against SARS-CoV-2, are warranted.
The Influence of a Suspended Cage Aquaculture Farm on the Hydrodynamic Environment in a Semienclosed Bay, SE China
Authors: Jiang Xintao , Tu Junbiao , Fan Daidu
Published: January 2022

Hydrodynamic responses of the aquaculture farm structures have been increasingly studied because of their importance in informing the aquaculture carrying capacity and ecological sustainability. The hydrodynamical effect of the suspended cage farm on flow structures and vertical mixing in the Sansha Bay, SE China, is examined using observational data of two comparative stations inside and outside the cage farm. The results show that current velocities are relatively uniform in the vertical except a bottom boundary layer outside the cage farm. Within the cage farm, the surface boundary layer produced by the cage-induced friction is obvious with current velocities decreasing upward, combining the classic bottom boundary layer to form a “double-drag layers” structure in the water column. The cage-induced drag decreases with water depth in the surface boundary layer with a maximum thickness of 3/4 the water column, and the current velocities can be reduced by 54%. The cage-induced friction can also significantly hinder the horizontal water exchange in the farm. Periodic stratification phenomena exist at both stations under the influence of lateral circulation. However, the subsurface (5–10 m below the sea surface) water column below the cage facilities is well-mixed as indicated by the vertical density profile, where the velocity shear (10–3 m–2) is about 10 times higher than that of the subsurface layer outside the cage farm. Therefore, we speculate that the well-mixing of the subsurface water column results from the local turbulence induced by the velocity shear, which in turn is produced by the friction of cage structures.
Seabird-Derived Nutrients Supply Modulates the Trophic Strategies of Mixotrophic Corals
Authors: Thibault Martin , Houlbreque Fanny , Duprey Nicolas N. , Choisnard Noémie , Gillikin David P. , Meunier Valentine , Benzoni Francesca , Ravache Andréas , Lorrain Anne
Published: January 2022

The ability of corals to modulate their nutrition strategy in response to variable nutrient supply remains poorly understood, limiting our understanding of energy flow in coral reef ecosystems and thus our comprehension of their resilience to global changes. We used a naturally occurring nutrient gradient along the reef flat of two seabird-inhabited islets in the SW Pacific to characterize spatiotemporal fluctuations in coastal nutrient availability, and how it modulates the trophic response of the mixotrophic coral Pocillopora damicornis. The clear gradients in dissolved [NOx] and δ15N values of macroalgae and both P. damicornis tissues and symbionts observed along the reef flat during the dry and the rainy season revealed that seabird-derived-N is supplied year-round to the reef flat. Yet, nitrogen isotope values of macroalgae show that the seabirds’ effect on coral reefs varies with sites and seasons. Metrics derived from the SIBER framework revealed that coral nutrition seasonally favored autotrophy when exposed to higher seabird guano concentrations and at inshore stations, while heterotrophy dominated in corals less exposed to seabird-derived nutrient supply. P. Damicornis is therefore able to cope with large changes in nitrogen supply induced by seabird island communities by switching between autotrophy and heterotrophy. These results shed light on the flexibility of resource sharing within the coral-algae symbiosis and highlight the importance of seabird populations to the functioning of coral reef ecosystems.
Integrating Biologging and Behavioral State Modeling to Identify Cryptic Behaviors and Post-capture Recovery Processes: New Insights From a Threatened Marine Apex Predator
Authors: Grainger Richard , Raubenheimer David , Peddemors Victor M. , Butcher Paul A. , Machovsky-Capuska Gabriel E.
Published: January 2022

Multisensor biologging provides a powerful tool for ecological research, enabling fine-scale observation of animals to directly link physiology and movement to behavior across ecological contexts. However, applied research into behavioral disturbance and recovery following human interventions (e.g., capture and translocation) has mostly relied on coarse location-based tracking or unidimensional approaches (e.g., dive profiles and activity/energetic metrics) that may not resolve behaviors and recovery processes. Biologging can improve insights into both disturbed and natural behavior, which is critical for management and conservation initiatives, although challenges remain in objectively identifying distinct behavioral modes from complex multisensor datasets. Using white sharks (Carcharodon carcharias) released from a non-lethal catch-and-release shark bite mitigation program, we explored how combining multisensor biologging (video, depth, accelerometers, gyroscopes, and magnetometers), track reconstruction and behavioral state modeling using hidden Markov models (HMMs) can improve our understanding of behavioral processes and recovery. Biologging tags were deployed on eight white sharks, recording their continuous behaviors, movements, and environmental context (habitat, interactions with other organisms/objects) for periods of 10–87 h post-release. Dive profiles and tailbeat analysis (as a standard, activity-based method for assessing recovery) indicated an immediate “disturbed” period of offshore movement, displaying rapid tailbeats and an average tailbeat-derived recovery period of 9.7 h, with evidence of smaller individuals having longer recoveries. However, further integrating magnetometer-derived headings, track reconstruction and HMM modeling revealed a cryptic shift to diurnal clockwise-counterclockwise circling behavior, which we argue represents compelling new evidence for hypothesized unihemispheric sleep amongst elasmobranchs. By simultaneously providing critical information toward conservation-focused shark management and understudied aspects of shark behavior, our study highlights how integrating multisensor information through HMMs can improve our understanding of both post-release and natural behavior, especially in species that are difficult to observe directly.
Inter-eye Differences in Ocular Biometric Parameters of Concomitant Exotropia
Authors: Gong Weifen , Chen Haoyu , Yang Fan , Lin Shibin , Li Chao , Wang Geng
Published: January 2022

Purpose: To evaluate the ocular biometric parameters in patients with constant and intermittent exotropia by the measurement of swept-source optical coherence tomography (SS-OCT) optical biometer OA-2000 and comparing it with the normal control subjects.

Design: Cross-sectional case-control study.

Participants: Fifty-five constant and 24 intermittent patients with exotropia with central fixation and 77 orthotropic normal control participants aged 4–18 years old.

Methods: Non-contact and high-resolution optical biometric OA-2000 measurements were conducted under uniform ambient light conditions. The statistical analysis included intraclass correlation coefficient (ICC), Bland-Altman plot, and independent t-tests.

Main Outcome Measures: Spherical equivalent (SE), ocular biological parameters such as pupil diameter (PD), anterior chamber depth (ACD), lens thickness (LT), and axial lengths (AL). The absolute values of inter-eye differences for SE, PD, ACD, LT, and AL were recorded as AnisoSE, AnisoPD, AnisoACD, AnisoLT, and AnisoAL, respectively.

Results: AnisoSE (0.878 vs. 0.577, P = 0.019), AnisoAL (0.395 vs. 0.208, P = 0.001), AnisoACD (0.060 vs. 0.032, P < 0.001), AnisoLT (0.060 vs. 0.031, P = 0.002), and AnisoPD (0.557 vs. 0.340, P = 0.002) were significantly larger in concomitant patients with exotropia. The SE, AL, ACD, LT, and PD showed excellent binocular correlation with ICC values that ranged from 0.943 to 0.987 in control participants and from 0.767 to 0.955 in concomitant exotropia patients. Bland-Altman plots showed the wider range of agreement in patients with concomitant exotropia than the control participants (SE: 5.0288 vs. 3.3258; AL: 2.2146 vs. 1.3172; ACD:0.3243 vs. 0.1682; PD: 2.4691 vs. 1.9241; and LT:0.3723 vs 0.1858).

Conclusion: Patients with concomitant exotropia showed larger inter-eye differences in SE, ACD, LT, PD, and AL. Advice should be given to suspicious children to avoid or delay the development of concomitant exotropia.
Bacillus spp. Contamination: A Novel Risk Originated From Animal Feed to Human Food Chains in South-Eastern Bangladesh
Authors: Haque Md Atiqul , Wang Fei , Chen Yi , Hossen Foysal , Islam Md Aminul , Hossain Md Amzad , Siddique Naila , He Cheng , Ahmed Firoz
Published: January 2022

The current study provides information on Bacillus spp. contamination along with present status in commercially available poultry and animal feeds as well as animal-derived products in Bangladesh. The research has been conducted to determine if animal feed and its components are a source of Bacillus spp. contamination in feed and food chain. Out of 180 different feeds, milk, egg, and human stool samples, 218 Bacillus spp. were isolated and identified by cultural morphology, microscopic, biochemical, and molecular characteristics where B. cereus, B. subtilis, B. amyloliquefaciens, B. licheniformis, B. thuringiensis, B. megaterium, and B. coagulans accounted for 51, 22, 9.1, 5.9, 5, 3.6, and 2.2%, respectively. Regarding the enumeration of total viable count and total Bacillus count, correspondingly 67 and 39% samples were found to be contaminated with above 10,000 CFU/g, while highest contamination was 85 and 75% in broiler feed, respectively. The total number of bacteria above the regulatory limits in commercially available feeds indicates a poor compliance with regulation and abuse administration in the Bangladeshi market. Moreover, a hospital-based survey showed that food-borne Bacillus spp. contributed to 4.5% human diarrhea cases and 25% food contamination associated with vegetables, rice, RTE food, milk, and egg, accounting for 46, 34, 14, 4, and 2%, respectively. B. cereus was the dominant isolate correspondingly accounting for 56 and 51% egg and milk contamination followed by B. amyloliquefaciens (32%) and B. thuringiensis (12%) in egg and B. subtilis (25%), B. amyloliquefaciens (12%), B. thuringiensis (6.4%), and B. coagulans (3.2%) in milk, respectively. Toxin gene profiling of Bacillus spp. revealed that B. cereus constituted a principal part of virulence, while B. thuringiensis, B. licheniformis, B. megaterium, B. coagulans, and B. subtilis showed genetic diversity and B. amyloliquefaciens had not carried any toxin gene. Detection rate of enterotoxin genes (nheA, nheB, nheC, cytK, hblA, hblC, hblD, and entFM) showed that 55% isolates carried nheABC genes, 80% entFM, and 71% cytK, whereas only 33% of the isolates contained hblACD gene clusters. These virulence genes were posing a threat to human health due to spread across the food and feed chain. Finally, our findings support the hypothesis that B. cereus might contribute to clinical diarrhea, gizzard erosion, and lung infection in duck and poultry, and that it contaminates animal-derived foods resulting in toxicity and antibacterial resistance to humans. Therefore, maximal tolerance limits of Bacillus spp. and their potential risks to the animal industry are urgently needed to clarify. Moreover, Bacillus spp.–induced toxin residual must be altered for human health via food chain transmission.
Isolation and Characterization of Bacillus velezensis Strain P2-1 for Biocontrol of Apple Postharvest Decay Caused by Botryosphaeria dothidea
Authors: Yuan Hongbo , Shi Bingke , Wang Li , Huang Tianxiang , Zhou Zengqiang , Hou Hui , Tu Hongtao
Published: January 2022

Botryosphaeria dothidea causes apple ring rot, which is among the most prevalent postharvest diseases of apples and causes significant economic loss during storage. In this study, we investigated the biocontrol activity and possible mechanism of Bacillus velezensis strain P2-1 isolated from apple branches against B. dothidea in postharvest apple fruit. The results showed strain P2-1, one of the 80 different endophytic bacterial strains from apple branches, exhibited strong inhibitory effects against B. dothidea growth and resulted in hyphal deformity. B. velezensis P2-1 treatment significantly reduced the ring rot caused by B. dothidea. Additionally, the supernatant of strain P2-1 exhibited antifungal activity against B. dothidea. Re-isolation assay indicated the capability of strain P2-1 to colonize and survive in apple fruit. PCR and qRT-PCR assays revealed that strain P2-1 harbored the gene clusters required for biosynthesis of antifungal lipopeptides and polyketides. Strain P2-1 treatment significantly enhanced the expression levels of pathogenesis-related genes (MdPR1 and MdPR5) but did not significantly affect apple fruit qualities (measured in fruit firmness, titratable acid, ascorbic acid, and soluble sugar). Thus, our results suggest that B. velezensis strain P2-1 is a biocontrol agent against B. dothidea-induced apple postharvest decay. It acts partially by inhibiting mycelial growth of B. dothidea, secreting antifungal substances, and inducing apple defense responses.
Clinical Manifestations and Pathogenesis of Acute Necrotizing Encephalopathy: The Interface Between Systemic Infection and Neurologic Injury
Authors: Shukla Priya , Mandalla Abby , Elrick Matthew J. , Venkatesan Arun
Published: January 2022

Acute necrotizing encephalopathy (ANE) is a devastating neurologic condition that can arise following a variety of systemic infections, including influenza and SARS-CoV-2. Affected individuals typically present with rapid changes in consciousness, focal neurological deficits, and seizures. Neuroimaging reveals symmetric, bilateral deep gray matter lesions, often involving the thalami, with evidence of necrosis and/or hemorrhage. The clinical and radiologic picture must be distinguished from direct infection of the central nervous system by some viruses, and from metabolic and mitochondrial disorders. Outcomes following ANE are poor overall and worse in those with brainstem involvement. Specific management is often directed toward modulating immune responses given the potential role of systemic inflammation and cytokine storm in potentiating neurologic injury in ANE, though benefits of such approaches remain unclear. The finding that many patients have mutations in the nucleoporin gene RANBP2, which encodes a multifunctional protein that plays a key role in nucleocytoplasmic transport, may allow for the development of disease models that provide insights into pathogenic mechanisms and novel therapeutic approaches.
Post-concussive Dizziness: A Review and Clinical Approach to the Patient
Authors: Gianoli Gerard J.
Published: January 2022

Dizziness is a frequent complaint after head trauma. Among patients who suffer a concussion (mild traumatic brain injury or mTBI), dizziness is second only to headache in symptom frequency. The differential diagnosis of post-concussive dizziness (PCD) can be divided into non-vestibular, central vestibular and peripheral vestibular causes with growing recognition that patients frequently exhibit both central and peripheral findings on vestibular testing. Symptoms that traditionally have been ascribed to central vestibular dysfunction may be due to peripheral dysfunction. Further, our ability to test peripheral vestibular function has improved and has allowed us to identify peripheral disorders that in the past would have remained unnoticed. The importance of the identification of the peripheral component in PCD lies in our ability to remedy the peripheral vestibular component to a much greater extent than the central component. Unfortunately, many patients are not adequately evaluated for vestibular disorders until long after the onset of their symptoms. Among the diagnoses seen as causes for PCD are (1) Central vestibular disorders, (2) Benign Paroxysmal Positional Vertigo (BPPV), (3) Labyrinthine dehiscence/perilymph fistula syndrome, (4) labyrinthine concussion, (5) secondary endolymphatic hydrops, (6) Temporal bone fracture, and (7) Malingering (particularly when litigation is pending). These diagnoses are not mutually exclusive and PCD patients frequently exhibit a combination of these disorders. A review of the literature and a general approach to the patient with post-concussive dizziness will be detailed as well as a review of the above-mentioned diagnostic categories.
Spectrum of Neurological Symptoms in Glycosylphosphatidylinositol Biosynthesis Defects: Systematic Review
Authors: Paprocka Justyna , Hutny Michał , Hofman Jagoda , Tokarska Agnieszka , Kłaniewska Magdalena , Szczałuba Krzysztof , Stembalska Agnieszka , Jezela-Stanek Aleksandra , Śmigiel Robert
Published: January 2022

Background: Mutations of genes involved in the synthesis of glycosylphosphatidylinositol and glycosylphosphatidylinositol-anchored proteins lead to rare syndromes called glycosylphosphatidylinositol-anchored proteins biosynthesis defects. Alterations of their structure and function in these disorders impair often fundamental processes in cells, resulting in severe clinical image. This study aimed to provide a systematic review of GPIBD cases reports published in English-language literature.

Methods: The browsing of open-access databases (PubMed, PubMed Central. and Medline) was conducted, followed by statistical analysis of gathered information concerning neurological symptomatology. The inclusion criteria were: studies on humans, age at onset (<18 y.o.), and report of GPIBD cases with adequate data on the genetic background and symptomatology. Exclusion criteria were: publication type (manuscripts, personal communication, review articles); reports of cases of GPI biosynthesis genes mutations in terms of other disorders; reports of GPIBD cases concentrating on non-neurological symptoms; or articles concentrating solely on the genetic issues of GPI biosynthesis. Risk of bias was assessed using Joanna Brigs Institute Critical Appraisal Checklists. Data synthesis was conducted using STATISTICA 13.3.721.1 (StatSoft Polska Sp. z.o.o.). Used tests were chi-square, Fisher's exact test (for differences in phenotype), and Mann-Whitney U test (for differences in onset of developmental delay).

Results: Browsing returned a total of 973 articles which, after ruling out the repetitions and assessing the inclusion and exclusion criteria, led to final inclusion of 77 articles (337 GPIBD cases) in the analysis. The main outcomes were prevalence of neurological symptoms, onset and semiology of seizures and their response to treatment, and onset of developmental delay. Based on this data a synthesis of phenotypical differences between the groups of GPIBD cases and the general GPIBD cases population was made.

Discussion: A synthetical analysis of neurological components in clinical image of GPIBD patients was presented. It highlights the main features of these disorders, which might be useful in clinical practice for consideration in differential diagnosis with children presenting with early-onset seizures and developmental delay. The limitation of this review is the scarcity of the specific data in some reports, concerning the semiology and onset of two main features of GPIBD.
Neurodevelopmental Trajectories Following Prenatal Alcohol Exposure
Authors: Moore Eileen M. , Xia Yingjing
Published: January 2022

Prenatal alcohol exposure (PAE) interferes with neurodevelopment. The brain is particularly susceptible to the adverse consequences of prenatal alcohol exposure, and numerous studies have documented changes to brain anatomy and function, as well as consequences for cognition, behavior, and mental health. Studies in typically developing individuals have shown that the brain undergoes dynamic developmental processes over an individual’s lifespan. Furthermore, magnetic resonance imaging (MRI) studies in other neurodevelopmental and psychiatric disorders have shown that their developmental trajectories differ from the typical pattern. Therefore, to understand long-term clinical outcomes of fetal alcohol spectrum disorders (FASD), it is necessary to investigate changes in neurodevelopmental trajectories in this population. Here we review studies that have used MRI to evaluate changes in brain structure and function over time via cross-sectional or longitudinal methods in individuals with PAE. Research demonstrates that individuals with PAE have atypical cortical and white matter microstructural developmental trajectories through childhood and adolescence. More research is needed to understand how factors such as sex and postnatal experiences may further mediate these trajectories. Furthermore, nothing is known about the trajectories beyond young adulthood.
Closed-Loop Transcutaneous Auricular Vagal Nerve Stimulation: Current Situation and Future Possibilities
Authors: Yu Yutian , Ling Jing , Yu Lingling , Liu Pengfei , Jiang Min
Published: January 2022

Closed-loop (CL) transcutaneous auricular vagal nerve stimulation (taVNS) was officially proposed in 2020. This work firstly reviewed two existing CL-taVNS forms: motor-activated auricular vagus nerve stimulation (MAAVNS) and respiratory-gated auricular vagal afferent nerve stimulation (RAVANS), and then proposed three future CL-taVNS systems: electroencephalography (EEG)-gated CL-taVNS, electrocardiography (ECG)-gated CL-taVNS, and subcutaneous humoral signals (SHS)-gated CL-taVNS. We also highlighted the mechanisms, targets, technical issues, and patterns of CL-taVNS. By reviewing, proposing, and highlighting, this work might draw a preliminary blueprint for the development of CL-taVNS.
Mechanisms of Human Motor Learning Do Not Function Independently
Authors: Therrien Amanda S. , Wong Aaron L.
Published: January 2022

Human motor learning is governed by a suite of interacting mechanisms each one of which modifies behavior in distinct ways and rely on different neural circuits. In recent years, much attention has been given to one type of motor learning, called motor adaptation. Here, the field has generally focused on the interactions of three mechanisms: sensory prediction error SPE-driven, explicit (strategy-based), and reinforcement learning. Studies of these mechanisms have largely treated them as modular, aiming to model how the outputs of each are combined in the production of overt behavior. However, when examined closely the results of some studies also suggest the existence of additional interactions between the sub-components of each learning mechanism. In this perspective, we propose that these sub-component interactions represent a critical means through which different motor learning mechanisms are combined to produce movement; understanding such interactions is critical to advancing our knowledge of how humans learn new behaviors. We review current literature studying interactions between SPE-driven, explicit, and reinforcement mechanisms of motor learning. We then present evidence of sub-component interactions between SPE-driven and reinforcement learning as well as between SPE-driven and explicit learning from studies of people with cerebellar degeneration. Finally, we discuss the implications of interactions between learning mechanism sub-components for future research in human motor learning.
Farnesoid X Receptor Activation in Brain Alters Brown Adipose Tissue Function via the Sympathetic System
Authors: Deckmyn Benjamin , Domenger Dorothée , Blondel Chloé , Ducastel Sarah , Nicolas Emilie , Dorchies Emilie , Caron Emilie , Charton Julie , Vallez Emmanuelle , Deprez Benoit , Annicotte Jean-Sébastien , Lestavel Sophie , Tailleux Anne , Magnan Christophe , Staels Bart , Bantubungi Kadiombo
Published: January 2022

The nuclear bile acid (BA) receptor farnesoid X receptor (FXR) is a major regulator of metabolic/energy homeostasis in peripheral organs. Indeed, enterohepatic-expressed FXR controls metabolic processes (BA, glucose and lipid metabolism, fat mass, body weight). The central nervous system (CNS) regulates energy homeostasis in close interaction with peripheral organs. While FXR has been reported to be expressed in the brain, its function has not been studied so far. We studied the role of FXR in brain control of energy homeostasis by treating wild-type and FXR-deficient mice by intracerebroventricular (ICV) injection with the reference FXR agonist GW4064. Here we show that pharmacological activation of brain FXR modifies energy homeostasis by affecting brown adipose tissue (BAT) function. Brain FXR activation decreases the rate-limiting enzyme in catecholamine synthesis, tyrosine hydroxylase (TH), and consequently the sympathetic tone. FXR activation acts by inhibiting hypothalamic PKA-CREB induction of TH expression. These findings identify a function of brain FXR in the control of energy homeostasis and shed new light on the complex control of energy homeostasis by BA through FXR.
The Role of Hyperthermia in Methamphetamine-Induced Depression-Like Behaviors: Protective Effects of Coral Calcium Hydride
Authors: Wang Xintao , Tong Bonan , Hui Rongji , Hou Congcong , Zhang Zilu , Zhang Ludi , Xie Bing , Ni Zhiyu , Cong Bin , Ma Chunling , Wen Di
Published: January 2022

Methamphetamine (METH) abuse causes irreversible damage to the central nervous system and leads to psychiatric symptoms including depression. Notably, METH-induced hyperthermia is a crucial factor in the development of these symptoms, as it aggravates METH-induced neurotoxicity. However, the role of hyperthermia in METH-induced depression-like behaviors needs to be clarified. In the present study, we treated mice with different doses of METH under normal (NAT) or high ambient temperatures (HAT). We found that HAT promoted hyperthermia after METH treatment and played a key role in METH-induced depression-like behaviors in mice. Intriguingly, chronic METH exposure (10 mg/kg, 7 or 14 days) or administration of an escalating-dose (2 ∼ 15 mg/kg, 3 days) of METH under NAT failed to induce depression-like behaviors. However, HAT aggravated METH-induced damage of hippocampal synaptic plasticity, reaction to oxidative stress, and neuroinflammation. Molecular hydrogen acts as an antioxidant and anti-inflammatory agent and has been shown to have preventive and therapeutic applicability in a wide range of diseases. Coral calcium hydride (CCH) is a newly identified hydrogen-rich powder which produces hydrogen gas gradually when exposed to water. Herein, we found that CCH pretreatment significantly attenuated METH-induced hyperthermia, and administration of CCH after METH exposure also inhibited METH-induced depression-like behaviors and reduced the hippocampal synaptic plasticity damage. Moreover, CCH effectively reduced the activity of lactate dehydrogenase and decreased malondialdehyde, TNF-α and IL-6 generation in hippocampus. These results suggest that CCH is an efficient hydrogen-rich agent, which has a potential therapeutic applicability in the treatment of METH abusers.
LncRNA KRT19P3 Is Involved in Breast Cancer Cell Proliferation, Migration and Invasion
Authors: Fan Yanping , Dong Xiaotong , Li Meizeng , Liu Pengju , Zheng Jie , Li Hongli , Zhang Yunxiang
Published: January 2022

Long non-coding RNAs (LncRNAs) have already been taken as critical regulatory molecules in breast carcinoma (BC). Besides, the progression of BC is closely associated with the immune system. However, the relationship between lncRNAs and the tumor immune system in BC has not been fully studied. LncRNA KRT19P3 has been reported to inhibit the progression of gastric cancer. In the present study, we first discovered that KRT19P3 was downregulated in BC tissues compared with para cancer tissue. Then we showed that KRT19P3 could be used as a marker to differentiate BC from para cancer tissue. Increased expression of KRT19P3 markedly inhibited the proliferation, migration, and invasion rate of BC cells in vitro and tumor growth of BC in vivo. Conversely, KRT19P3 knockdown by siRNA markedly promoted the proliferation, migration, and invasion rate of BC cells after being transfected. Comparison of clinical parameters showed an inverse relationship between the expression of KRT19P3 and pathological grade. Furthermore, immunohistochemistry (IHC) was applied to reveal the positive rate of the expression of Ki-67, programmed death-ligand 1 (PD-L1), and CD8 in BC tissues. Correlation analysis showed that Ki-67 and PD-L1 were inversely proportional to KRT19P3 but CD8 was directly proportional to KRT19P3. In conclusion, this study demonstrated that lncRNA KRT19P3 inhibits BC progression, and may affect the expression of PD-L1 in BC, which in turn affects CD8+ T (CD8 positive Cytotoxic T lymphocyte) cells in the immune microenvironment.
Management of Pediatric Tumors With Vascular Extension
Authors: Fanelli Mayara Caroline Amorim , Guilhen José Cícero Stocco , Duarte Alexandre Alberto Barros , Souza Fernanda Kelly Marques de , Cypriano Monica dos Santos , Caran Eliana Maria Monteiro , Lederman Henrique Manoel , Seixas Alves Maria Teresa de , Abib Simone de Campos Vieira
Published: January 2022

Background: Pediatric tumors can present with vascular extension to the inferior vena cava and right atrium, which impacts the surgical strategy and can be challenging during surgical treatment. Wilms tumor (WT) is the most common retroperitoneal tumor that can present with vascular extension, but also adrenal tumors, clear cell tumors from the kidney, and hepatoblastomas can present with this situation. Surgical aims include obtaining complete tumor resection without risk for patients, to avoid severe bleeding, cardiac arrest, and embolization, and to avoid cardiac bypass if possible.

Objective: To describe and discuss the surgical strategies to deal with pediatric tumors with vascular extension and propose a protocol.

Method: Retrospectivly review the experience of treating patients with vascular extension in a single institution, describing different scenarios and a decision making fluxogram based on the preoperative evaluation regarding the surgical techniques and the need for cardiac bypass that are adequate for each situation. Image studies are important to guide the surgical strategy. Depending on the quality of image available, computerized tomography (CT) or magnetic resonance imaging (MRI) can be enough to give the information needed for surgical decisions. Ultrasonography (US) with Doppler is helpful to confirm diagnosis and describes factors to guide the adequate surgical strategy, like the upper level extension and presence or absence of blood flow around the thrombus. Neoadjuvant chemotherapy is indicated in most cases, in order to reduce the upper level of extension (and avoid the need for cardiac bypass) and to lower the risk of embolization. The approach is based on the upper level of the thrombus and can include cavotomy or cavectomy, sometimes with cardiac bypass and cardiac arrest with hypothermia, when the thrombus reaches the diaphragmatic level or above. Pathology analysis of the thrombus can guide staging and the need for radiotherapy postoperatively.

Results: A decision making fluxogram protocol is presented focusing on the surgical treatment of such condition.

Conclusion: Surgery strategy is highly impacted by the presence of vascular extension in pediatric tumors. Surgeons should be aware of potential complications and how to prevent them. Such cases should be treated in reference centers.
Model-Based Anticancer Effect of Botulinum Neurotoxin Type A1 on Syngeneic Melanoma Mice
Authors: Kang Won-Ho , Ryu Hyo-Jeong , Kwak Seongsung , Yun Hwi-Yeol
Published: January 2022

In recent, Botulinum Neurotoxin A1 (BoNT/A1) has been suggested as a potential anticancer agent due to neuronal innervation in tumor cells. Although potential BoNT/A1’s mechanism of action for the tumor suppression has been gradually revealed so far, there were no reports to figure out the exposure-response relationships because of the difficulty of its quantitation in the biological matrix. The main objectives of this study were to measure the anticancer effect of BoNT/A1 using a syngeneic mouse model transplanted with melanoma cells (B16-F10) and developed a kinetic-pharmacodynamic (K-PD) model for quantitative exposure-response evaluation. To overcome the lack of exposure information, the K-PD model was implemented by the virtual pharmacokinetic compartment link to the pharmacodynamic compartment of Simeoni’s tumor growth inhibition model and evaluated using curve-fitting for the tumor growth-time profile after intratumoral injection of BoNT/A1. The final K-PD model was adequately explained for a pattern of tumor growth depending on represented exposure parameters and simulation studies were conducted to determine the optimal dose under various scenarios considering dose strength and frequency. The optimal dose range and regimen of ≥13.8 units kg−1 once a week or once every 3 days was predicted using the final model in B16-F10 syngeneic model and it was demonstrated with an extra in-vivo experiment. In conclusion, the K-PD model of BoNT/A1 was well developed to optimize the dosing regimen for evaluation of anticancer effect and this approach could be expandable to figure out quantitative interpretation of BoNT/A1’s efficacy in various xenograft and/or syngeneic models.
Long-Term Enhancement of NMDA Receptor Function in Inhibitory Neurons Preferentially Modulates Potassium Channels and Cell Adhesion Molecules
Authors: Xia Dan , Zhang Xinyang , Deng Di , Ma Xiaoyan , Masri Samer , Wang Jianzheng , Bao Shaowen , Hu Songnian , Zhou Qiang
Published: January 2022

Effectively enhancing the activity of inhibitory neurons has great therapeutic potentials since their reduced function/activity has significant contributions to pathology in various brain diseases. We showed previously that NMDAR positive allosteric modulator GNE-8324 and M-8324 selectively increase NMDAR activity on the inhibitory neurons and elevates their activity in vitro and in vivo. Here we examined the impact of long-term administering M-8324 on the functions and transcriptional profiling of parvalbumin-containing neurons in two representative brain regions, primary auditory cortex (Au1) and prelimbic prefrontal cortex (PrL-PFC). We found small changes in key electrophysiological parameters and RNA levels of neurotransmitter receptors, Na+ and Ca2+ channels. In contrast, large differences in cell adhesion molecules and K+ channels were found between Au1 and PrL-PFC in drug-naïve mice, and differences in cell adhesion molecules became much smaller after M-8324 treatment. There was also minor impact of M-8324 on cell cycle and apoptosis, suggesting a fine safety profile.