Miracle-dz/UniFAR-FTUs huggingface dataset:
Adenoviral Vectors as Vaccines for Emerging Avian Influenza Viruses

It is evident that the emergence of infectious diseases, which have the potential for spillover from animal reservoirs, pose an ongoing threat to global health. Zoonotic transmission events have increased in frequency in recent decades due to changes in human behavior, including increased international travel, the wildlife trade, deforestation, and the intensification of farming practices to meet demand for meat consumption. Influenza A viruses (IAV) possess a number of features which make them a pandemic threat and a major concern for human health. Their segmented genome and error-prone process of replication can lead to the emergence of novel reassortant viruses, for which the human population are immunologically naïve. In addition, the ability for IAVs to infect aquatic birds and domestic animals, as well as humans, increases the likelihood for reassortment and the subsequent emergence of novel viruses. Sporadic spillover events in the past few decades have resulted in human infections with highly pathogenic avian influenza (HPAI) viruses, with high mortality. The application of conventional vaccine platforms used for the prevention of seasonal influenza viruses, such as inactivated influenza vaccines (IIVs) or live-attenuated influenza vaccines (LAIVs), in the development of vaccines for HPAI viruses is fraught with challenges. These issues are associated with manufacturing under enhanced biosafety containment, and difficulties in propagating HPAI viruses in embryonated eggs, due to their propensity for lethality in eggs. Overcoming manufacturing hurdles through the use of safer backbones, such as low pathogenicity avian influenza viruses (LPAI), can also be a challenge if incompatible with master strain viruses. Non-replicating adenoviral (Ad) vectors offer a number of advantages for the development of vaccines against HPAI viruses. Their genome is stable and permits the insertion of HPAI virus antigens (Ag), which are expressed in vivo following vaccination. Therefore, their manufacture does not require enhanced biosafety facilities or procedures and is egg-independent. Importantly, Ad vaccines have an exemplary safety and immunogenicity profile in numerous human clinical trials, and can be thermostabilized for stockpiling and pandemic preparedness. This review will discuss the status of Ad-based vaccines designed to protect against avian influenza viruses with pandemic potential.
Th17 Cell-Mediated Colitis Is Positively Regulated by Interferon Regulatory Factor 4 in a T Cell-Extrinsic Manner

Inflammatory bowel diseases (IBDs) are characterized by chronic, inflammatory gastrointestinal lesions and often require life-long treatment with immunosuppressants and repetitive surgical interventions. Despite progress in respect to the characterization of molecular mechanisms e.g. exerted by TNF-alpha, currently clinically approved therapeutics fail to provide long-term disease control for most patients. The transcription factor interferon regulatory factor 4 (IRF4) has been shown to play important developmental as well as functional roles within multiple immune cells. In the context of colitis, a T cell-intrinsic role of IRF4 in driving immune-mediated gut pathology is established. Here, we conversely addressed the impact of IRF4 inactivation in non-T cells on T cell driven colitis in vivo. Employing the CD4+CD25− naïve T cell transfer model, we found that T cells fail to elicit colitis in IRF4-deficient compared to IRF4-proficient Rag1 −/− mice. Reduced colitis activity in the absence of IRF4 was accompanied by hampered T cell expansion both within the mesenteric lymph node (MLN) and colonic lamina propria (cLP). Furthermore, the influx of various myeloids, presumably inflammation-promoting cells was abrogated overall leading to a less disrupted intestinal barrier. Mechanistically, gene profiling experiments revealed a Th17 response dominated molecular expression signature in colon tissues of IRF4-proficient, colitic Rag1 −/− but not in colitis-protected Rag1 −/− Irf4 −/− mice. Colitis mitigation in Rag1 −/− Irf4 −/− T cell recipients resulted in reduced frequencies and absolute numbers of IL-17a-producing T cell subsets in MLN and cLP possibly due to a regulation of conventional dendritic cell subset 2 (cDC2) known to impact Th17 differentiation. Together, extending the T cell-intrinsic role for IRF4 in the context of Th17 cell driven colitis, the provided data demonstrate a Th17-inducing and thereby colitis-promoting role of IRF4 through a T cell-extrinsic mechanism highlighting IRF4 as a putative molecular master switch among transcriptional regulators driving immune-mediated intestinal inflammation through both T cell-intrinsic and T cell-extrinsic mechanisms. Future studies need to further dissect IRF4 controlled pathways within distinct IRF4-expressing myeloid cell types, especially cDC2s, to elucidate the precise mechanisms accounting for hampered Th17 formation and, according to our data, the predominant mechanism of colitis protection in Rag1 −/− Irf4 −/− T cell receiving mice.
End-to-End Implementation of Various Hybrid Neural Networks on a Cross-Paradigm Neuromorphic Chip

Integration of computer-science oriented artificial neural networks (ANNs) and neuroscience oriented spiking neural networks (SNNs) has emerged as a highly promising direction to achieve further breakthroughs in artificial intelligence through complementary advantages. This integration needs to support individual modeling of ANNs and SNNs as well as their hybrid modeling, which not only simultaneously calculates single-paradigm networks but also converts their different information representations. It remains challenging to realize effective calculation and signal conversion on the existing dedicated hardware platforms. To solve this problem, we propose an end-to-end mapping framework for implementing various hybrid neural networks on many-core neuromorphic architectures based on the cross-paradigm Tianjic chip. We construct hardware configuration schemes for four typical signal conversions and establish a global timing adjustment mechanism among different heterogeneous modules. Experimental results show that our framework can implement these hybrid models with low execution latency and low power consumption with nearly no accuracy degradation. This work provides a new approach of developing hybrid neural network models for brain-inspired computing chips and further tapping the potential of these models.
Acetylcholine Upregulates Entamoeba histolytica Virulence Factors, Enhancing Parasite Pathogenicity in Experimental Liver Amebiasis

Entamoeba histolytica is an invasive enteric protozoan, whose infections are associated to high morbidity and mortality rates. However, only less than 10% of infected patients develop invasive amebiasis. The ability of E. histolytica to adapt to the intestinal microenvironment could be determinant in triggering pathogenic behavior. Indeed, during chronic inflammation, the vagus nerve limits the immune response through the anti-inflammatory reflex, which includes acetylcholine (ACh) as one of the predominant neurotransmitters at the infection site. Consequently, the response of E. histolytica trophozoites to ACh could be implicated in the establishment of invasive disease. The aim of this study was to evaluate the effect of ACh on E. histolytica virulence. Methods include binding detection of ACh to plasma membrane, quantification of the relative expression of virulence factors by RT-PCR and western blot, evaluation of the effect of ACh in different cellular processes related to E. histolytica pathogenesis, and assessment of the capability of E. histolytica to migrate and form hepatic abscesses in hamsters. Results demonstrated that E. histolytica trophozoites bind ACh on their membrane and show a clear increase of the expression of virulence factors, that were upregulated upon stimulation with the neurotransmitter. ACh treatment increased the expression of L220, Gal/GalNAc lectin heavy subunit (170 kDa), amebapore C, cysteine proteinase 2 (ehcp-a2), and cysteine proteinase 5 (ehcp-a5). Moreover, erythrophagocytosis, cytotoxicity, and actin cytoskeleton remodeling were augmented after ACh treatment. Likewise, by assessing the formation of amebic liver abscess, we found that stimulated trophozoites to develop greater hamster hepatic lesions with multiple granulomas. In conclusion, ACh enhanced parasite pathogenicity by upregulating diverse virulence factors, thereby contributing to disease severity, and could be linked to the establishment of invasive amebiasis.
Catalpol Protects Against Pulmonary Fibrosis Through Inhibiting TGF-β1/Smad3 and Wnt/β-Catenin Signaling Pathways

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by fibroblast proliferation and extracellular matrix remodeling; however, the molecular mechanisms underlying its occurrence and development are not yet fully understood. Despite it having a variety of beneficial pharmacological activities, the effects of catalpol (CAT), which is extracted from Rehmannia glutinosa, in IPF are not known. In this study, the differentially expressed genes, proteins, and pathways of IPF in the Gene Expression Omnibus database were analyzed, and CAT was molecularly docked with the corresponding key proteins to screen its pharmacological targets, which were then verified using an animal model. The results show that collagen metabolism imbalance, inflammatory response, and epithelial-mesenchymal transition (EMT) are the core processes in IPF, and the TGF-β1/Smad3 and Wnt/β-catenin pathways are the key signaling pathways for the development of pulmonary fibrosis. Our results also suggest that CAT binds to TGF-βR1, Smad3, Wnt3a, and GSK-3β through hydrogen bonds, van der Waals bonds, and other interactions to downregulate the expression and phosphorylation of Smad3, Wnt3a, GSK-3β, and β-catenin, inhibit the expression of cytokines, and reduce the degree of oxidative stress in lung tissue. Furthermore, CAT can inhibit the EMT process and collagen remodeling by downregulating fibrotic biomarkers and promoting the expression of epithelial cadherin. This study elucidates several key processes and signaling pathways involved in the development of IPF, and suggests the potential value of CAT in the treatment of IPF.
Foliar Application of Silicon Enhances Resistance Against Phytophthora infestans Through the ET/JA- and NPR1- Dependent Signaling Pathways in Potato

Late blight (LB), caused by the oomycete pathogen Phytophthora infestans, is a devastating disease of potato that is necessary to control by regularly treatment with fungicides. Silicon (Si) has been used to enhance plant resistance against a broad range of bacterial and fungal pathogens; however, the enhanced LB resistance and the molecular mechanisms involving the plant hormone pathways remain unclear. In this study, Si treatment of potato plants was found to enhance LB resistance in both detached leaves and living plants accompanied by induction of reactive oxygen species (ROS) production and pathogenesis-related genes expression. Regarding the hormone pathways involved in Si-mediated LB resistance, we found a rapidly increased content of ethylene (ET) 15 min after spraying with Si. Increased jasmonic acid (JA) and JA-Ile and decreased salicylic acid (SA) were identified in plants at 1 day after spraying with Si and an additional 1 day after P. infestans EC1 infection. Furthermore, pretreatment with Me-JA enhanced resistance to EC1, while pretreatment with DIECA, an inhibitor of JA synthesis, enhanced the susceptibility and attenuated the Si-mediated resistance to LB. Consistent with these hormonal alterations, Si-mediated LB resistance was significantly attenuated in StETR1-, StEIN2-, StAOS-, StOPR3-, StNPR1-, and StHSP90-repressed plants but not in StCOI1- and StSID2-repressed plants using virus-induced gene silencing (VIGS). The Si-mediated accumulation of JA/JA-Ile was significantly attenuated in StETR1-, StEIN2-, StOPR3- and StHSP90-VIGS plants but not in StCOI1-, StSID2- and StNPR1-VIGS plants. Overall, we reveal that Si can be used as a putative alternative to fungicides to control LB, and conclude that Si-mediated LB resistance is dependent on the ET/JA-signaling pathways in a StHSP90- and StNPR1-dependent manner.
Reduced Activity in an Inpatient Liaison Psychiatry Service During the First Wave of the COVID-19 Pandemic: Comparison With 2019 Data and Characterization of the SARS-CoV-2 Positive Cohort

Background: The COVID-19 pandemic led to changes in the way that healthcare was accessed and delivered in the United Kingdom (UK), particularly during the peak of the first lockdown period (the “first wave”) beginning in March 2020. In some patients, COVID-19 is associated with acute neuropsychiatric manifestations, and there is suggestion that there may also be longer term neuropsychiatric complications. Despite this, at the time of writing there are only emerging data on the direct effects of the COVID-19 pandemic on psychiatric care. Methods: In this retrospective study we analyzed referrals to an inpatient liaison psychiatry department of a large acute teaching hospital during the first wave of covid-19 in the UK and compared this data to the same period in 2019. Results: We saw a 40% reduction in the number of referrals in 2020, with an increase in the proportion of referrals for both psychosis or mania and delirium. Almost one third (28%) of referred patients tested positive for COVID-19 at some point during their admission, with 40% of these presenting with delirium as a consequence of their COVID-19 illness. Save delirium, we did not find evidence for high prevalence of new-onset acute mental illness in COVID-19 positive patients. Conclusion: Our data indicate decreased clinical activity in our inpatient psychiatry liaison department during the first wave of the COVID-19 pandemic, although a relative increase in relative increase in referrals for psychosis or mania, suggesting less of a relative decrease in more severe cases of mental illness. The reasons for this are likely multifactorial, including structural changes in the NHS and patient reluctance to present to emergency departments (ED) due to infection fears and Government advice. Our data also supports the literature suggesting the high relative prevalence of delirium in COVID-19, and we support integration of psychiatry liaison teams in acute general hospital wards to optimize delirium management. Finally, consideration should be given to adequate staffing of community and crisis mental health teams to safely manage the mental health of people reluctant to visit EDs.
Evidence of Mitochondrial Dysfunction in Bacterial Chondronecrosis With Osteomyelitis–Affected Broilers

A leading cause of lameness in modern broilers is bacterial chondronecrosis with osteomyelitis (BCO). While it is known that the components of BCO are bacterial infection, necrosis, and inflammation, the mechanism behind BCO etiology is not yet fully understood. In numerous species, including chicken, mitochondrial dysfunction has been shown to have a role in the pathogenicity of numerous diseases. The mitochondria is a known target for intracellular bacterial infections, similar to that of common causative agents in BCO, as well as a known regulator of cellular metabolism, stress response, and certain types of cell death. This study aimed to determine the expression profile of genes involved in mitochondrial biogenesis, dynamics, and function. RNA was isolated form the tibias from BCO-affected and healthy broilers and used to measure target gene expression via real-time qPCR. Mitochondrial biogenesis factors PGC-1α and PGC-1β were both significantly upregulated in BCO along with mitochondrial fission factors OMA1, MTFR1, MTFP1, and MFF1 as well as cellular respiration-related genes FOXO3, FOXO4, and av-UCP. Conversely, genes involved in mitochondrial function, ANT, COXIV, and COX5A showed decreased mRNA levels in BCO-affected tibia. This study is the first to provide evidence of potential mitochondrial dysfunction in BCO bone and warrants further mechanistic investigation into how this dysfunction contributes to BCO etiology.
Microstructural and Cerebral Blood Flow Abnormalities in Subjective Cognitive Decline Plus: Diffusional Kurtosis Imaging and Three-Dimensional Arterial Spin Labeling Study

Objective: To explore microstructural and cerebral blood flow (CBF) abnormalities in individuals with subjective cognitive decline plus (SCD plus) using diffusional kurtosis imaging (DKI) and three-dimensional (3D) arterial spin labeling (ASL). Methods: Twenty-seven patients with SCD plus, 31 patients with amnestic mild cognitive impairment (aMCI), and 33 elderly controls (ECs) were recruited and underwent DKI and 3D ASL using a GE 3.0-T MRI. Mean kurtosis (MK), fractional anisotropy (FA), mean diffusivity (MD), and CBF values were acquired from 24 regions of interest (ROIs) in the brain, including the bilateral hippocampal (Hip) subregions (head, body, and tail), posterior cingulate cortex (PCC), precuneus, dorsal thalamus subregions (anterior nucleus, ventrolateral nucleus, and medial nucleus), lenticular nucleus, caput nuclei caudati, white matter (WM) of the frontal lobe, and WM of the occipital lobe. Pearson's correlation analysis was performed to assess the relationships among the DKI-derived parameters, CBF values, and key neuropsychological tests for SCD plus. Results: Compared with ECs, participants with SCD plus showed a significant decline in MK and CBF values, mainly in the Hip head and PCC, and participants with aMCI exhibited more significant abnormalities in the MK and CBF values than individuals with ECs and SCD plus in multiple regions. Combined MK values showed better discrimination between patients with SCD plus and ECs than that obtained using CBF levels, with areas under the receiver operating characteristic (ROC) curve (AUC) of 0.874 and 0.837, respectively. Similarly, the AUC in discriminating SCD plus from aMCI patients obtained using combined MK values was 0.823, which was also higher than the combined AUC of 0.779 obtained using CBF values. Moreover, MK levels in the left Hip (h) and left PCC positively correlated with the auditory verbal learning test-delayed recall (AVLT-DR) score in participants with SCD plus. By contrast, only the CBF value in the left Hip head positively correlated with the AVLT-DR score. Conclusions: Our results provide new evidence of microstructural and CBF changes in patients with SCD plus. MK may be used as an early potential neuroimaging biomarker and may be a more sensitive DKI parameter than CBF at the very early stage of Alzheimer's disease (AD).
Pathophysiological Changes and the Role of Notch-1 Activation After Decompression in a Compressive Spinal Cord Injury Rat Model

Surgical decompression is the primary treatment for cervical spondylotic myelopathy (CSM) patients with compressive spinal cord injury (CSCI). However, the prognosis of patients with CSCI varies, and the pathophysiological changes following decompression remain poor. This study aimed to investigate the pathophysiological changes and the role of Notch-1 activation after decompression in a rat CSCI model. Surgical decompression was conducted at 1 week post-injury (wpi). DAPT was intraperitoneally injected to down-regulate Notch-1 expression. Basso, Beattie, and Bresnahan scores and an inclined plane test were used to evaluate the motor function recovery. Hematoxylin and eosin staining was performed to assess pathophysiological changes, while hypoxia-inducible factor 1 alpha, vascular endothelial growth factor (VEGF), von Willebrand factor (vWF), matrix metalloproteinase (MMP)-9, MMP-2, Notch-1, and Hes-1 expression in the spinal cord were examined by immunohistochemical analysis or quantitative PCR. The results show that early decompression can partially promote motor function recovery. Improvements in structural and cellular damage and hypoxic levels were also observed in the decompressed spinal cord. Moreover, decompression resulted in increased VEGF and vWF expression, but decreased MMP-9 and MMP-2 expression at 3 wpi. Expression levels of Notch-1 and its downstream gene Hes-1 were increased after decompression, and the inhibition of Notch-1 significantly reduced the decompression-induced motor function recovery. This exploratory study revealed preliminary pathophysiological changes in the compressed and decompressed rat spinal cord. Furthermore, we confirmed that early surgical decompression partially promotes motor function recovery may via activation of the Notch-1 signaling pathway after CSCI. These results could provide new insights for the development of drug therapy to enhance recovery following surgery.
Patients and Parents’ Experience of Multi-Family Therapy for Anorexia Nervosa: A Pilot Study

Background: Family therapy is considered as the gold standard in treatment of adolescents with anorexia nervosa (AN). Among the different types of family therapy, multi-family therapy (MFT) is increasingly used for treating AN, and shows promising results. In this article, our focus relied on the patients’ and their parents’ perceptions of the effectiveness and the underlying mechanisms of the MFT. Methods: The present pilot exploratory qualitative study included two focus groups conducted using a semi-structured approach: one with the adolescents (n = 3), and another with one or two of their parents (n = 4 mothers; n = 2 fathers). The subjects discussed were the changes observed in both AN symptoms and family interactions following therapy, and the mechanisms underlying these changes. We crossed the perspectives of the adolescents and of the parents on these two points. Results: Qualitative analysis revealed that while both adolescents and parents had difficulties relating the changes they observed in the last year to MFT, they were able to say that the group cohesion had several positive effects and that their family dynamics had improved. In the light of analysis the adolescents perceived more improvements related eating disorders symptoms than their parents did, while parents were concerned about a negative effect of MFT on their children. Discussion: While both patients and parents perceived improvements in both AN symptoms and family interactions in the past year, it was not clear if they considered MFT to have led to these improvements. FG also explored the MFT mechanisms underlying changes. Both adolescents and their parents stressed the beneficial effects of identification to others members of the group and shared experience to overcome social isolation. Parents also mentioned the sympathy they felt for each other. The idea that they give a central place to families in the therapy was also described by the families.