Miracle-dz/UniFAR-FTUs huggingface dataset:
Computational drug repurposing against SARS-CoV-2 reveals plasma membrane cholesterol depletion as key factor of antiviral drug activity

Comparing SARS-CoV-2 infection-induced gene expression signatures to drug treatment-induced gene expression signatures is a promising bioinformatic tool to repurpose existing drugs against SARS-CoV-2. The general hypothesis of signature based drug repurposing is that drugs with inverse similarity to a disease signature can reverse disease phenotype and thus be effective against it. However, in the case of viral infection diseases, like SARS-CoV-2, infected cells also activate adaptive, antiviral pathways, so that the relationship between effective drug and disease signature can be more ambiguous. To address this question, we analysed gene expression data from in vitro SARS-CoV-2 infected cell lines, and gene expression signatures of drugs showing anti-SARS-CoV-2 activity. Our extensive functional genomic analysis showed that both infection and treatment with in vitro effective drugs leads to activation of antiviral pathways like NFkB and JAK-STAT. Based on the similarity - and not inverse similarity - between drug and infection-induced gene expression signatures, we were able to predict the in vitro antiviral activity of drugs. We also identified SREBF1/2, key regulators of lipid metabolising enzymes, as the most activated transcription factors by several in vitro effective antiviral drugs. Using a fluorescently labeled cholesterol sensor, we showed that these drugs decrease the cholesterol levels of plasma-membrane. Supplementing drug-treated cells with cholesterol reversed the in vitro antiviral effect, suggesting the depleting plasma-membrane cholesterol plays a key role in virus inhibitory mechanism. Our results can help to more effectively repurpose approved drugs against SARS-CoV-2, and also highlights key mechanisms behind their antiviral effect.
GRASP55 regulates intra‐Golgi localization of glycosylation enzymes to control glycosphingolipid biosynthesis

The Golgi apparatus, the main glycosylation station of the cell, consists of a stack of discontinuous cisternae. Glycosylation enzymes are usually concentrated in one or two specific cisternae along the cis‐trans axis of the organelle. How such compartmentalized localization of enzymes is achieved and how it contributes to glycosylation are not clear. Here, we show that the Golgi matrix protein GRASP55 directs the compartmentalized localization of key enzymes involved in glycosphingolipid (GSL) biosynthesis. GRASP55 binds to these enzymes and prevents their entry into COPI‐based retrograde transport vesicles, thus concentrating them in the trans‐Golgi. In genome‐edited cells lacking GRASP55, or in cells expressing mutant enzymes without GRASP55 binding sites, these enzymes relocate to the cis‐Golgi, which affects glycosphingolipid biosynthesis by changing flux across metabolic branch points. These findings reveal a mechanism by which a matrix protein regulates polarized localization of glycosylation enzymes in the Golgi and controls competition in glycan biosynthesis.
How Do Partner Support, Psychological Aggression, and Attachment Anxiety Contribute to Distressed Couples’ Relationship Outcomes?

Abstract Few studies have simultaneously looked at the relative contribution of positive and negative behaviors to understand relationship outcomes. This study examined the relative roles of perceived partner support and psychological aggression in two relationship outcomes—relationship satisfaction and the willingness to invest in the relationship—as well as the contribution of attachment anxiety as a moderator in 307 couples seeking relationship therapy. Path analyses revealed that perceived partner support was associated with individuals’ own higher relationship satisfaction and willingness to invest in the relationship. Attachment anxiety moderated these associations. Perceived partner psychological aggression was not associated with relationship outcomes.
NKp30 Receptor Upregulation in Salivary Glands of Sjögren’s Syndrome Characterizes Ectopic Lymphoid Structures and Is Restricted by Rituximab Treatment

Primary Sjögren’s syndrome (pSS) is a chronic autoimmune disease resulting from the inflammatory infiltration of exocrine glands, mainly salivary and lacrimal glands, leading to secretory dysfunction and serious complications including debilitating fatigue, systemic autoimmunity, and lymphoma. Like other autoimmune disorders, a strong interferon (IFN) signature is present among subsets of pSS patients, suggesting the involvement of innate immunity in pSS pathogenesis. NCR3/NKp30 is a natural killer (NK) cell-specific activating receptor regulating the cross talk between NK and dendritic cells including type II IFN secretion upon NK-cell activation. A genetic association between single-nucleotide polymorphisms (SNPs) in the NCR3/NKp30 promoter gene and a higher susceptibility for pSS has been previously described, with pSS patients most frequently carrying the major allele variant associated with a higher NKp30 transcript and IFN-γ release as a consequence of the receptor engagement. In the present study, we combined RNA-sequencing and histology from pSS salivary gland biopsies to better characterize NKp30 (NCR3) and its ligand B7/H6 (NCR3LG1) in pSS salivary gland tissues. Levels of NCR3/NKp30 were significantly increased both in salivary glands and in circulating NK cells of pSS patients compared with sicca controls, especially in salivary glands with organized ectopic lymphoid structures. In line with this observation, a strong correlation between NCR3/NKp30 levels and salivary gland infiltrating immune cells (CD3, CD20) was found. Furthermore, NCR3/NKp30 levels also correlated with higher IFN-γ, Perforin, and Granzyme-B expression in pSS SGs with organized ectopic lymphoid structures, suggesting an activation state of NK cells infiltrating SG tissue. Of note, NKp30+ NK cells accumulated at the border of the inflammatory foci, while the NKp30 ligand, B7/H6, is shown to be expressed mainly by ductal epithelial cells in pSS salivary glands. Finally, immunomodulatory treatment, such as the B-cell depleting agent rituximab, known to reduce the infiltration of immune cells in pSS SGs, prevented the upregulation of NCR3/NKp30 within the glands.
Microbiome and Metabolic Changes of Milk in Response to Dietary Supplementation With Bamboo Leaf Extract in Dairy Cows

Bamboo leaf extracts, with high content of flavonoids and diverse biological activities, are used in animal husbandry. Increasing evidence has suggested an association between the bovine physiology and the udder microbiome, yet whether the microbiota and the metabolites of milk affect the mammary gland health or the milk quality remains unknown. In this study, we provide a potential mechanism for the effects of bamboo leaf extracts on milk microbiota and metabolites of dairy cows. Twelve multiparous lactating Chinese Holstein dairy cows were randomly separated into two groups: basal diet as the control group (CON, n = 6) and a diet supplemented with 30 g/d bamboo leaf extract per head as antioxidants of bamboo leaf (AOB) group (AOB, n = 6) for 7 weeks (2-week adaptation, 5-week treatment). Milk samples were collected at the end of the trial (week 7) for microbiome and associated metabolic analysis by 16S ribosomal RNA (rRNA) gene sequencing and liquid chromatography-mass spectrometry (LC-MS). The results showed that the milk protein was increased (p < 0.0001) and somatic cell count (SCC) showed a tendency to decrease (p = 0.09) with AOB supplementation. The relative abundance of Firmicutes was significantly decreased (p = 0.04) while a higher relative abundance of Probacteria (p = 0.01) was seen in the group receiving AOB compared to the CON group. The AOB group had a significantly lower relative abundance of Corynebacterium_1 (p = 0.01), Aerococcus (p = 0.01), and Staphylococcus (p = 0.02). There were 64 different types of metabolites significantly upregulated, namely, glycerophospholipids and fatty acyls, and 15 significantly downregulated metabolites, such as moracetin, sphinganine, and lactulose in the AOB group. Metabolic pathway analysis of the different metabolites revealed that the sphingolipid signaling pathway was significantly enriched, together with glycerophospholipid metabolism, sphingolipid metabolism, and necroptosis in response to AOB supplementation. Several typical metabolites were highly correlated with specific ruminal bacteria, demonstrating a functional correlation between the milk microbiome and the associated metabolites. These insights into the complex mechanism and corresponding biological responses highlight the potential function of AOB, warranting further investigation into the regulatory role of specific pathways in the metabolism.
High-Salt Diet Accelerated the Decline of Residual Renal Function in Patients With Peritoneal Dialysis

Objective: This study aims to investigate the relationship between dietary salt intake and residual renal function in peritoneal dialysis (PD) patients. Methods: The daily salt intake of the patients was calculated based on a 3 day dietary record. Sixty-two patients were divided into three groups: 33 patients in the low salt intake group (salt intake <6.0 g/day), 17 in the medium salt intake group (salt intake 6.0 to <8.0 g/day), and 12 in the high salt intake group (salt intake ≥8.0 g/day). Regular follow-up was conducted every 3 months. Urine volume, peritoneal ultrafiltration volume, and other clinical indicators were recorded. Biochemical indexes were detected to evaluate the changes in residual renal function and peritoneal function during follow-up. Results: A positive correlation between dietary sodium intake and sodium excretion was found. During 12-month follow-up, a decrease of residual renal function showed a significant difference among the three groups (p = 0.041) (15.3 ± 27.5 vs. 12.5 ± 11.5 vs. 32.9 ± 18.4 L/W/1.73 m2 in the low-, medium-, and high salt intake groups, respectively). Consistently, a higher decline of residual renal function (adjusted β, 20.37; 95% CI, 2.83, 37.91) was found in participants with high salt intake (salt intake ≥8 g/day) compared with those in non-high salt intake. Conclusion: Our study showed that the sodium excretion by peritoneal dialysis was positively correlated with dietary sodium intake in PD patients. The high salt intake diet (salt intake ≥8 g/day) may lead to a faster decline of residual renal function in PD patients.
Secondary primary malignancies in patients with multiple myeloma: A single institution experience

The purpose of our study is to highlight the demographic characteristics, pathological features, and clinical course of multiple myeloma (MM) patients with secondary primary malignancies (SPM). A retrospective chart review was performed from January 2009 to February 2020. Patients' demographic, pathologic and cytogenetic features, treatment characteristics and clinical outcomes were collected. We identified 871 MM patients including 40 patients who developed SPM. Among the 40 patients with SPM, 17 patients developed hematological SPM and 23 patients developed solid SPM. The median time from diagnosis of MM to the occurrence of hematological SPM was 6.85 versus 3.91 years in solid SPM, with a median overall survival (OS) after diagnosis of SPM of 120 and 880 days, respectively. Interestingly, we observed that there was no significant difference in OS between MM patients with or without SPM. Multivariable analysis showed that age and autologous stem cell transplantation were independent factors associated with patients' clinical outcomes. Our study highlights the importance of understanding the etiology, biology, clinical outcome and management in MM patients with SPM.
The effect of analytical temperature on thromboelastography tracings in dogs

Viscoelastic testing methods such as thromboelastography (TEG) are becoming increasingly available to veterinarians in a clinical setting. TEG is useful in determining therapeutic transfusion needs and assessing global abnormalities of hemostasis of patients, given that it provides a more comprehensive assessment of coagulation than traditional tests. TEG is standardly performed at 37°C, which is considered a normal body temperature for human patients; however, 37°C is lower than normal body temperature for most canine patients. In an in vitro study, we investigated the potential effect that this difference in body temperature and test temperature might have on TEG results. Citrated blood samples were collected from clinically normal, as well as sick, dogs with various body temperatures. Samples were analyzed concurrently at the patient’s body temperature and at 37°C. There was very high correlation between TEG performed at body temperature and at 37°C for R (min) and MA (mm), high correlation for K (min) and alpha angle (deg), and moderate correlation for LY30 (%) and LY60 (%). For canine patients with normal to mildly abnormal body temperatures, performance of TEG at the standard 37°C is acceptable.
A multinational case−control study comparing forensic and non-forensic patients with schizophrenia spectrum disorders: the EU-VIORMED project

Abstract Background The relationship between schizophrenia and violence is complex. The aim of this multicentre case–control study was to examine and compare the characteristics of a group of forensic psychiatric patients with a schizophrenia spectrum disorders and a history of significant interpersonal violence to a group of patients with the same diagnosis but no lifetime history of interpersonal violence. Method Overall, 398 patients (221 forensic and 177 non-forensic patients) were recruited across five European Countries (Italy, Germany, Poland, Austria and the United Kingdom) and assessed using a multidimensional standardised process. Results The most common primary diagnosis in both groups was schizophrenia (76.4%), but forensic patients more often met criteria for a comorbid personality disorder, almost always antisocial personality disorder (49.1 v. 0%). The forensic patients reported lower levels of disability and better social functioning. Forensic patients were more likely to have been exposed to severe violence in childhood. Education was a protective factor against future violence as well as higher levels of disability, lower social functioning and poorer performances in cognitive processing speed tasks, perhaps as proxy markers of the negative syndrome of schizophrenia. Forensic patients were typically already known to services and in treatment at the time of their index offence, but often poorly compliant. Conclusions This study highlights the need for general services to stratify patients under their care for established violence risk factors, to monitor patients for poor compliance and to intervene promptly in order to prevent severe violent incidents in the most clinically vulnerable.
The Incidence of Surgical Site Infections and Acute Kidney Injuries After Topical Antibiotic Powder Application in Orthopaedic Trauma Surgery.

OBJECTIVES To compare the incidence of deep surgical site infections (SSI) and acute kidney injuries (AKI) in patients that did and did not receive topical antibiotics during the open treatment of fractures. Design: Retrospective comparative cohort Setting: Level one trauma centerPatients/Participants: 396 patients undergoing open fixation of fractures. INTERVENTION The topical antibiotic group included 78 (20%) patients. Vancomycin only was used in 28 (7%) patients with the median dose of 1 g (1 g to 2 g) and vancomycin/tobramycin was used in 48 (12%) patients with a median dose of 2 g (1 g to 2 g)/1.2 g (1.2 g to 1.2 g). MAIN OUTCOME MEASUREMENTS Deep SSI requiring debridement and AKI (>50% increase in creatinine compared to preoperative level). RESULTS There was no detectable difference in SSI between the topical antibiotic and control groups (13% vs. 10%, Odds ratio (OR) 1.3, 95% confidence interval (CI) 0.6 to 2.9). Variables associated with SSI on multivariate analysis included open fracture (OR 3.2, CI 1.5 to 6.5) and an American Society of Anesthesiologists (ASA) classification of > 2 (OR 2.7, CI 1.3 to 5.3). There was no detectable difference in AKI between the topical antibiotic and control groups (1 (2%) vs. 7 (5%); OR 0.3, CI 0.04 to 3). CONCLUSION There was no detectable difference, with wide confidence intervals, in SSI and AKI between the topical antibiotic and control groups. Further studies need to be conducted to evaluate the relationship between topical antibiotics and clinical outcomes in orthopaedic trauma surgery. LEVEL OF EVIDENCE Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.
Longitudinal Human Milk miRNA Composition over the First 3 mo of Lactation in a Cohort of Healthy Mothers Delivering Term Infants.

BACKGROUND MicroRNAs (miRNAs) are small noncoding RNAs involved in posttranscriptional regulation. miRNAs can be secreted and found in many body fluids, and although they are particularly abundant in breastmilk, their functions remain elusive. Human milk (HM) miRNAs start to raise considerable interest, but a comprehensive understanding of the repertoire and expression profiles along lactation has not been well characterized. OBJECTIVES This study aimed to characterize the longitudinal profile of HM miRNA between the second week and third month postpartum. METHODS We used a new sensitive technology to measure HM miRNAs in a cohort of 44 French mothers [mean ± SD age: 31 ± 3.5; BMI (in kg/m2) 21.8 ± 2.3] who delivered at term and provided HM samples at 3 time points (17 ± 3 d, 60 ± 3 d, and 90 ± 3 d) during follow-up visits. RESULTS We detected 685 miRNAs, of which 35 showed a high and stable expression along the lactation period analyzed. We also described for the first time a set of 11 miRNAs with a dynamic expression profile. To gain insight into the potential functional relevance of this set of miRNAs, we selected miR-3126 and miR-3184 to treat undifferentiated Caco-2 human intestinal cells and then assessed differentially expressed genes and modulation of related biological pathways. CONCLUSIONS Overall, our study provides new insights into HM miRNA composition and, to our knowledge, the first description of its longitudinal dynamics in mothers who delivered at term. Our in vitro results obtained in undifferentiated Caco-2 human intestinal cells transfected with HM miRNAs also provide further support to the hypothesized mother-to-neonate signaling role of HM miRNAs. This trial was registered at clinicaltrials.gov as NCT01894893.
The Clinical Utility of Magnetic Resonance Imaging According to Field Strength, Specifically Addressing the Breadth of Current State-of-the-Art Systems, Which Include 0.55 T, 1.5 T, 3 T, and 7 T

Abstract This review provides a balanced perspective regarding the clinical utility of magnetic resonance systems across the range of field strengths for which current state-of-the-art units exist (0.55 T, 1.5 T, 3 T, and 7 T). Guidance regarding this issue is critical to appropriate purchasing, usage, and further dissemination of this important imaging modality, both in the industrial world and in developing nations. The review serves to provide an important update, although to a large extent this information has never previously been openly presented. In that sense, it serves also as a position paper, with statements and recommendations as appropriate.
Cortical Frontoparietal Network Dysfunction in CHMP2B-Frontotemporal Dementia

A rare cause of inherited frontotemporal dementia (FTD) is a mutation in the CHMP2B gene on chromosome 3 leading to the autosomal dominantly inherited FTD (CHMP2B-FTD). Since CHMP2B-FTD is clinically well-characterized, and patients show a distinct pattern of executive dysfunction, the condition offers possible insight in the early electroencephalographic (EEG) changes in the cortical networks. Specifically, EEG microstate analysis parses the EEG signals into topographies believed to represent discrete network activations. We investigated the EEG dynamics in patients with symptomatic CHMP2B-FTD (n = 5) as well as pre-symptomatic mutation carriers (n = 5) compared to non-carrier family members (n = 6). The data was parsed into four archetypal microstates and global power was calculated. A trend was found for lower occurrence in microstate D in CHMP2B-FTD (p-value = 0.177, F-value = 2.036). Patients with recent symptom onset (<1 year) showed an increased duration of microstate D, whereas patients who had been symptomatic for longer periods (>2 years) showed decreased duration. Patients with CHMP2B-FTD present with executive dysfunction, and microstate D has previously been shown to be associated with the fronto-parietal network. The biphasic pattern may represent the pathophysiological changes in brain dynamics during neurodegeneration, which may apply to other neurodegenerative diseases.
The Role of Cutaneous Microcirculatory Responses in Tissue Injury, Inflammation and Repair at the Foot in Diabetes

Diabetic foot syndrome is one of the most costly complications of diabetes. Damage to the soft tissue structure is one of the primary causes of diabetic foot ulcers and most of the current literature focuses on factors such as neuropathy and excessive load. Although the role of blood supply has been reported in the context of macro-circulation, soft tissue damage and its healing in the context of skin microcirculation have not been adequately investigated. Previous research suggested that certain microcirculatory responses protect the skin and their impairment may contribute to increased risk for occlusive and ischemic injuries to the foot. The purpose of this narrative review was to explore and establish the possible link between impairment in skin perfusion and the chain of events that leads to ulceration, considering the interaction with other more established ulceration factors. This review highlights some of the key skin microcirculatory functions in response to various stimuli. The microcirculatory responses observed in the form of altered skin blood flow are divided into three categories based on the type of stimuli including occlusion, pressure and temperature. Studies on the three categories were reviewed including: the microcirculatory response to occlusive ischemia or Post-Occlusive Reactive Hyperaemia (PORH); the microcirculatory response to locally applied pressure such as Pressure-Induced Vasodilation (PIV); and the interplay between microcirculation and skin temperature and the microcirculatory responses to thermal stimuli such as reduced/increased blood flow due to cooling/heating. This review highlights how microcirculatory responses protect the skin and the plantar soft tissues and their plausible dysfunction in people with diabetes. Whilst discussing the link between impairment in skin perfusion as a result of altered microcirculatory response, the review describes the chain of events that leads to ulceration. A thorough understanding of the microcirculatory function and its impaired reactive mechanisms is provided, which allows an understanding of the interaction between functional disturbances of microcirculation and other more established factors for foot ulceration.