Miracle-dz/UniFAR-FTUs huggingface dataset:
Tomato Brown Rugose Fruit Virus: Seed Transmission Rate and Efficacy of Different Seed Disinfection Treatments †

Tomato brown rugose fruit virus (ToBRFV) is a highly infectious virus, that is becoming a threat to tomato production worldwide. In this work we evaluated the localization of ToBRFV particles in tomato seeds, its seed transmission rate and efficacy of disinfection, and the effects of different thermal- and chemical-based treatments on ToBRFV-infected seeds’ germination. Analyses demonstrated that ToBRFV was located in the seed coat, sometime in the endosperm, but never in the embryo; its transmission from infected seeds to plantlets occurs by micro-lesions during the germination. The ToBRFV seed transmission rate was 2.8% in cotyledons and 1.8% in the third true leaf. Regarding the different disinfection treatments, they returned 100% of germination at 14 days post-treatment (dpt), except for the treatment with 2% hydrochloric acid +1.5% sodium hypochlorite for 24 h, for which no seed germinated after 14 dpt. All treatments have the ability to inactivate ToBRFV, but in six out of seven treatments ToBRFV was still detectable by RT-qPCR. These results raise many questions about the correct way to carry out diagnosis at customs. To our knowledge, this is the first study on the effective localization of ToBRFV particles in seeds.
The discovery and development of oncolytic viruses: are they the future of cancer immunotherapy?

ABSTRACT Introduction: Despite diverse treatment modalities and novel therapies, many cancers and patients are not effectively treated. Cancer immunotherapy has recently achieved breakthrough status yet is not effective in all cancer types or patients and can generate serious adverse effects. Oncolytic viruses (OVs) are a promising new therapeutic modality that harnesses virus biology and host interactions to treat cancer. OVs, genetically engineered or natural, preferentially replicate in and kill cancer cells, sparing normal cells/tissues, and mediating anti-tumor immunity. Areas covered: This review focuses on OVs as cancer therapeutic agents from a historical perspective, especially strategies to boost their immunotherapeutic activities. OVs offer a multifaceted platform, whose activities are modulated based on the parental virus and genetic alterations. In addition to direct viral effects, many OVs can be armed with therapeutic transgenes to also act as gene therapy vectors, and/or combined with other drugs or therapies. Expert opinion: OVs are an amazingly versatile and malleable class of cancer therapies. They tend to target cellular and host physiology as opposed to specific genetic alterations, which potentially enables broad responsiveness. The biological complexity of OVs have hindered their translation; however, the recent approval of talimogene laherparepvec (T-Vec) has invigorated the field.
Interactions and Signal Transduction Pathways Involved during Central Nervous System Entry by Neisseria meningitidis across the Blood–Brain Barriers

The Gram-negative diplococcus Neisseria meningitidis, also called meningococcus, exclusively infects humans and can cause meningitis, a severe disease that can lead to the death of the afflicted individuals. To cause meningitis, the bacteria have to enter the central nervous system (CNS) by crossing one of the barriers protecting the CNS from entry by pathogens. These barriers are represented by the blood–brain barrier separating the blood from the brain parenchyma and the blood–cerebrospinal fluid (CSF) barriers at the choroid plexus and the meninges. During the course of meningococcal disease resulting in meningitis, the bacteria undergo several interactions with host cells, including the pharyngeal epithelium and the cells constituting the barriers between the blood and the CSF. These interactions are required to initiate signal transduction pathways that are involved during the crossing of the meningococci into the blood stream and CNS entry, as well as in the host cell response to infection. In this review we summarize the interactions and pathways involved in these processes, whose understanding could help to better understand the pathogenesis of meningococcal meningitis.
Orally administered self-emulsifying drug delivery system in disease management: advancement and patents

ABSTRACT Introduction: Oral administration of a drug is the most common, ideal and preferred route of administration. The main problem of oral drug formulations is their low bioavailability arises from poor aqueous solubility of drug. Aqueous solubility of lipophilic drugs can be improved by various techniques like salt formation, complexation, addition of co-solvent etc. but self-emulsifying drug-delivery system (SEDDS) is getting more attention for increasing the solubility of such drugs. The SEDDS is an isotropic mixture of drug, lipids, and emulsifiers, usually with one or more hydrophilic co-solvents/co-emulsifiers. This system is having ability to generate oil-in-water (o/w) emulsions or microemulsions upon gentle agitation followed by dilution with aqueous phase. The SEDDSs are relatively newer, lipid-based technological innovations possessing unparalleled potential in improving oral bioavailability of poorly water-soluble drugs. Areas covered: This review provides updated information regarding the types of SEDDS, their preparation techniques, drug delivery and related recent patents along with marketed formulations. Expert opinion: The SEDDS has been explored for improving bioavailability, rising intra-subject heterogeneity, and increasing solubility. SEDDS offers the benefit of a protective effect against the hostile environment in the gut. The unique fabrication techniques provide specific strategy to overcome the low bioavailability and poor solubility problems.
Refractory disseminated superficial actinic porokeratosis effectively treated with cholesterol/lovastatin cream: A case report

Dear Editor Disseminated Superficial Actinic Porokeratosis (DSAP) is an autosomal dominantly inherited disorder of epidermal keratinization, with local autoinflammatory features. Recently, gene mutations in mevalonate kinase (MVK) pathway have been implicated in the pathogenesis of DSAP, linear porokeratosis and porokeratosis palmaris et plantaris disseminata. MVK pathway plays a pivotal role in human physiology and disease, underlying multiple conditions of dermatological interest, such as HyperImmunoglobulin D Syndrome (HIDS) and Congenital Hemidysplasia with Ichthyosiform nevus and Limb Defects (CHILD) syndrome. In DSAP and related porokeratotic disorders, cutaneous lesion development requires: (a) an inherited monoallelic germline mutation in MVK genes, (b) a second hit somatic mutation at keratinocyte level with subsequent clonal expansion. Diseased keratinocytes account for the central, moderately atrophic portion of each lesion, while the characteristic peripheral ring (cornoid lamella) consists of a mixture of second-hit and naïve cells. The resulting cholesterol-depleted phenotype is speculated to display higher susceptibility to ultraviolet A (UVA)-induced apoptosis, hence the relationship with sunlight exposure. Moreover, local mevalonate accumulation may promote training of innate immune cells via Insulin-like Growth Factor 1 Receptor (IGF1-R) and mammalian Target Of Rapamycin (mTOR) activation and epigenetic phenomena, leading to an autoinflammatory microenvironment. An analogous mechanism at a systemic level is believed to be responsible of HIDS autoinflammation. Pathogenesis-based therapeutic approaches include topical Cholesterol/Lovastatin and topical Lovastatin monotherapy. The rationale of the former consists in simultaneously impairing intermediate metabolites formation in mutated cells and replenishing them with the final product. In vitro, statins inhibit keratinocyte proliferation, through complex cell cycle regulation. Surprisingly, replenishment with cholesterol—but not with MVK pathway intermediates—rescues the defect, at least partially. Statin monotherapy also seems to be an option, possibly leveraging the anti-inflammatory consequences of mevalonate pathway inhibition. Efficacy appears to be higher in DSAP, with a more modest response in linear porokeratosis and porokeratosis palmaris et plantaris disseminata.
Reactive Oxygen Species: Modulators of Phenotypic Switch of Vascular Smooth Muscle Cells

Reactive oxygen species (ROS) are natural byproducts of oxygen metabolism in the cell. At physiological levels, they play a vital role in cell signaling. However, high ROS levels cause oxidative stress, which is implicated in cardiovascular diseases (CVD) such as atherosclerosis, hypertension, and restenosis after angioplasty. Despite the great amount of research conducted to identify the role of ROS in CVD, the image is still far from being complete. A common event in CVD pathophysiology is the switch of vascular smooth muscle cells (VSMCs) from a contractile to a synthetic phenotype. Interestingly, oxidative stress is a major contributor to this phenotypic switch. In this review, we focus on the effect of ROS on the hallmarks of VSMC phenotypic switch, particularly proliferation and migration. In addition, we speculate on the underlying molecular mechanisms of these cellular events. Along these lines, the impact of ROS on the expression of contractile markers of VSMCs is discussed in depth. We conclude by commenting on the efficiency of antioxidants as CVD therapies.
The Cell-Autonomous Clock of VIP Receptor VPAC2 Cells Regulates Period and Coherence of Circadian Behavior

Circadian (approximately daily) rhythms pervade mammalian behavior. They are generated by cell-autonomous, transcriptional/translational feedback loops (TTFLs), active in all tissues. This distributed clock network is coordinated by the principal circadian pacemaker, the hypothalamic suprachiasmatic nucleus (SCN). Its robust and accurate time-keeping arises from circuit-level interactions that bind its individual cellular clocks into a coherent time-keeper. Cells that express the neuropeptide vasoactive intestinal peptide (VIP) mediate retinal entrainment of the SCN; and in the absence of VIP, or its cognate receptor VPAC2, circadian behavior is compromised because SCN cells cannot synchronize. The contributions to pace-making of other cell types, including VPAC2-expressing target cells of VIP, are, however, not understood. We therefore used intersectional genetics to manipulate the cell-autonomous TTFLs of VPAC2-expressing cells. Measuring circadian behavioral and SCN rhythmicity in these temporally chimeric male mice thus enabled us to determine the contribution of VPAC2-expressing cells (∼35% of SCN cells) to SCN time-keeping. Lengthening of the intrinsic TTFL period of VPAC2 cells by deletion of the CK1εTau allele concomitantly lengthened the period of circadian behavioral rhythms. It also increased the variability of the circadian period of bioluminescent TTFL rhythms in SCN slices recorded ex vivo. Abrogation of circadian competence in VPAC2 cells by deletion of Bmal1 severely disrupted circadian behavioral rhythms and compromised TTFL time-keeping in the corresponding SCN slices. Thus, VPAC2-expressing cells are a distinct, functionally powerful subset of the SCN circuit, contributing to computation of ensemble period and maintenance of circadian robustness. These findings extend our understanding of SCN circuit topology.
Epigenome-wide association scan identifies methylation sites associated with HIV infection.

Aim: To investigate the role of epigenetics in HIV pathophysiology. Materials & methods: We conducted an epigenome-wide association scan on HIV infection status among people who inject drugs in the AIDS Linked to the IntraVenous Experience study with primary (n = 397) and validation samples (n = 390). DNA methylation from blood was measured by the Illumina EPIC BeadChip. We controlled for cell type heterogeneity by HIV status. Results: HIV infection status was associated (p < 10-8) with DNA methylation at 49 CpG sites. Sites were enriched in response to virus, interferon signaling pathway, etc. Among these sites, discovery and validation t-statistics were highly correlated (r = 0.96). Conclusion: In a cohort of people who inject drugs, HIV status was associated with differential DNA methylation at biologically meaningful sites.
Management of Iron Overload in Beta-Thalassemia Patients: Clinical Practice Update Based on Case Series

Thalassemia syndromes are characterized by the inability to produce normal hemoglobin. Ineffective erythropoiesis and red cell transfusions are sources of excess iron that the human organism is unable to remove. Iron that is not saturated by transferrin is a toxic agent that, in transfusion-dependent patients, leads to death from iron-induced cardiomyopathy in the second decade of life. The availability of effective iron chelators, advances in the understanding of the mechanism of iron toxicity and overloading, and the availability of noninvasive methods to monitor iron loading and unloading in the liver, heart, and pancreas have all significantly increased the survival of patients with thalassemia. Prolonged exposure to iron toxicity is involved in the development of endocrinopathy, osteoporosis, cirrhosis, renal failure, and malignant transformation. Now that survival has been dramatically improved, the challenge of iron chelation therapy is to prevent complications. The time has come to consider that the primary goal of chelation therapy is to avoid 24-h exposure to toxic iron and maintain body iron levels within the normal range, avoiding possible chelation-related damage. It is very important to minimize irreversible organ damage to prevent malignant transformation before complications set in and make patients ineligible for current and future curative therapies. In this clinical case-based review, we highlight particular aspects of the management of iron overload in patients with beta-thalassemia syndromes, focusing on our own experience in treating such patients. We review the pathophysiology of iron overload and the different ways to assess, quantify, and monitor it. We also discuss chelation strategies that can be used with currently available chelators, balancing the need to keep non-transferrin-bound iron levels to a minimum (zero) 24 h a day, 7 days a week and the risk of over-chelation.
Astrocytic Connexin43 Channels as Candidate Targets in Epilepsy Treatment

In epilepsy research, emphasis is put on exploring non-neuronal targets such as astrocytic proteins, since many patients remain pharmacoresistant to current treatments, which almost all target neuronal mechanisms. This paper reviews available data on astrocytic connexin43 (Cx43) signaling in seizures and epilepsy. Cx43 is a widely expressed transmembrane protein and the constituent of gap junctions (GJs) and hemichannels (HCs), allowing intercellular and extracellular communication, respectively. A plethora of research papers show altered Cx43 mRNA levels, protein expression, phosphorylation state, distribution and/or functional coupling in human epileptic tissue and experimental models. Human Cx43 mutations are linked to seizures as well, as 30% of patients with oculodentodigital dysplasia (ODDD), a rare genetic condition caused by mutations in the GJA1 gene coding for Cx43 protein, exhibit neurological symptoms including seizures. Cx30/Cx43 double knock-out mice show increased susceptibility to evoked epileptiform events in brain slices due to impaired GJ-mediated redistribution of K+ and glutamate and display a higher frequency of spontaneous generalized chronic seizures in an epilepsy model. Contradictory, Cx30/Cx43 GJs can traffic nutrients to high-energy demanding neurons and initiate astrocytic Ca2+ waves and hyper synchronization, thereby supporting proconvulsant effects. The general connexin channel blocker carbenoxolone and blockers from the fenamate family diminish epileptiform activity in vitro and improve seizure outcome in vivo. In addition, interventions with more selective peptide inhibitors of HCs display anticonvulsant actions. To conclude, further studies aiming to disentangle distinct roles of HCs and GJs are necessary and tools specifically targeting Cx43 HCs may facilitate the search for novel epilepsy treatments.
Synthesis and study of frustrated oxide and mixed anion materials

Mixed anion systems, such as oxynitrides and oxyfluorides, are an emerging class of interesting materials. The lower stability of mixed anion systems in comparison to oxide materials has had the consequence that this area of materials research is relatively less well explored. However, the development of new synthesis techniques has resulted in the preparation of many new mixed anion systems and so a detailed understanding of their structure and how this relates to their electronic and magnetic properties is necessary. Within this Thesis, several oxide, oxynitride and oxyfluoride systems are investigated with a particular focus on the magnetic behaviour of materials based on geometrically frustrated pyrochlore and kagome lattices. The Lu2Mo2O7 pyrochlore contains a geometrically frustrated network of vertex sharing Mo (d S = 1) tetrahedra. Here, the solid state synthesis of Lu2Mo2O7−x is reported along with a discussion of the coexistence of two cubic pyrochlore phases that has been discovered in samples synthesised at 1600 ◦C. Powder neutron diffraction and thermogravimetric analysis have revealed that this two-phase behaviour originates from a miscibility gap between stoichiometric Lu2Mo2O7 and oxygen deficient Lu2Mo2O6.6. Magnetic susceptibility and muon spin relaxation measurements support the formation of a geometrically frustrated spin glass ground state in Lu2Mo2O7 with a spin freezing temperature Tf ∼ 16 K. Low temperature neutron diffraction has confirmed the absence of long range magnetic order and magnetic diffuse neutron scattering data have indicated the presence of competing nearest and next nearest neighbour antiferromagnetic exchange interactions in the spin glass state. The magnetic heat capacity of Lu2Mo2O7 follows a T -dependence at the low temperatures, indicating that Lu2Mo2O7 is another rare example of an unconventional, topological spin glass, which is stable in the absence of significant chemical disorder. The magnetic properties of the oxygen deficient pyrochlore phase Lu2Mo2O6.6 are qualitatively
Expression of Pro-Angiogenic Markers Is Enhanced by Blue Light in Human RPE Cells

Inherited retinal dystrophies are characterized by photoreceptor death. Oxidative stress usually occurs, increasing vision loss, and oxidative damage is often reported in retinitis pigmentosa (RP). More than 300 genes have been reported as RP causing. In contrast, choroidal neovascularization (CNV) only occasionally develops in the late stages of RP. We herein study the regulation of RP causative genes that are likely linked to CNV onset under oxidative conditions. We studied how the endogenous adduct N-retinylidene-N-retinylethanolamine (A2E) affects the expression of angiogenic markers in human retinal pigment epithelium (H-RPE) cells and a possible correlation with RP-causing genes. H-RPE cells were exposed to A2E and blue light for 3 and 6h. By transcriptome analysis, genes differentially expressed between A2E-treated cells and untreated ones were detected. The quantification of differential gene expression was performed by the Limma R package. Enrichment pathway analysis by the FunRich tool and gene prioritization by ToppGene allowed us to identify dysregulated genes involved in angiogenesis and linked to RP development. Two RP causative genes, AHR and ROM1, can be associated with an increased risk of CNV development. Genetic analysis of RP patients affected by CNV will confirm this hypothesis.
Associations between Intensity, Frequency, Duration, and Volume of Physical Activity and the Risk of Stroke in Middle- and Older-Aged Chinese People: A Cross-Sectional Study

Context: Persuasive evidence has shown the inverse associations between physical activity (PA) and the risk of stroke. However, few studies have investigated the associations between different dimensions (intensity, frequency, duration, volume) of PA and the risk of stroke. Objective: To investigate the associations between different dimensions of PA and the risk of stroke in total participants and subgroups. Method: This study included 6250 individuals aged 45 years old and above from the China Health and Retirement Longitudinal Study (CHARLS). PA was divided into vigorous PA (VPA), moderate PA (MPA), and light PA (LPA), and described in different dimensions (intensity, frequency, duration, volume). Stroke was defined on the basis of self-reported diagnosis and related treatments. Binary logistic regression models were established to assess the associations between different dimensions of PA and the risk of stroke in total participants and subgroups stratified by sex. Results: Individuals taking VPA with a frequency of 3–5 d/w, duration of ≥240 min/d, volume of ≥300 min/w had lower risks of strokes in total participants (Odds ratio (OR) = 0.32, 95% confidence interval (CI): 0.13, 0.75; OR = 0.60, 95% CI: 0.38, 0.94; OR = 0.68, 95% CI: 0.46, 0.99, respectively). However, significant associations of VPA with the risk of stroke in men were only observed in the duration of ≥240 min/d and volume of ≥300 min/w (OR = 0.53, 95% CI: 0.30, 0.93; OR = 0.61, 95% CI: 0.38, 0.99, respectively) whereas no significance in women. Compared with individuals taking no MPA, inverse significant associations between the risk of stroke and any level of frequency, duration and volume in MPA were observed in total sample (OR ranging from 0.16–0.40, all p < 0.05), whereas significant associations between the risk of stroke and MPA were found in men except the duration of 10–29 min/d and volume of 150–299 min/w (OR ranging from 0.26–0.35, all p < 0.05), and in women except the frequency of 1–2 d/w and duration of ≥240 min/d (OR ranging from 0.14–0.49, all p < 0.05). No significant associations could be observed in total participants and subgroups between LPA and the risk of stroke. Conclusion: This study revealed some significant associations between different dimensions of PA, especially MPA, and the risk of stroke. Furthermore, the difference of association was observed in the groups with different sex. Further prospective study is needed to determine deeper associations between PA and the risk of stroke.
Diagnostic and Therapeutic Implications of microRNAs in Non-Small Cell Lung Cancer

microRNAs (miRNAs), endogenous suppressors of target mRNAs, are deeply involved in every step of non-small cell lung cancer (NSCLC) development, from tumor initiation to progression and metastasis. They play roles in cell proliferation, apoptosis, angiogenesis, epithelial-to-mesenchymal transition, migration, invasion, and metastatic colonization, as well as immunosuppression. Due to their versatility, numerous attempts have been made to use miRNAs for clinical applications. miRNAs can be used as cancer subtype classifiers, diagnostic markers, drug-response predictors, prognostic markers, and therapeutic targets in NSCLC. Many challenges remain ahead of their actual clinical application; however, when achieved, the use of miRNAs in the clinic is expected to enable great progress in the diagnosis and treatment of patients with NSCLC.