Miracle-dz/UniFAR-FTUs huggingface dataset:
A Small Key for a Heavy Door: Genetic Therapies for the Treatment of Hemoglobinopathies

Throughout the past decades, the search for a treatment for severe hemoglobinopathies has gained increased interest within the scientific community. The discovery that ɤ-globin expression from intact HBG alleles complements defective HBB alleles underlying β-thalassemia and sickle cell disease, has provided a promising opening for research directed at relieving ɤ-globin repression mechanisms and, thereby, improve clinical outcomes for patients. Various gene editing strategies aim to reverse the fetal-to-adult hemoglobin switch to up-regulate ɤ-globin expression through disabling either HBG repressor genes or repressor binding sites in the HBG promoter regions. In addition to these HBB mutation-independent strategies involving fetal hemoglobin (HbF) synthesis de-repression, the expanding genome editing toolkit is providing increased accuracy to HBB mutation-specific strategies encompassing adult hemoglobin (HbA) restoration for a personalized treatment of hemoglobinopathies. Moreover, besides genome editing, more conventional gene addition strategies continue under investigation to restore HbA expression. Together, this research makes hemoglobinopathies a fertile ground for testing various innovative genetic therapies with high translational potential. Indeed, the progressive understanding of the molecular clockwork underlying the hemoglobin switch together with the ongoing optimization of genome editing tools heightens the prospect for the development of effective and safe treatments for hemoglobinopathies. In this context, clinical genetics plays an equally crucial role by shedding light on the complexity of the disease and the role of ameliorating genetic modifiers. Here, we cover the most recent insights on the molecular mechanisms underlying hemoglobin biology and hemoglobinopathies while providing an overview of state-of-the-art gene editing platforms. Additionally, current genetic therapies under development, are equally discussed.
Glucose Control Has an Impact on Cerebral Blood Flow Alterations in Chronic Tinnitus Patients

Purpose Both tinnitus and type 2 diabetes mellitus (T2DM) are linked with cognitive decline and brain dysfunction. This study used arterial spin labeling (ASL) perfusion functional magnetic resonance imaging (fMRI) to examine the abnormal cerebral blood flow (CBF) patterns existed in tinnitus patients and potential relationships between the abnormal CBF and cognitive performance. The impact of T2DM on CBF alterations in tinnitus patients was further explored. Methods Sixty tinnitus patients and 40 non-tinnitus subjects were recruited. CBF images were collected and analyzed using ASL perfusion fMRI. Brain regions with CBF alterations between tinnitus patients and non-tinnitus controls were identified by one-way analysis of variance. Interaction effects between tinnitus and T2DM for CBF changes were also selected. Then, correlation analyses were calculated to specify the link between CBF changes and cognitive performance and between CBF changes and diabetic characteristics. Results Tinnitus patients showed decreased CBF, primarily in the auditory area and default mode network (DMN), compared with non-tinnitus controls. Decreased CBF in these regions was correlated with executive function and attention. The interaction effect between tinnitus and T2DM was significant in the right medial prefrontal gyrus. Additionally, CBF in the right medial prefrontal gyrus was correlated with tinnitus distress and cognitive performance. In tinnitus patients, Hemoglobin A1c was associated with CBF in the right medial prefrontal gyrus. Conclusion Tinnitus affects brain perfusion in the auditory area and DMN. T2DM and uncontrolled glucose levels may aggravate a CBF decrease in tinnitus patients. These new findings implied that tinnitus patients may benefit from blood glucose control in terms of their cognitive function and tinnitus distress.
The Impact of Behavioral Biases on Herding Behavior of Investors in Islamic Financial Products

The study aimed to investigate the impact of behavioral biases on herding for Islamic financial products with the mediation of shariah literacy. An adopted questionnaire from several published studies was used to collect data. The data were collected from 410 respondents and were analyzed with SmartPLS. The results for the direct impact showed that self-attribution, illusion of control, and information availability have a positive and significant impact on herding for Islamic financial products while shariah literacy showed an insignificant impact on herding. The results for mediation showed that previously significant and positive impact turned to insignificant when shariah literacy was introduced as mediating variable between the illusion of control, self-attribution, information availability, and herding. From a theoretical perspective, this study would contribute to the existing body of knowledge of financial decision making from shariah literacy point-out. On the other hand, the findings of this study may be useful for investors to avoid herding in the Islamic financial markets. The authors synthesize the contribution made by behavioral finance studies in extending the knowledge of herding behavior in Islamic financial products with a mediating role of shariah literacy. The key limitation of the study includes data that were collected from three districts of Punjab, Pakistan.
Endolymphatic Hydrops in Patients With Intralabyrinthine Schwannomas

Purpose: The presence of endolymphatic hydrops (EH) in patients with intralabyrinthine schwannomas (ILSs) is poorly understood. This study aims to determine whether there is a correlation between endolymphatic hydrops and clinical presentations of ILS. Methods: Data from nine patients with ILSs were retrospectively reviewed between 2007 and 2020. Temporal bone MRI with intratympanic or intravenous injection of gadolinium was applied to detect ILSs and EH. Results: 3D real inversion recovery (IR) sequence MRI of the temporal bone confirmed ipsilateral EH in four patients (4/6). All four patients with EH on MRI presented with vertigo similar to Meniere's disease. Among these patients with EH, one patient with EH in the cochlea showed moderate sensorineural hearing loss, while three patients with EH in both the vestibule and cochlea showed profound hearing loss. MRI demonstrated a transmacular tumor (TMA) in one patient, intravestibular (IV) in four patients, and vestibulocochlear (VC) in four patients. Two IV cases showed moderated hearing loss, while the TMA and VC cases showed profound hearing loss. Transotic resection of the tumor was applied in five patients; translabyrinthine resection was applied in one patient; two patients were under observation; and one patient was given intratympanic injection of gentamicin (ITG). During follow-up, all of the treated patients reported relief of vertigo, and postoperative MRI was performed in two patients, which showed no tumor recurrence. The two patients under observation showed no deterioration of hearing loss or vertigo. One patient was lost to follow-up. Conclusion: EH concurrent with ILSs has been underestimated previously. With the extensive application of temporal bone MRI paradigms, such as 3D-real IR sequence MRI, more cases of potential EH in patients with ILS will be identified. The severity of hearing loss may be associated with the location of the tumor and the degree of EH.
Silver Nanoparticles Biosynthesized With Salvia officinalis Leaf Exert Protective Effect on Hepatic Tissue Injury Induced by Plasmodium chabaudi

Malaria is an important health problem in subtropical and tropical areas around the world. Infection with protozoan parasites of the Plasmodium genus, which grow inside host erythrocytes, causes malaria and may lead to morbidity and mortality. Liver tissue plays an important role in the pathogenesis of malaria and is closely involved in parasitic pre-erythrocytic development. Numerous published studies have demonstrated that the liver is not only the source of Plasmodium parasites prior to erythrocytic growth but is also a primary immune effector toward the blood stage of the malaria life cycle. Despite efforts to improve antimalarial drugs and vaccines, Plasmodium species that cause severe malaria are being detected increasingly frequently in endemic regions. In this study, Salvia officinalis (S. officinalis) leaf extract was employed to synthesize silver nanoparticles (Ag-NPs). This method is eco-friendly and represents a single-step technique for the biosynthetic process; therefore, it has attracted considerable attention. Accordingly, we biosynthesized Ag-NPs with extract of the S. officinalis leaf and examined the antimalarial activity of these nanoparticles in a murine model of Plasmodium chabaudi malaria (P. chabaudi malaria). Forty mice were chosen and classified into four types: infected group, healthy control, pretreated mice infected after treatment with 50 mg/kg of S. officinalis leaf extract-biosynthesized Ag-NPs for two weeks, and post-treated mice infected before treatment with 50 mg/kg of S. officinalis leaf extract-biosynthesized Ag-NPs (administered daily for 7 d). In this study, both pre-treatment and post-treatment with Ag-NPs produced a substantial reduction in parasitemia relative to the infected group. We investigated the antiplasmodial and hepatoprotective effects of S. officinalis leaf extract-biosynthesized Ag-NPs on P. chabaudi-induced inflammation and hepatic oxidative stress markers.
Lead Toxicity in Cereals: Mechanistic Insight Into Toxicity, Mode of Action, and Management

Cereals are the major contributors to global food supply, accounting for more than half of the total human calorie requirements. Sustainable availability of quality cereal grains is an important step to address the high-priority issue of food security. High concentrations of heavy metals specifically lead (Pb) in the soil negatively affect biochemical and physiological processes regulating grain quality in cereals. The dietary intake of Pb more than desirable quantity via food chain is a major concern for humans, as it can predispose individuals to chronic health issues. In plant systems, high Pb concentrations can disrupt several key metabolic processes such as electron transport chain, cellular organelles integrity, membrane stability index, PSII connectivity, mineral metabolism, oxygen-evolving complex, and enzymatic activity. Plant growth-promoting rhizobacteria (PGPR) has been recommended as an inexpensive strategy for remediating Pb-contaminated soils. A diverse group of Ascomycetes fungi, i.e., dark septate endophytes is successfully used for this purpose. A symbiotic relationship between endophytes and host cereal induces Pb tolerance by immobilizing Pb ions. Molecular and cellular modifications in plants under Pb-stressed environments are explained by transcription factor families such as bZIP, ERF, and GARP as a regulator. The role of metal tolerance protein (MTP), natural resistance-associated macrophage protein (NRAMP), and heavy metal ATPase in decreasing Pb toxicity is well known. In the present review, we provided the contemporary synthesis of existing data regarding the effects of Pb toxicity on morpho-physiological and biochemical responses of major cereal crops. We also highlighted the mechanism/s of Pb uptake and translocation in plants, critically discussed the possible management strategies and way forward to overcome the menace of Pb toxicity in cereals.
Statistical Analysis of Magnetic Field Fluctuations in Coronal Mass Ejection-Driven Sheath Regions

We report a statistical analysis of magnetic field fluctuations in 79 coronal mass ejection- (CME-) driven sheath regions that were observed in the near-Earth solar wind. Wind high-resolution magnetic field data were used to investigate 2 h regions adjacent to the shock and ejecta leading edge (Near-Shock and Near-LE regions, respectively), and the results were compared with a 2 h region upstream of the shock. The inertial-range spectral indices in the sheaths are found to be mostly steeper than the Kolmogorov −5/3 index and steeper than in the solar wind ahead. We did not find indications of an f − 1 spectrum, implying that magnetic fluctuation properties in CME sheaths differ significantly from planetary magnetosheaths and that CME-driven shocks do not reset the solar wind turbulence, as appears to happen downstream of planetary bow shocks. However, our study suggests that new compressible fluctuations are generated in the sheath for a wide variety of shock/upstream conditions. Fluctuation properties particularly differed between the Near-Shock region and the solar wind ahead. A strong positive correlation in the mean magnetic compressibility was found between the upstream and downstream regions, but the compressibility values in the sheaths were similar to those in the slow solar wind (<0.2), regardless of the value in the preceding wind. However, we did not find clear correlations between the inertial-range spectral indices in the sheaths and shock/preceding solar wind properties, nor with the mean normalized fluctuation amplitudes. Correlations were also considerably lower in the Near-LE region than in the Near-Shock region. Intermittency was also considerably higher in the sheath than in the upstream wind according to several proxies, particularly so in the Near-Shock region. Fluctuations in the sheath exhibit larger rotations than upstream, implying the presence of strong current sheets in the sheath that can add to intermittency.
Simple Catchments and Where to Find Them: The Storage-Discharge Relationship as a Proxy for Catchment Complexity

Hydrological theory often assumes an exponential relationship between storage and discharge, but how often do we find such a behavior in real catchments? We analyze catchment attributes, discharge and weather conditions from 1992 to 2018 for 88 catchments in Hesse, Germany. All catchments have similar weather conditions, but a wide range of catchment characteristics. We find that only a fraction of catchments follow a roughly exponential behavior in their storage-discharge relationship. Far more catchments are complex and depict irregular patterns with even extreme variation from 1 year to another. This large set of catchments with similar weather conditions reveals that physical attributes that drive catchment complexity are diverse and include soil permeability, hydraulic conductivity, geology, and soil type. We link the examined simple and complex behavior to the fill and spill hypotheses and the interconnectedness of the catchments. Simpler catchments have more preferential flow and more connected hillslopes and thus lower runoff generation thresholds. This creates a more straightforward relationship between storage and discharge.
Microwave Spectrum, Barrier to Internal Rotation, and Structure of Methyl Formate

Rotational constants have been assigned to the following isotopic species of methyl formate by investigation of their microwave spectra: HCOOCH3, DCOOCH3, HCOOCH2D, HCOOCD3, HC13OOCH3, HCOOC13H3, HCO18OCH3, and HCOO18CH3. The following structural parameters were obtained from these rotational constants: r (C=O) = 1.200±0.01 A, r (C–O carboxyl) = 1.334±0.01 A, r (C–O methoxyl) = 1.437±0.01 A, r (C–H carboxyl) = 1.101±0.01 A, r (C–H methyl) = 1.086±0.015 A, ∠O=C–O=125°52′±1°, ∠H–C–O (carboxyl) = 109°18′±1°, ∠C–O–C = 114°47′±1°, and ∠H–C–H = 110°40′±1.5°. The carbon‐oxygen skeleton is planar with the methyl group cis to the carboxyl oxygen. The methyl group axis has been assumed to be along the C–O (methoxyl) bond, although some evidence suggests that it may be tilted.The barrier to internal rotation of the methyl group was calculated from the splittings observed in the rotational transitions of the ground torsional state for several isotopic species and found to be 1190±40 cal/mole.The dipole moment was cal.
Functional Dystonia: Differentiation From Primary Dystonia and Multidisciplinary Treatments

Dystonia is a common movement disorder, involving sustained muscle contractions, often resulting in twisting and repetitive movements and abnormal postures. Dystonia may be primary, as the sole feature (isolated) or in combination with other movement disorders (combined dystonia), or as one feature of another neurological process (secondary dystonia). The current hypothesis is that dystonia is a disorder of distributed brain networks, including the basal ganglia, cerebellum, thalamus and the cortex resulting in abnormal neural motor programs. In comparison, functional dystonia (FD) may resemble other forms of dystonia (OD) but has a different pathophysiology, as a subtype of functional movement disorders (FMD). FD is the second most common FMD and amongst the most diagnostically challenging FMD subtypes. Therefore, distinguishing between FD and OD is important, as the management of these disorders is distinct. There are also different pathophysiological underpinnings in FD, with for example evidence of involvement of the right temporoparietal junction in functional movement disorders that is believed to serve as a general comparator of internal predictions/motor intentions with actual motor events resulting in disturbances in self-agency. In this article, we present a comprehensive review across the spectrum of FD, including oromandibular and vocal forms and discuss the history, clinical clues, evidence for adjunctive “laboratory-based” testing, pathophysiological research and prognosis data. We also provide the approach used at the Massachusetts General Hospital Dystonia Center toward the diagnosis, management and treatment of FD. A multidisciplinary approach, including neurology, psychiatry, physical, occupational therapy and speech therapy, and cognitive behavioral psychotherapy approaches are frequently required; pharmacological approaches, including possible targeted use of botulinum toxin injections and inpatient programs are considerations in some patients. Early diagnosis and treatment may help prevent unnecessary investigations and procedures, while facilitating the appropriate management of these highly complex patients, which may help to mitigate frequently poor clinical outcomes.
Eradication of Helicobacter pylori and Gastric Cancer: A Controversial Relationship

Worldwide, gastric cancer (GC) represents the fifth cancer for incidence, and the third as cause of death in developed countries. Indeed, it resulted in more than 780,000 deaths in 2018. Helicobacter pylori appears to be responsible for the majority of these cancers. On the basis of recent studies, and either alone or combined with additional etiological factors, H. pylori is considered a “type I carcinogen. ” Over recent decades, new insights have been obtained into the strategies that have been adopted by H. pylori to survive the acidic conditions of the gastric environment, and to result in persistent infection, and dysregulation of host functions. The multistep processes involved in the development of GC are initiated by transition of the mucosa into chronic non-atrophic gastritis, which is primarily triggered by infection with H. pylori. This gastritis then progresses into atrophic gastritis and intestinal metaplasia, and then to dysplasia, and following Correa’s cascade, to adenocarcinoma. The use of antibiotics for eradication of H. pylori can reduce the incidence of precancerous lesions only in the early stages of gastric carcinogenesis. Here, we first survey the etiology and risk factors of GC, and then we analyze the mechanisms underlying tumorigenesis induced by H. pylori, focusing attention on virulence factor CagA, inflammation, oxidative stress, and ErbB2 receptor tyrosine kinase. Moreover, we investigate the relationships between H. pylori eradication therapy and other diseases, considering not only cardia (upper stomach) cancers and Barrett’s esophagus, but also asthma and allergies, through discussion of the “hygiene hypothesis. ” This hypothesis suggests that improved hygiene and antibiotic use in early life reduces microbial exposure, such that the immune response does not become primed, and individuals are not protected against atopic disorders, asthma, and autoimmune diseases. Finally, we overview recent advances to uncover the complex interplay between H. pylori and the gut microbiota during gastric carcinogenesis, as characterized by reduced bacterial diversity and increased microbial dysbiosis. Indeed, it is of particular importance to identify the bacterial taxa of the stomach that might predict the outcome of gastric disease through the stages of Correa’s cascade, to improve prevention and therapy of gastric carcinoma.
Melt block copolymerization of ε-caprolactone and L-lactide

AB block copolymers of e-caprolactone and (L)-lactide could be prepared by ring-opening polymerization in the melt at 110°C using stannous octoate as a catalyst and ethanol as an initiator provided e-caprolactone was polymerized first. Ethanol initiated the polymerization of e-caprolactone producing a polymer with e-caprolactone derived hydroxyl end groups which after addition of L-lactide in the second step of the polymerization initiated the ring-opening copolymerization of L-lactide. The number-average molecular weights of the poly(e-caprolactone) blocks varied from 1.5 to 5.2 × 103, while those of the poly(L-lactide) blocks ranged from 17.4 to 49.7 × 103. The polydispersities of the block copolymers varied from 1.16 to 1.27. The number-average molecular weights of the polymers were controlled by the monomer/hydroxyl group ratio, and were independent on the monomer/stannous octoate ratio within the range of experimental conditions studied. When L-lactide was polymerized first, followed by copolymerization of e-caprolactone, random copolymers were obtained. The formation of random copolymers was attributed to the occurrence of transesterification reactions. These side reactions were caused by the e-caprolactone derived hydroxyl end groups generated during the copolymerization of e-caprolactone with pre-polymers of L-lactide. The polymerization proceeds through an ester alcoholysis reaction mechanism, in which the stannous octoate activated ester groups of the monomers react with hydroxyl groups.