Miracle-dz/UniFAR-FTUs huggingface dataset:
Baseline dysmegakaryopoiesis in inherited thrombocytopenia/platelet disorder with predisposition to haematological malignancies

Germline mutations in runt-related transcription factor 1 (RUNX1), ETS variant transcription factor 6 (ETV6) and ankyrin repeat domain 26 (ANKRD26) have been recognised as responsible of autosomal dominant inherited thrombocytopenia or platelet disorder, with an increased risk of developing haematological malignancies (HM), mainly acute leukaemia (AL) and myelodysplastic syndrome (MDS) (Duployez et al., 2016). Importantly, while all these disorders are associated with abnormalities in platelet count and functions, thrombocytopenia may be mild and a bleeding tendency may be absent contributing to a lack of clinical recognition. Platelet-aggregation studies may also be difficult to assess in the setting of thrombocytopenia. Another major concern is the early detection of progression-associated genetic and morphological findings. Only a few studies have focussed on the morphological aspects in bone marrow (BM) from patients with a germline disorder. Overall, regarding the rarity of these disorders, more cases need to be described to support their conclusions and deliver strong messages to pathologists. We report here the BM morphological and genetic findings from six patients diagnosed with congenital thrombocytopenia, with predisposition to HM in the absence of active HM and define a baseline morphological aspect in these still under-recognised disorders. Germline variant detection in RUNX1 (n = 3), ETV6 (n = 1) and ANKRD26 (n = 2) was performed on genomic DNA extracted from both BM and peripheral blood (PB) samples by targeted high-throughput sequencing (HTS). In patients for whom a hereditary transmission could not be demonstrated, the germline status of the mutation was determined using skin fibroblasts. None of the six patients had additional genetic lesions in 36 genes-HTS panel and single nucleotide polymorphism (SNP)-array karyotyping performed on BM samples (Appendix S1). Four patients (B, C, E and F) had no personal history of HM and two (A and D) were in complete remission (CR; demonstrated by sensitive molecular approaches). Morphological investigations were performed at the end of induction and 2 years after CR in patients A and D (Antony-Debr e et al., 2016; Duployez et al., 2018). Clinical information about these patients is provided in the Appendix S1. The clinical and biological characteristics of these patients at the time of BM aspirate are presented in Table I. All patients harboured severe-to-moderate thrombocytopenia (range: 19–100 9 10/l). BM from all six patients with congenital thrombocytopenia displayed
Environmental factors and microbial diversity and abundance jointly regulate soil nitrogen and carbon biogeochemical processes in Tibetan wetlands.

Wetlands have numerous critical ecological functions, some of which are regulated by several nitrogen (N) and carbon (C) biogeochemical processes, such as denitrification, organic matter decomposition and methane emission. Until now, the underlying pathways of the effects of environmental and biological factors on wetland N and C cycling rates are still not fully understood. Here, we investigated soil potential/net nitrification, potential/unamended denitrification, methane production/oxidation rates in 36 riverine, lacustrine and palustrine wetland sites on the Tibet Plateau. The results showed that all the measured N and C cycling rates did not differ significantly among the wetland types. Stepwise multiple regression analyses revealed that soil physicochemical properties (e.g., moisture, C and N concentration) explained a large amount of variance in most of the N and C cycling rates. Microbial abundance and diversity were also important in controlling potential and unamended denitrification rates, respectively. Path analysis further revealed that soil moisture and N and C availability could impact wetland C and N processes both directly and indirectly. For instance, the indirect effect of soil moisture on methane production rates was mainly by regulating soil C content and methanogenic community structure. Our findings highlight that many N and C cycling processes in high-altitude and remote Tibetan wetlands are jointly regulated by soil environments and functional microorganisms. Soil properties affecting on the N and C cycling rates in wetlands through altering microbial diversity and abundance represents an important but previously underestimated indirect pathway.
The vessel-depleted neck in head and neck microvascular reconstruction: extreme solutions for extreme situations.

PURPOSE OF REVIEW The vessel-depleted neck is the ultimate challenge for the head and neck reconstructive surgeon. In patients who have had previous neck dissections or radiotherapy, the arterial and venous options for future reconstruction can be very limited, and it is important for the surgeon to consider alternative options for vessels. RECENT FINDINGS Appropriate preoperative planning is crucial in these patients with a thorough history including previous operation notes, details of previous treatments, and previously used vessels for reconstruction. Clinical examination and a dual phase CT angiogram/MR angiogram can identify vessels available for reconstruction. Arterial options are discussed including tips on using the common carotid artery and the use of Corlett loops for utilizing contralateral arteries. Venous options are also discussed including cephalic vein transposition and Corlett loops. Novel options, such as use of extracorporeal perfusion of flaps have been shown to be effective when all other options have been depleted. SUMMARY Creative solutions are needed for these extreme circumstances, and reconstructive surgeons need to be aware of the options available to select the best one in each case. Careful planning and having multiple back-up choices is crucial to successful reconstruction in these cases.
In Silico, Ex Vivo and In Vivo Studies of Roflumilast as a Potential Antidiarrheal and Antispasmodic agent: Inhibition of the PDE-4 Enzyme and Voltage-gated Ca++ ion Channels

The aim of the present study was to evaluate the possible gut inhibitory role of the phosphodiesterase (PDE) inhibitor roflumilast. Increasing doses of roflumilast were tested against castor oil-induced diarrhea in mice, whereas the pharmacodynamics of the same effect was determined in isolated rabbit jejunum tissues. For in silico analysis, the identified PDE protein was docked with roflumilast and papaverine using the Autodock vina program from the PyRx virtual screening tool. Roflumilast protected against diarrhea significantly at 0.5 and 1.5 mg/kg doses, with 40% and 80% protection. Ex vivo findings from jejunum tissues show that roflumilast possesses an antispasmodic effect by inhibiting spontaneous contractions in a concentration-dependent manner. Roflumilast reversed carbachol (CCh, 1 µM)-mediated and potassium (K+, 80 mM)-mediated contractile responses with comparable efficacies but different potencies. The observed potency against K+ was significantly higher in comparison to CCh, similar to verapamil. Experiments were extended to further confirm the inhibitory effect on Ca++ channels. Interestingly, roflumilast deflected Ca++ concentration–response curves (CRCs) to the right with suppression of the maximum peak at both tested doses (0.001-0.003 mg/mL), similar to verapamil. The PDE-inhibitory effect was authenticated when pre-incubation of jejunum tissues with roflumilast (0.03-0.1 mg/mL) produced a leftward deflection of isoprenaline-mediated inhibitory CRCs and increased the tissue level of cAMP, similar to papaverine. This idea was further strengthened by molecular docking studies, where roflumilast exhibited a better binding affinity (-9.4 kcal/mol) with the PDE protein than the standard papaverine (-8.3 kcal/mol). In conclusion, inhibition of Ca++ channels and the PDE-4 enzyme explains the pharmacodynamics of the gut inhibitory effect of roflumilast.
Neurons, Glia, Extracellular Matrix and Neurovascular Unit: A Systems Biology Approach to the Complexity of Synaptic Plasticity in Health and Disease

The synaptic cleft has been vastly investigated in the last decades, leading to a novel and fascinating model of the functional and structural modifications linked to synaptic transmission and brain processing. The classic neurocentric model encompassing the neuronal pre- and post-synaptic terminals partly explains the fine-tuned plastic modifications under both pathological and physiological circumstances. Recent experimental evidence has incontrovertibly added oligodendrocytes, astrocytes, and microglia as pivotal elements for synapse formation and remodeling (tripartite synapse) in both the developing and adult brain. Moreover, synaptic plasticity and its pathological counterpart (maladaptive plasticity) have shown a deep connection with other molecular elements of the extracellular matrix (ECM), once considered as a mere extracellular structural scaffold altogether with the cellular glue (i.e., glia). The ECM adds another level of complexity to the modern model of the synapse, particularly, for the long-term plasticity and circuit maintenance. This model, called tetrapartite synapse, can be further implemented by including the neurovascular unit (NVU) and the immune system. Although they were considered so far as tightly separated from the central nervous system (CNS) plasticity, at least in physiological conditions, recent evidence endorsed these elements as structural and paramount actors in synaptic plasticity. This scenario is, as far as speculations and evidence have shown, a consistent model for both adaptive and maladaptive plasticity. However, a comprehensive understanding of brain processes and circuitry complexity is still lacking. Here we propose that a better interpretation of the CNS complexity can be granted by a systems biology approach through the construction of predictive molecular models that enable to enlighten the regulatory logic of the complex molecular networks underlying brain function in health and disease, thus opening the way to more effective treatments.
The Impact of Normalization Approaches to Automatically Detect Radiogenomic Phenotypes Characterizing Breast Cancer Receptors Status

In breast cancer studies, combining quantitative radiomic with genomic signatures can help identifying and characterizing radiogenomic phenotypes, in function of molecular receptor status. Biomedical imaging processing lacks standards in radiomic feature normalization methods and neglecting feature normalization can highly bias the overall analysis. This study evaluates the effect of several normalization techniques to predict four clinical phenotypes such as estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and triple negative (TN) status, by quantitative features. The Cancer Imaging Archive (TCIA) radiomic features from 91 T1-weighted Dynamic Contrast Enhancement MRI of invasive breast cancers were investigated in association with breast invasive carcinoma miRNA expression profiling from the Cancer Genome Atlas (TCGA). Three advanced machine learning techniques (Support Vector Machine, Random Forest, and Naïve Bayesian) were investigated to distinguish between molecular prognostic indicators and achieved an area under the ROC curve (AUC) values of 86%, 93%, 91%, and 91% for the prediction of ER+ versus ER−, PR+ versus PR−, HER2+ versus HER2−, and triple-negative, respectively. In conclusion, radiomic features enable to discriminate major breast cancer molecular subtypes and may yield a potential imaging biomarker for advancing precision medicine.
A systematic review of lopinavir therapy for SARS coronavirus and MERS coronavirus—A possible reference for coronavirus disease‐19 treatment option

In the past few decades, coronaviruses have risen as a global threat to public health. Currently, the outbreak of coronavirus disease‐19 (COVID‐19) from Wuhan caused a worldwide panic. There are no specific antiviral therapies for COVID‐19. However, there are agents that were used during the severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) epidemics. We could learn from SARS and MERS. Lopinavir (LPV) is an effective agent that inhibits the protease activity of coronavirus. In this review, we discuss the literature on the efficacy of LPV in vitro and in vivo, especially in patients with SARS and MERS, so that we might clarify the potential for the use of LPV in patients with COVID‐19.
Significance of minimal residual disease monitoring by real‐time quantitative polymerase chain reaction in core binding factor acute myeloid leukemia for transplantation outcomes

Despite the well‐defined role of minimal residual disease (MRD) monitoring by real‐time quantitative polymerase chain reaction (RT‐PCR) for RUNX1/RUNX1T1 and CBFB‐MYH11 transcripts in core binding factor (CBF) acute myeloid leukemia (AML) after intensive chemotherapy, there has been a paucity of data assessing the utility of MRD monitoring at and after allogeneic hematopoietic stem cell transplantation (HSCT).
Topography of the Interfacial Shear Strength and the Mean Intrinsic Tensile Strength of Hemp Fibers as a Reinforcement of Polypropylene

The strength of the interphase between the reinforcements and the matrix has a major role in the mechanical properties of natural fiber reinforced polyolefin composites. The creation of strong interphases is hindered by the hydrophobic and hydrophilic natures of the matrix and the reinforcements, respectively. Adding coupling agents has been a common strategy to solve this problem. Nonetheless, a correct dosage of such coupling agents is important to, on the one hand guarantee strong interphases and high tensile strengths, and on the other hand ensure a full exploitation of the strengthening capabilities of the reinforcements. The paper proposes using topographic profile techniques to represent the effect of reinforcement and coupling agent contents of the strength of the interphase and the exploitation of the reinforcements. This representation allowed identifying the areas that are more or less sensitive to coupling agent content. The research also helped by finding that an excess of coupling agent had less impact than a lack of this component.
Titanium Dioxide Nanoparticles: Prospects and Applications in Medicine

Metallic and metal oxide nanoparticles (NPs), including titanium dioxide NPs, among polymeric NPs, liposomes, micelles, quantum dots, dendrimers, or fullerenes, are becoming more and more important due to their potential use in novel medical therapies. Titanium dioxide (titanium(IV) oxide, titania, TiO2) is an inorganic compound that owes its recent rise in scientific interest to photoactivity. After the illumination in aqueous media with UV light, TiO2 produces an array of reactive oxygen species (ROS). The capability to produce ROS and thus induce cell death has found application in the photodynamic therapy (PDT) for the treatment of a wide range of maladies, from psoriasis to cancer. Titanium dioxide NPs were studied as photosensitizing agents in the treatment of malignant tumors as well as in photodynamic inactivation of antibiotic-resistant bacteria. Both TiO2 NPs themselves, as well as their composites and combinations with other molecules or biomolecules, can be successfully used as photosensitizers in PDT. Moreover, various organic compounds can be grafted on TiO2 nanoparticles, leading to hybrid materials. These nanostructures can reveal increased light absorption, allowing their further use in targeted therapy in medicine. In order to improve efficient anticancer and antimicrobial therapies, many approaches utilizing titanium dioxide were tested. Results of selected studies presenting the scope of potential uses are discussed in this review.
Comparison of the efficacy of MOE and PMO modifications of systemic antisense oligonucleotides in a severe SMA mouse model

Abstract Spinal muscular atrophy (SMA) is a motor neuron disease. Nusinersen, a splice-switching antisense oligonucleotide (ASO), was the first approved drug to treat SMA. Based on prior preclinical studies, both 2′-O-methoxyethyl (MOE) with a phosphorothioate backbone and morpholino with a phosphorodiamidate backbone—with the same or extended target sequence as nusinersen—displayed efficient rescue of SMA mouse models. Here, we compared the therapeutic efficacy of these two modification chemistries in rescue of a severe mouse model using ASO10-29—a 2-nt longer version of nusinersen—via subcutaneous injection. Although both chemistries efficiently corrected SMN2 splicing in various tissues, restored motor function and improved the integrity of neuromuscular junctions, MOE-modified ASO10-29 (MOE10-29) was more efficacious than morpholino-modified ASO10-29 (PMO10-29) at the same molar dose, as seen by longer survival, greater body-weight gain and better preservation of motor neurons. Time-course analysis revealed that MOE10-29 had more persistent effects than PMO10-29. On the other hand, PMO10-29 appears to more readily cross an immature blood-brain barrier following systemic administration, showing more robust initial effects on SMN2 exon 7 inclusion, but less persistence in the central nervous system. We conclude that both modifications can be effective as splice-switching ASOs in the context of SMA and potentially other diseases, and discuss the advantages and disadvantages of each.
Food and temperature stressors have opposing effects in determining flexible migration decisions in brown trout (Salmo trutta)

With rapid global change, organisms in natural systems are exposed to a multitude of stressors that likely co‐occur, with uncertain impacts. We explored individual and cumulative effects of co‐occurring environmental stressors on the striking, yet poorly understood, phenomenon of facultative migration. We reared offspring of a brown trout population that naturally demonstrates facultative anadromy (sea migration), under different environmental stressor treatments and measured life history responses in terms of migratory tactics and freshwater maturation rates. Juvenile fish were exposed to reduced food availability, temperatures elevated to 1.8°C above natural conditions or both treatments in combination over 18 months of experimental tank rearing. When considered in isolation, reduced food had negative effects on the size, mass and condition of fish across the experiment. We detected variable effects of warm temperatures (negative effects on size and mass, but positive effect on lipids). When combined with food restriction, temperature effects on these traits were less pronounced, implying antagonistic stressor effects on morphological traits. Stressors combined additively, but had opposing effects on life history tactics: migration increased and maturation rates decreased under low food conditions, whereas the opposite occurred in the warm temperature treatment. Not all fish had expressed maturation or migration tactics by the end of the study, and the frequency of these ‘unassigned’ fish was higher in food deprivation treatments, but lower in warm treatments. Fish showing migration tactics were smaller and in poorer condition than fish showing maturation tactics, but were similar in size to unassigned fish. We further detected effects of food restriction on hypo‐osmoregulatory function of migrants that may influence the fitness benefits of the migratory tactic at sea. We also highlight that responses to multiple stressors may vary depending on the response considered. Collectively, our results indicate contrasting effects of environmental stressors on life history trajectories in a facultatively migratory species.
Public Awareness and Practices towards Self-Medication with Antibiotics among the Malaysian Population. A Development of Questionnaire and Pilot-Testing

It is well documented that injudicious antibiotic use and practicing self-medication with antibiotics (SMA) can lead to antibiotic resistance. The objective was to validate and develop an instrument in Bahasa Melayu to assess the awareness and practices towards SMA in the Malaysian population. A pilot study was conducted among 100 Malaysians participants. Reliability testing in terms of test-retest, internal consistency, and content validity was performed. One-way ANOVA and t-test were applied to determine significant differences between groups. A panel of nine experts evaluated the research instrument for content validity and it was found to have strong content item validity (Indices = 1). Each domain (level of knowledge and understanding about antibiotic use and antibiotic resistance: Practice towards self-medication) showed good internal consistency of Cronbach’s alpha 0.658 and 0.90. While test-retest reliability value for each domain was 0.773 (p = 0.009), and 0.891 (p = 0.001. The mean ± standard deviation (SD) for level of knowledge about antibiotic use and antibiotic resistance was 21.8 ± 7.02 and for practice scores (SMA) 6.03 ± 2.30. The instrument established sound reliability and validity and, therefore, can be an effective tool for assessing public awareness, and practices toward self-medication with antibiotics in the Malaysian population.
A pioneer of psy: The first Ugandan psychiatric nurse and her (different) tale of psychiatry in Uganda

In Africa, the emergence of a “modern” mental health regime centered on psychiatry is often portrayed as a unidirectional intervention by “the West. ” Analyses ranging from medical histories of colonial psychiatry to more recent studies of Global Mental Health focus mostly on the role of external actors and the ways their actions impact(ed) on local populations. Uncritical studies simply reduce the complexity of African therapeutic landscapes to a “treatment gap” and see the introduction of “science-based” mental health approaches as necessary “civilizing” missions. Critical studies emphasize the harms of psychiatric interventions and celebrate local healing practices instead. Both approaches are problematic: they ignore the many interconnections between highly dynamic treatment regimes that cannot be neatly designated as African or western, portray local populations as largely passive, and neglect the multiple ways in which psychiatry has been embraced, adapted, and disrupted by Africans themselves. This article challenges simplistic depictions of “western” psychiatry in Africa by providing a portrait of Rwashana Selina, the first Ugandan psychiatric nurse who—after being sent to the UK in the 1950s for training—became a central figure in Ugandan psychiatry. Based on interview material, I recount her life story and discuss her formative role in the development of psychiatric care in the colonial and postcolonial era. Rwashana's tale of Ugandan psychiatry emphasizes co-operation, mutual acknowledgments and pluralistic leadership and thus breaks with typical images of and dichotomies between white doctors and supposedly inferior African medical staff.
Overcoming Resistance to FLT3 Inhibitors in the Treatment of FLT3-Mutated AML

Acute myeloid leukaemia (AML) carrying internal tandem duplication (ITD) of Fms-Like Tyrosine kinase 3 (FLT3) gene is associated with high risk of relapse and poor clinical outcome upon treatment with conventional chemotherapy. FLT3 inhibitors have been approved for the treatment of this AML subtype but leukaemia relapse remains to be a major cause of treatment failure. Mechanisms of drug resistance have been proposed, including evolution of resistant leukaemic clones; adaptive cellular mechanisms and a protective leukaemic microenvironment. These models have provided important leads that may inform design of clinical trials. Clinically, FLT3 inhibitors in combination with conventional chemotherapy as induction treatment for fit patients; with low-intensity treatment as salvage treatment or induction for unfit patients as well as maintenance treatment with FLT3 inhibitors post HSCT hold promise to improve survival in this AML subtype.