Miracle-dz/UniFAR-FTUs huggingface dataset:
Cryo-electron microscopy-based drug design

Structure-based drug design (SBDD) has gained popularity owing to its ability to develop more potent drugs compared to conventional drug-discovery methods. The success of SBDD relies heavily on obtaining the three-dimensional structures of drug targets. X-ray crystallography is the primary method used for solving structures and aiding the SBDD workflow; however, it is not suitable for all targets. With the resolution revolution, enabling routine high-resolution reconstruction of structures, cryogenic electron microscopy (cryo-EM) has emerged as a promising alternative and has attracted increasing attention in SBDD. Cryo-EM offers various advantages over X-ray crystallography and can potentially replace X-ray crystallography in SBDD. To fully utilize cryo-EM in drug discovery, understanding the strengths and weaknesses of this technique and noting the key advancements in the field are crucial. This review provides an overview of the general workflow of cryo-EM in SBDD and highlights technical innovations that enable its application in drug design. Furthermore, the most recent achievements in the cryo-EM methodology for drug discovery are discussed, demonstrating the potential of this technique for advancing drug development. By understanding the capabilities and advancements of cryo-EM, researchers can leverage the benefits of designing more effective drugs. This review concludes with a discussion of the future perspectives of cryo-EM-based SBDD, emphasizing the role of this technique in driving innovations in drug discovery and development. The integration of cryo-EM into the drug design process holds great promise for accelerating the discovery of new and improved therapeutic agents to combat various diseases.
Some Stylized Facts on Italian Inter-regional Migration

In this chapter we provide a descriptive analysis of inter-regional mobility in Italy for the period between 1992 and 2005. We use ISTAT data on the change of residence for groups of individuals according to age and education. We find evidence of two different types of migration. The first is the migration of working age individuals who respond to changes in economic conditions. The second is the return migration, which involves older cohorts of individuals, it is mainly driven by factors non-economic in nature and it is roughly constant over time. We also find that migration intensity generally increases over the period, but only for the first type of migration, while return migration, after a phase of stability, decreases in 2004 and 2005. Overall, the use of disaggregated data by age and education appears crucial for the correct identification of the determinants of migration.
Comparison of empathy profiles of medical students at the start and in the advanced clinical phase of their training

Background: The National Competence Based Catalogue of Learning Objectives for Undergraduate Medical Education (NKLM) cites empathy as a basic competence for medical doctors. Based on a multidimensional concept of clinical empathy, empathy profiles of medical students at the start of their training and in the 9th semester were identified and compared in order to draw conclusions for the conception of effective course offers. Method: Using the Saarbrücker Personality Questionnaire on Empathy (SPF-IRI), self-rated empathy was recorded in a cross-sectional study of medical students (1st semester: N=192/9th semester: N=221). Two Stage Clustering was performed for data analysis. Result: Three empathy profiles which could be meaningfully delineated by content were identified: 1. reflected, functional empathy, 2. unreflected, burdensome empathy and 3. distancing and avoidance. Students in the 9th semester mostly tended toward unreflected, burdensome empathy. Only one-third appeared capable of feeling empathy with patients while at the same time adequately regulating their own emotions and thus protecting themselves from emotional overload. Conclusion: An adequately reflected and functional empathy among medical students can neither be assumed at the start of their training, nor do existing course offers appear to provide sufficient training for this. Empathy should thus be implemented as a competence which needs to be promoted over the entire course of study. Emotion regulation plays a key role.
Stomach-specific drug delivery of 5-fluorouracil using floating alginate beads

A multiple-unit-type oral floating dosage form (FDF) of 5-fluorouracil (5-FU) was developed to prolong gastric residence time, target stomach cancer, and increase drug bioavailability. The floating bead formulations were prepared by dispersing 5-FU together with calcium carbonate into a mixture of sodium alginate and hydroxypropyl methylcellulose solution and then dripping the dispersion into an acidified solution of calcium chloride. Calcium alginate beads were formed, as alginate undergoes ionotropic gelation by calcium ions and carbon dioxide develops from the reaction of carbonate salts with acid. The evolving gas permeated through the alginate matrix, leaving gas bubbles or pores, which provided the beads buoyancy. The prepared beads were evaluated for percent drug loading, drug entrapment efficiency, image, surface topography, buoyancy, and in vitro release. The formulations were optimized for different weight ratios of gas-forming agent and sodium alginate. The beads containing higher amounts of calcium carbonate demonstrated instantaneous, complete, and excellent floating ability over a period of 24 hours. The optimized formulation was subjected to in vivo antitumor studies to check the therapeutic efficacy of the floating dosage forms containing 5-FU against benzo(a)pyrene-induced stomach tumors in albino female mice (Balb/C strain). The multiple-bead FDF was found to reduce the tumor incidence in mice by 74%, while the conventional tablet dosage form reduced this incidence by only 25%. Results indicate that FDF performed significantly better than the simple tablet dosage form.
Delays in health seeking, diagnosis and treatment for tuberculosis patients in Mongolia: an analysis of surveillance data, 2018–2021

Early diagnosis and treatment of infectious tuberculosis (TB) is essential to the attainment of global targets specified in the End TB Strategy. Using case-based TB surveillance data, we analysed delays in health seeking, diagnosis and treatment among TB patients in Mongolia from 2018 to 2021. We calculated the median and interquartile range (IQR) for “diagnostic delay,” defined as the time from symptom onset to diagnosis, subdivided into “health-seeking delay” (time from symptom onset to first visit to a health facility) and “health facility diagnostic delay” (time from first health facility visit to diagnosis), and for “treatment delay,” defined as the time from diagnosis to start of treatment. We also calculated “total delay,” defined as the time from symptom onset to treatment start. Based on data for 13 968 registered TB patients, the median total delay was estimated to be 37 days (IQR, 19–76). This was mostly due to health-seeking delay (median, 23 days; IQR, 8–53); in contrast, health facility diagnostic delay and treatment delay were relatively short (median, 1 day; IQR, 0–7; median, 1 day; IQR, 0–7, respectively). In 2021, health-seeking delay did not differ significantly between men and women but was shorter in children than in adults and shorter in clinically diagnosed than in bacteriologically confirmed TB cases. Health-seeking delay was longest in the East region (median, 44.5 days; IQR, 20–87) and shortest in Ulaanbaatar (median, 9; IQR, 14–64). TB treatment delay was similar across sexes, age groups and types of TB diagnosis but slightly longer among retreated cases and people living in Ulaanbaatar. Efforts to reduce TB transmission in Mongolia should prioritize decreasing delays in health seeking.
Efficacy of Trovafloxacin, a New Quinolone Antibiotic, in Experimental Staphylococcal Endocarditis Due to Oxacillin-Resistant Strains

ABSTRACT Therapeutic options for severe infections caused by strains of oxacillin-resistant Staphylococcus aureus (ORSA) and coagulase-negative staphylococci (ORSE) are very limited. With the increasing resistance of such strains to aminoglycosides, rifampin, and currently available quinolone agents, as well as the recent documentation of increasing resistance of ORSA to vancomycin (VANCO), new treatment alternatives are imperative. The in vivo efficacy of trovafloxacin (TROVA), a new quinolone agent with excellent antistaphylococcal activity in vitro, against experimental endocarditis (IE) due to β-lactamase-producing ORSA and ORSE strains (ORSA and ORSE IE) was evaluated. TROVA (25 mg/kg of body weight intravenously [i.v.] twice daily [b.i.d.]) was compared to VANCO (20 mg/kg i.v. b.i.d.) and two regimens of ampicillin-sulbactam (AMP-SUL; 200 mg/kg intramuscularly [i.m.] three times a day [t.i.d.] and 20 mg/kg i.m. b.i.d.), with all agents given for 3 or 6 days. AMP-SUL was included as a comparative treatment regimen because of its proven efficacy against experimental ORSA and ORSE IE. For both ORSA and ORSE IE, TROVA, AMP-SUL, and VANCO each reduced staphylococcal densities in vegetations compared to untreated controls (P < 0.01). For ORSA IE, TROVA was the most rapidly bactericidal agent—although not to a statistically significant degree—correlating with its superior bactericidal effect in vitro compared to those of VANCO and AMP-SUL.
A pathway towards high-quality development of the manufacturing industry: Does scientific and technological talent matter?

Against the background of the accelerated evolution of the new round of scientific and technological revolution and industrial change, scientific and technical talents, as essential innovation resources, play an important role in promoting the high-quality development of the manufacturing industry. Based on the panel data of 30 provinces in China from 2012 to 2021, the article constructs a fixed-effects model and systematically researches the impact of scientific and technological talents on the high-quality development of the manufacturing industry. The results show that scientific and technical talents play a significant role in promoting the high-quality development of the manufacturing industry, and the upgrading of the consumption structure and the accumulation of productive service industries play a mediating role. Heterogeneity analysis found that the promotion effect of scientific and technical talents is more favorable in the eastern region, medium-technology level manufacturing, and labor-intensive manufacturing. Among the three sub-dimensions of scientific and technological talents, the scale of scientific and technical talents has the most significant impact on the development of the manufacturing industry. The analysis of the spatial spillover effect finds that scientific and technological talents will have a positive spillover effect on the development of the manufacturing industry in neighboring areas. The study provides a basis for relevant departments to formulate effective strategies and policies.
Intradiscal administration of autologous platelet‐rich plasma in patients with Modic type 1 associated low back pain: A prospective pilot study

Abstract Background Various treatments for chronic low back pain (LBP) have been reported; among them, platelet‐rich plasma (PRP) as a regenerative medicine has attracted much attention. Although Modic type 1 change (MC1) is associated with LBP, no treatment has been established so far. In addition, no studies have administered PRP to intervertebral discs (IVDs) in patients with LBP, targeting MC1 only. Thus, the purpose of this study was to determine the safety and efficacy of PRP administration to the IVDs in patients with MC1 experiencing LBP. Methods PRP was injected intradiscally to 10 patients with MC1 experiencing LBP. Patients were followed prospectively for up to 24 weeks after primary administration. Physical condition, laboratory data, and lumbar x‐ray images were evaluated for safety assessment. Furthermore, to evaluate the effectiveness of PRP, patient‐reported outcomes were considered. In addition, changes in MC1 were assessed using magnetic resonance imaging (MRI). Results There were no adverse events in the laboratory data or lumbar X‐ray images after administration. The mean visual analog scale, which was 70.0 ± 13.3 before the treatment, significantly decreased 1 week after PRP administration and was 39.0 ± 28.8 at the last observation. Oswestry disability index and Roland Morris disability questionnaire scores promptly improved after treatment, and both improved significantly 24 weeks after PRP administration. Follow‐up MRI 24 weeks after treatment showed a significant decrease in the mean high‐signal intensity of fat‐suppressed T2‐weighted imaging from 10.1 to 7.90 mm2 compared with that before PRP administration. Conclusions The safety and efficacy of PRP administration to the IVDs of patients with MC1 experiencing LBP were identified. Post‐treatment MRI suggested improvement in inflammation, speculating that PRP suppressed inflammation and consequently relieved the patient's symptoms. Despite the small number of patients, this treatment is promising for patients with MC1 experiencing LBP. The study protocol has been reviewed and approved by the Certified Committee for Regenerative Medicine and the Japanese Ministry of Health, Labor and Welfare (Japan Registry of Clinical Trials [jRCT] No. jRCTb042210159).
Quality of descriptions of treatments: a review of published randomised controlled trials

Objectives To be useable in clinical practise, treatments studied in trials must provide sufficient information to enable clinicians and researchers to replicate. We sought to assess the completeness of treatment descriptions in published randomised controlled trials (RCTs) using a checklist and to determine the extent to which peer reviewers and editors comment on the quality of reporting of treatments. Design A cross-sectional study. Setting Trials published in the BMJ, a general medical journal. Participants Fifty-one trials published in the BMJ were independently evaluated by two raters using a checklist. Reviewers’ and editors’ comments were also assessed for statements on treatment descriptions. Primary and secondary outcome measures Proportion of trials rated as replicable (primary outcome). Results For 57% (29/51) of the papers, published treatment descriptions were not considered sufficient to allow replication. Most poorly described aspects were the actual procedures involved including the sequencing of the technique (what happened and when) and the physical or informational materials used (eg, training materials): 53% and 43% not clear, respectively. For a third of treatments, the dose/duration of individual sessions was not clear and for a quarter the schedule (interval, frequency, duration or timing) was not clear. Although the majority of problems were not picked up by reviewers and editors, when they were detected only about two-thirds were fixed before publication. Conclusions Journals wanting to publish the research of use to practising healthcare professionals need to pay more attention to descriptions of treatments. Our checklist, may be useful for reviewers, and editors and could help ensure that important details of treatments are provided before papers are in the public domain.
Upregulation of PGC-1α expression by pioglitazone mediates prevention of sepsis-induced acute lung injury

Abstract The imbalance between pro-inflammatory M1 and anti-inflammatory M2 macrophages plays a critical role in the pathogenesis of sepsis-induced acute lung injury (ALI). Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) may modulate macrophage polarization toward the M2 phenotype by altering mitochondrial activity. This study aimed to investigate the role of the PGC-1α agonist pioglitazone (PGZ) in modulating sepsis-induced ALI. A mouse model of sepsis-induced ALI was established using cecal ligation and puncture (CLP). An in vitro model was created by stimulating MH-S cells with lipopolysaccharide (LPS). qRT-PCR was used to measure mRNA levels of M1 markers iNOS and MHC-II and M2 markers Arg1 and CD206 to evaluate macrophage polarization. Western blotting detected expression of peroxisome proliferator-activated receptor gamma (PPARγ) PGC-1α, and mitochondrial biogenesis proteins NRF1, NRF2, and mtTFA. To assess mitochondrial content and function, reactive oxygen species levels were detected by dihydroethidium staining, and mitochondrial DNA copy number was measured by qRT-PCR. In the CLP-induced ALI mouse model, lung tissues exhibited reduced PGC-1α expression. PGZ treatment rescued PGC-1α expression and alleviated lung injury, as evidenced by decreased lung wet-to-dry weight ratio, pro-inflammatory cytokine secretion (tumor necrosis factor-α, interleukin-1β, interleukin-6), and enhanced M2 macrophage polarization. Mechanistic investigations revealed that PGZ activated the PPARγ/PGC-1α/mitochondrial protection pathway to prevent sepsis-induced ALI by inhibiting M1 macrophage polarization. These results may provide new insights and evidence for developing PGZ as a potential ALI therapy.
Metabolomic Profile of Umbilical Cord Blood Plasma from Early and Late Intrauterine Growth Restricted (IUGR) Neonates with and without Signs of Brain Vasodilation

Objectives To characterize via NMR spectroscopy the full spectrum of metabolic changes in umbilical vein blood plasma of newborns diagnosed with different clinical forms of intrauterine growth restriction (IUGR). Methods 23 early IUGR cases and matched 23 adequate-for-gestational-age (AGA) controls and 56 late IUGR cases with 56 matched AGAs were included in this study. Early IUGR was defined as a birth weight <10th centile, abnormal umbilical artery (UA) Doppler and delivery <35 weeks. Late IUGR was defined as a birth weight <10th centile with normal UA Doppler and delivery >35 weeks. This group was subdivided in 18 vasodilated (VD) and 38 non-VD late IUGR fetuses. All AGA patients had a birth weight >10th centile. 1H nuclear magnetic resonance (NMR) metabolomics of the blood samples collected from the umbilical vein at delivery was obtained. Multivariate statistical analysis identified several metabolites that allowed the discrimination between the different IUGR subgroups, and their comparative levels were quantified from the NMR data. Results The NMR-based analysis showed increased unsaturated lipids and VLDL levels in both early and late IUGR samples, decreased glucose and increased acetone levels in early IUGR. Non-significant trends for decreased glucose and increased acetone levels were present in late IUGR, which followed a severity gradient when the VD and non-VD subgroups were considered. Regarding amino acids and derivatives, early IUGR showed significantly increased glutamine and creatine levels, whereas the amounts of phenylalanine and tyrosine were decreased in early and late-VD IUGR samples. Valine and leucine were decreased in late IUGR samples. Choline levels were decreased in all clinical subforms of IUGR. Conclusions IUGR is not associated with a unique metabolic profile, but important changes are present in different clinical subsets used in research and clinical practice. These results may help in characterizing comprehensively specific alterations underlying different IUGR subsets.
Organization of projections from the basomedial nucleus of the amygdala: A PHAL study in the rat

The organization of axonal projections from the basomedial nucleus of the amygdala (BMA) was examined with the Phaseolus vulgaris leucoagglutinin (PHAL) method in adult male rats. The anterior and posterior parts of the BMA, recognized on cytoarchitectonic grounds, display very different projection patterns. Within the amygdala, the anterior basomedial nucleus (BMAa) heavily innervates the central, medial, and anterior cortical nuclei. In contrast, the posterior basomedial nucleus (BMAp) sends a dense projection to the lateral nucleus, and to restricted parts of the central and medial nuclei. Extra‐amygdalar projections from the BMA are divided into ascending and descending components. The former end in the cerebral cortex, striatum, and septum. The BMAa mainly innervates olfactory (piriform, transitional) and insular areas, whereas the BMAp also innervates inferior temporal (perirhinal, ectorhinal) and medial prefrontal (infralimbic, prelimbic) areas and the hippocampal formation. Within the striatum, the BMAa densely innervates the striatal fundus, whereas the nucleus accumbens receives a heavy input from the BMAp. Both parts of the BMA send massive projections to distinct regions of the bed nuclei of the stria terminalis. Descending projections from the BMA end primarily in the hypothalamus. The BMAa sends a major input to the lateral hypothalamic area, whereas the BMAp innervates the ventromedial nucleus particularly heavily.
Differential engagement of cognitive and affective neural systems in pediatric bipolar disorder and attention deficit hyperactivity disorder

Abstract This fMRI study investigates the neural bases of cognitive control of emotion processing in pediatric bipolar disorder (PBD) and attention deficit hyperactivity disorder (ADHD). Seventeen un-medicated PBD patients, 15 un-medicated ADHD patients, and 14 healthy controls (HC) (mean age = 13.78 ± 2.47) performed an emotional valence Stroop Task, requiring them to match the color of an emotionally valenced word to the color of either of two adjacent circles. Both patient groups responded significantly slower than HC, but there were no group differences in accuracy. A voxel-wise analysis of variance on brain activation revealed a significant interaction of group by word valence [F(2,41) = 4.44; p = . 02]. Similar group differences were found for negative and positive words. For negative versus neutral words, both patient groups exhibited greater activation in dorsolateral prefrontal cortex (DLPFC) and parietal cortex relative to HC. The PBD group exhibited greater activation in ventrolateral prefrontal cortex (VLPFC) and anterior cingulate cortex (ACC) relative to HC. The ADHD group exhibited decreased VLPFC activation relative to HC and the PBD group. During cognitive control of emotion processing, PBD patients deployed the VLPFC to a greater extent than HC. The ADHD patients showed decreased VLPFC engagement relative to both HC and PBD patients. (JINS, 2010, 16, 106–117.)