Miracle-dz/UniFAR-FTUs huggingface dataset:
Investigation of buffer-cyclodextrin systems

Equilibrium constants for the formation of inclusion compounds of 3-hydroxy-2-naphthoic acid with β-cyclodextrin were determined in aqueous solutions, in the absence and presence of buffers, by the steady-state fluorescence Benesi–Hildebrand method. Almost all the buffers that are usually used have been tested and they are found to have an influence on the formation constants. We suggest that buffers should not be used in aqueous solutions of cyclodextrins unless the experimental error is unacceptable. Furthermore, we obtained the inclusion compound formation constants (Ksalt) of β-CD with some buffer components by using a fluorescence competitive inhibition technique. NaClO4, KClO4, KCl, KHC8H4O4, KH2C6H5O7 and NaHC4H4O6 can form 1:1 inclusion complexes with β-cyclodextrin (Ksalt>0) while KF, K2SO4, NaH2PO4, NaAc, Na2HPO4 and NaHCO3 cannot (Ksalt<0).
Traumatic Epidural and Subdural Hematoma: Epidemiology, Outcome, and Dating

Epidural hematomas (EDHs) and subdural hematomas (SDHs), or so-called extra-axial bleedings, are common clinical entities after a traumatic brain injury (TBI). A forensic pathologist often analyzes cases of traumatic EDHs or SDHs due to road accidents, suicides, homicides, assaults, domestic or on-the-job accidents, and even in a medical responsibility scenario. The aim of this review is to give an overview of the published data in the medical literature, useful to forensic pathologists. We mainly focused on the data from the last 15 years, and considered the most updated protocols and diagnostic-therapeutic tools. This study reviews the epidemiology, outcome, and dating of extra-axial hematomas in the adult population; studies on the controversial interdural hematoma are also included.
Therapeutic Response to Thermotherapy in Cutaneous Leishmaniasis Treatment Failures for Sodium Stibogluconate: A Randomized Controlled Proof of Principle Clinical Trial.

Treatment failure to intralesional sodium stibogluconate (IL-SSG) is a health challenge for cutaneous leishmaniasis (CL) in Sri Lanka. A randomized controlled proof of principle clinical trial, with two arms (viz., radio frequency-induced heat therapy [RFHT] by a ThermoMed™ device and thermotherapy by a handheld exothermic crystallization thermotherapy for CL [HECT-CL] device) was conducted on 40 CL treatment failures to IL-SSG, from three hospitals in Tangalle, Hambantota, and Anuradhapura, from January 2017 to January 2018, followed up for 180 days post-thermotherapy with a final follow-up in February 2020. Intention-to-treat cure rates were calculated at day 90 (initial cure rate) and at day 180 (final cure rate) posttreatment. Radio frequency-induced heat therapy group: the initial cure rate was 100% (20/20) and the final cure rate was 95% (19/20), with one patient relapsing. The HECT-CL group: both the initial and final cure rates were 80% (16/20), with no relapses and one excluded from the trial. In February 2020 (1.6-3 years posttreatment), 27 traceable patients (RFHT = 16, HECT-CL = 11) remained healed. Second-degree burns were observed with RFHT in 65% (13/20), with HECT-CL in 15% (3/20), which completely resolved subsequently. The cure rates between the two treatment groups were comparable (P = 0.15). Radio frequency-induced heat therapy consumed less time and required only a single hospital visit. Handheld exothermic crystallization thermotherapy for CL is potentially usable at community settings with both being less costly than IL-SSG. This study is the first proof that thermotherapy is an efficacious and safe treatment for CL patients in Sri Lanka, complicated by treatment failure to IL-SSG.
Targeting Aberrant FGFR Signaling to Overcome CDK4/6 Inhibitor Resistance in Breast Cancer

Breast cancer (BC) is the most common cause of cancer-related death in women worldwide. Therapies targeting molecular pathways altered in BC had significantly enhanced treatment options for BC over the last decades, which ultimately improved the lives of millions of women worldwide. Among various molecular pathways accruing substantial interest for the development of targeted therapies are cyclin-dependent kinases (CDKs)—in particular, the two closely related members CDK4 and CDK6. CDK4/6 inhibitors indirectly trigger the dephosphorylation of retinoblastoma tumor suppressor protein by blocking CDK4/6, thereby blocking the cell cycle transition from the G1 to S phase. Although the CDK4/6 inhibitors abemaciclib, palbociclib, and ribociclib gained FDA approval for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative BC as they significantly improved progression-free survival (PFS) in randomized clinical trials, regrettably, some patients showed resistance to these therapies. Though multiple molecular pathways could be mechanistically responsible for CDK4/6 inhibitor therapy resistance, one of the most predominant ones seems to be the fibroblast growth factor receptor (FGFR) pathway. FGFRs are involved in many aspects of cancer formation, such as cell proliferation, differentiation, and growth. Importantly, FGFRs are frequently mutated in BC, and their overexpression and/or hyperactivation correlates with CDK4/6 inhibitor resistance and shortened PFS in BC. Intriguingly, the inhibition of aberrant FGFR activity is capable of reversing the resistance to CDK4/6 inhibitors. This review summarizes the molecular background of FGFR signaling and discusses the role of aberrant FGFR signaling during cancer development in general and during the development of CDK4/6 inhibitor resistance in BC in particular, together with other possible mechanisms for resistance to CDK4/6 inhibitors. Subsequently, future directions on novel therapeutic strategies targeting FGFR signaling to overcome such resistance during BC treatment will be further debated.
Molecular Profiling of Merkel Cell Polyomavirus-Associated Merkel Cell Carcinoma and Cutaneous Melanoma

Merkel cell carcinoma (MCC) is a rare, high-grade, aggressive cutaneous neuroendocrine malignancy most commonly associated with sun-exposed areas of older individuals. A relatively newly identified human virus, the Merkel cell polyomavirus (MCPyV) has been implicated in the pathogenesis of MCC. Our study aimed to examine nine MCC cases and randomly selected 60 melanoma cases to identify MCPyV status and to elucidate genetic differences between virus-positive and -negative cases. Altogether, seven MCPyV-positive MCC samples and four melanoma samples were analyzed. In MCPyV-positive MCC RB1, TP53, FBXW7, CTNNB1, and HNF1A pathogenic variants were identified, while in virus-negative cases only benign variants were found. In MCPyV-positive melanoma cases, besides BRAF mutations the following genes were also affected: PIK3CA, STK11, CDKN2A, SMAD4, and APC. In contrast to studies found in the literature, a higher tumor burden was detected in virus-associated MCC compared to MCPyV-negative cases. No association was identified between virus infection and tumor burden in melanoma samples. We concluded that analyzing the key morphologic and immunohistological features of MCC is critical to avoid confusion with other cutaneous malignancies. Molecular genetic investigations such as next-generation sequencing (NGS) enable molecular stratification, which may have future clinical impact.
Granular Hall Sensors for Scanning Probe Microscopy

Scanning Hall probe microscopy is attractive for minimally invasive characterization of magnetic thin films and nanostructures by measurement of the emanating magnetic stray field. Established sensor probes operating at room temperature employ highly miniaturized spin-valve elements or semimetals, such as Bi. As the sensor layer structures are fabricated by patterning of planar thin films, their adaption to custom-made sensor probe geometries is highly challenging or impossible. Here we show how nanogranular ferromagnetic Hall devices fabricated by the direct-write method of focused electron beam induced deposition (FEBID) can be tailor-made for any given probe geometry. Furthermore, we demonstrate how the magnetic stray field sensitivity can be optimized in situ directly after direct-write nanofabrication of the sensor element. First proof-of-principle results on the use of this novel scanning Hall sensor are shown.
Orthographic Knowledge, and Reading and Spelling: A Longitudinal Study in an Intermediate Depth Orthography

Abstract Orthographic knowledge is an important contributor to reading and spelling. However, empirical research is unclear about its long-lasting influence along with literacy development. We examined whether reading and spelling benefitted from an independent contribution of lexical and sublexical orthographic knowledge in European Portuguese, an intermediate depth orthography. This was investigated longitudinally from Grade 2 to 5 with two cohorts of Portuguese children, using common measures of orthographic knowledge, and word and pseudoword reading and spelling tasks. Regression analyses showed that lexical orthographic knowledge assessed at the beginning of Grade 2 predicted word reading at the beginning of Grade 3 (p < .05, variance explained = 6%), word spelling at the end of Grade 2 (p < .05, variance explained = 6%) and pseudoword spelling at the beginning of Grade 3 (p < .05, variance explained = 8%). They also revealed that lexical orthographic knowledge assessed at the beginning of Grade 4 predicted word spelling at the end of Grade 4 (p < .001, variance explained = 21%). Differently, sublexical orthographic knowledge evaluated at the beginning of Grade 2 and of Grade 4 only contributed to pseudoword spelling at the beginning of Grade 3 (p < .01, variance explained = 12%), and to pseudoword reading at the end of Grade 5 (p < .01, variance explained = 9%), respectively. Therefore, orthographic knowledge predicted spelling more often and earlier than reading. Furthermore, the results suggest that the influence of orthographic knowledge may vary during literacy development and, along with findings from other studies, that this influence at the lexical level may depend on orthographic consistency.
CD8 and CD4 T Cell Populations in Human Kidneys

Background: At border sites, and in internal organs, tissue resident memory T cells (TRM) contribute to the immune barrier against pathogens like viruses, bacteria, fungi, and cancer. However, information on the presence and function of these cells in the human kidney is scant. In order to better understand the T cell-mediated immunological defense in this organ, we aimed to determine phenotypic and functional aspects of CD8 and CD4 T cells present in healthy and allograft kidney tissue. Methods: Using multichannel flow cytometry, we assessed the phenotype and function of T cells in healthy renal tissue samples (n = 5) and kidney allograft tissue (n = 7) and compared these aspects to T cells in peripheral blood from healthy controls (n = 13). Results: Kidney tissue samples contained substantial amounts of CD8 and CD4 T cells. In contrast to the circulating cells, kidney T cells frequently expressed CD69 and CD103, and were more often actively cycling. Furthermore, nearly all kidney T cells expressed CXCR3, and often expressed CXCR6 compared to T cells in the circulation. Markedly, kidney T cells produced greater quantities of IFNγ than circulating cells and were frequently polyfunctional. Conclusion: Functional T cells with the characteristic traits of TRM reside in human kidney tissues. These cells are more often actively cycling and frequently express CXCR3 and CXCR6.
Missense, silent, non-sense and frame-shift mutations in exon 3 of the filaggrin gene in patients with bronchial asthma, atopic dermatitis, allergic rhinitis and mixed atopy

Abstract This study investigated the atopic march on the basis of genetics. This research detected 227 variants in the filaggrin gene (FLG gene). Missense, silent, non-sense, frame-shift and non-coding mutations were detected in exon 3 of the FLG gene in patients with bronchial asthma, atopic dermatitis, allergic rhinitis and mixed atopy. Missense mutation was detected at c.8343 G > C (p. Asp2781Glu) in all adult asthmatic and allergic rhinitis patients. Whereas, mutation at c.8360 C > T/A (p. Arg2787 His/Leu) was detected in all childhood asthmatic and mixed atopic patients. A non-coding mutation was detected at c.12365 in atopic dermatitis and bronchial asthma patients. Furthermore, DNA sequencing of asthmatic and mixed atopic patients showed missense mutations at c.6073 C > T (p. Gly2025Glu) and a silent mutation at c. 8341 G > A (p. Asp2781Asp).
Seasonal variations in levels of human thyroid-stimulating hormone and thyroid hormones: a meta-analysis

ABSTRACT Seasonal dynamics in biological functions of mammals is regulated by melatonin-mediated circannual fluctuations in the secretion of thyroid-stimulating hormone (TSH) and thyroid hormones. Most anatomical and molecular structures responsive to photoperiod and melatonin secretion changes and the associated receptors are preserved in modern humans. This work aimed to determine the seasonal dynamics of TSH and thyroid hormone levels (total triiodothyronine (T3), free triiodothyronine (FT3), thyroxine (T4), free thyroxine (FT4) and to investigate the dependence of these variations on gender, age and amplitude of meteorological fluctuations. A meta-analysis of 13 panel and 7 cross-sectional studies was performed using Review Manager 5.3 (Cochrane Library). We found that circulating TSH levels were higher in winter than in other seasons, and FT4 levels were higher in autumn than in winter. T4 level had no pronounced seasonal dynamics. The level of circulating T3 was significantly higher in winter than in summer and FT3 levels were lower in summer than in autumn and spring. In addition, analysis of TSH seasonal dynamics (winter vs summer) accounting for gender differences showed pronounced increases in TSH levels during winter in women, but not in men; and also significant increases in FT4 levels during summer in men, but not in women. Seasonal dynamics of FT3 and T4 did not depend on gender. Seasonal dynamics of TSH did not change with respect to age. We also found that the extent of the seasonal dynamics of TSH is influenced by the extent of the annual dynamics of the partial density of oxygen in the air, as well as the magnitude of the annual dynamic of meteorological factors that determine it (atmospheric pressure and relative humidity).
A Retrospective Cohort Study on Mortality and Neurodevelopmental Outcomes of Preterm Very Low Birth Weight Infants Born to Mothers with Hypertensive Disorders of Pregnancy

Abstract Objective We examined the effects of maternal hypertensive disorders of pregnancy (HDP) on the mortality and neurodevelopmental outcomes in preterm very low birth weight (VLBW) infants (BW ≤1,500 g) based on their intrauterine growth status and gestational age (GA). Study Design We included singleton VLBW infants born at <32 weeks' gestation registered in the Neonatal Research Network Japan database. The composite outcomes including death, cerebral palsy (CP), and developmental delay (DD) at 3 years of age were retrospectively compared among three groups: appropriate for GA (AGA) infants of mothers with and without HDP (H-AGA and N-AGA) and small for GA (SGA) infants of mothers with HDP (H-SGA). The adjusted odds ratios (AOR) and 95% confidence intervals (CI) stratified by the groups of every two gestational weeks were calculated after adjusting for the center, year of birth, sex, maternal age, maternal diabetes, antenatal steroid use, clinical chorioamnionitis, premature rupture of membranes, non-life-threatening congenital anomalies, and GA. Results Of 19,323 eligible infants, outcomes were evaluated in 10,192 infants: 683 were H-AGA, 1,719 were H-SGA, and 7,790 were N-AGA. Between H-AGA and N-AGA, no significant difference was observed in the risk for death, CP, or DD in any GA groups. H-AGA had a lower risk for death, CP, or DD than H-SGA in the 24 to 25 weeks group (AOR: 0.434, 95% CI: 0.202–0.930). The odds for death, CP, or DD of H-SGA against N-AGA were found to be higher in the 24 to 25 weeks (AOR: 2.558, 95% CI: 1.558–3.272) and 26 to 27 weeks (AOR: 1.898, 95% CI: 1.427–2.526) groups, but lower in the 30 to 31 weeks group (AOR: 0.518, 95% CI: 0.335–0.800). Conclusion There was a lack of follow-up data; however, the outcomes of liveborn preterm VLBW infants of mothers with HDP depended on their intrauterine growth status and GA at birth. Key Points The effects of HDP on preterm low birth weight infants need to be further examined. The outcomes were not different between AGA infants with and without maternal HDP. The outcomes of SGA infants with maternal HDP were dependent on their GA.
Laboratory Aspects of Donor Screening for Fecal Microbiota Transplantation at a Korean Fecal Microbiota Bank

Fecal microbiota transplantation (FMT) is a widely accepted alternative therapy for Clostridioides difficile infection and other gastrointestinal disorders. Thorough donor screening is required as a safety control measure to minimize transmission of infectious agents in FMT. We report the donor screening process and outcomes at a fecal microbiota bank in Korea. From August 2017 to June 2020, the qualification of 62 individuals as FMT donors was evaluated using clinical assessment and laboratory tests. Forty-six (74%) candidates were excluded after clinical assessment; high body mass index (>25) was the most common reason for exclusion, followed by atopy, asthma, and allergy history. Four of the remaining 16 (25%) candidates failed to meet laboratory test criteria, resulting in a 19% qualification rate. FMT donor re-qualification was conducted monthly as an additional safety control measure, and only three (5%) candidates were eligible for repeated donation. As high prevalence of multidrug-resistant organisms (55%) and Helicobacter pylori (44%) were detected in qualified donors during the screening, a urea breath test was added to the existing protocol. The present results emphasize the importance of implementing a donor re-qualification system to minimize risk factors not identified during initial donor screening.
NMR Structure Determinations of Small Proteins Using Only One Fractionally 20% 13C- and Uniformly 100% 15N-Labeled Sample

Uniformly 13C- and 15N-labeled samples ensure fast and reliable nuclear magnetic resonance (NMR) assignments of proteins and are commonly used for structure elucidation by NMR. However, the preparation of uniformly labeled samples is a labor-intensive and expensive step. Reducing the portion of 13C-labeled glucose by a factor of five using a fractional 20% 13C- and 100% 15N-labeling scheme could lower the total chemical costs, yet retaining sufficient structural information of uniformly [13C, 15N]-labeled sample as a result of the improved sensitivity of NMR instruments. Moreover, fractional 13C-labeling can facilitate reliable resonance assignments of sidechains because of the biosynthetic pathways of each amino-acid. Preparation of only one [20% 13C, 100% 15N]-labeled sample for small proteins (<15 kDa) could also eliminate redundant sample preparations of 100% 15N-labeled and uniformly 100% [13C, 15N]-labeled samples of proteins. We determined the NMR structures of a small alpha-helical protein, the C domain of IgG-binding protein A from Staphylococcus aureus (SpaC), and a small beta-sheet protein, CBM64 module using [20% 13C, 100% 15N]-labeled sample and compared with the crystal structures and the NMR structures derived from the 100% [13C, 15N]-labeled sample. Our results suggest that one [20% 13C, 100% 15N]-labeled sample of small proteins could be routinely used as an alternative to conventional 100% [13C, 15N]-labeling for backbone resonance assignments, NMR structure determination, 15N-relaxation analysis, and ligand–protein interaction.
Novel Anti-FOLR1 Antibody–Drug Conjugate MORAb-202 in Breast Cancer and Non-Small Cell Lung Cancer Cells

Antibody–drug conjugates (ADCs), which are currently being developed, may become promising cancer therapeutics. Folate receptor α (FOLR1), a glycosylphosphatidylinositol-anchored membrane protein, is an attractive target of ADCs, as it is largely absent from normal tissues but is overexpressed in malignant tumors of epithelial origin, including ovarian, lung, and breast cancer. In this study, we tested the effects of novel anti-FOLR1 antibody–eribulin conjugate MORAb-202 in breast cancer and non-small cell lung cancer (NSCLC) cell lines. FOLR1 expression, cell proliferation, bystander killing effects, and apoptosis were evaluated in seven breast cancer and nine NSCLC cell lines treated with MORAb-202. Tumor growth and FOLR1 expression were assessed in T47D and MCF7 orthotopic xenograft mouse models after a single intravenous administration of MORAb-202 (5 mg/kg). MORAb-202 was associated with inhibited cell proliferation, with specific selectivity toward FOLR1-expressing breast cancer cell lines. Eribulin, the payload of MORAb-202, was unleashed in HCC1954 cells, diffused into intercellular spaces, and then killed the non-FOLR1-expressing MCF7 cells in co-culture systems. In orthotopic xenograft mouse models, FOLR1-expressing T47D tumors and non-FOLR1-expressing MCF7 tumors were suppressed upon MORAb-202 administration. The novel anti-FOLR1 antibody–eribulin conjugate MORAb-202 has potential antitumor effects in breast cancer.
Effect of gravity and kinematic constraints on muscle synergies in arm cycling.

Arm cycling is a bi-manual motor task used in medical rehabilitation and in sports training. Understanding how muscle coordination changes across different biomechanical constraints in arm cycling is a step towards improved rehabilitation approaches. This exploratory study aims to get new insights on motor control during arm cycling. To achieve our main goal, we used the muscle synergies analysis to test three hypotheses: 1) body position with respect to gravity (sitting and supine) has an effect on muscle synergies; 2) the movement size (crank length) has an effect on the synergistic behavior; 3) the bimanual cranking mode (asynchronous and synchronous) requires different synergistic control. Thirteen able-bodied volunteers performed arm cranking on a custom-made device with unconnected cranks, which allowed testing three different conditions: body position (sitting versus supine), crank length (10cm versus 15cm) and cranking mode (synchronous versus asynchronous). For each of the eight possible combinations, subjects cycled for 30 seconds while electromyography of 8 muscles (4 from each arm) were recorded: biceps brachii, triceps brachii, anterior deltoid and posterior deltoid. Muscle synergies in this 8-dimensional muscle space were extracted by non-negative matrix factorization. Four synergies accounted for over 90% of muscle activation variances in all conditions. Results showed that synergies were affected by body position and cranking mode but practically unaffected by movement size. These results suggest that the central nervous system may employ different motor control strategies in response to external constraints such as cranking mode and body position during arm cycling.