Miracle-dz/UniFAR-FTUs huggingface dataset:
Effect of Wind on Horizontal Displacement of Fatal Fall from a Height

The horizontal displacement of the human body resulting from fatal fall from a height is an important variable commonly used to inversely determine the cause or identify other forensic aspects of the fall. When examining the horizontal displacement, the wind effect is generally ignored. This technical note reports analytical modeling of the falling process, utilizing previous measurements of wind force acting on the human body, for determining the functional relationship between the wind speed and the horizontal displacement in the falling process. The result reveals that it does not take extremely rare wind conditions to cause a considerable shift of the human body, highlighting the importance to consider wind as a factor in investigations of fatal falls.
Self-assembled micelles based on gambogenic acid-phospholipid complex for sustained-release drug delivery

Abstract Objective: To improve the water solubility and enhance the oral bioavailability of gambogenic acid (GNA). Methods: GNA-phospholipid complex (GNA-PLC) micelles were successfully prepared by anti-solvent method. Results: The encapsulation efficiency of GNA-PLC micelles can reach 99.33 % (w/w). The average particle size of the GNA-PLC micelles was 291.23 nm which was approximate agreed with the transmission electron microscopy (TEM). In vitro release profile showed the GNA-PLC and GNA-PLC micelles have significant sustained-release of GNA compared with crude GNA. Pharmacokinetic parameters indicated that the area under concentration–time curve (AUC0→t) of GNA in cases of GNA-PLC and GNA-PLC micelles are 2.04- and 3.92-fold higher than crude GNA, respectively. Conclusions: The better water solubility and higher bioavailability of GNA in GNA-PLC micelles with significant sustained-release of GNA endow the nanoparticle with great potential in GNA delivery system.
Gene replacement therapy after neuropathy onset provides therapeutic benefit in a model of CMT1X.

X-linked Charcot-Marie-Tooth disease (CMT1X), one of the commonest forms of inherited demyelinating neuropathy, results from GJB1 gene mutations causing loss of function of the gap junction protein connexin32 (Cx32). The aim of this study was to examine whether delayed gene replacement therapy after the onset of peripheral neuropathy can provide a therapeutic benefit in the Gjb1-null/Cx32 knockout (KO) model of CMT1X. After delivery of the LV-Mpz.GJB1 lentiviral vector by a single lumbar intrathecal injection into 6-month old Gjb1-null mice we confirmed expression of Cx32 in lumbar roots and sciatic nerves correctly localized at the paranodal myelin areas. Gjb1-null mice treated with LV-Mpz.GJB1 compared to LV-Mpz.Egfp (mock) vector at the age of 6 months showed improved motor performance at 8 and 10 months. Furthermore, treated mice showed increased sciatic nerve conduction velocities, improvement of myelination and reduced inflammation in lumbar roots and peripheral nerves at 10 months of age, along with enhanced quadriceps muscle innervation. Plasma neurofilament light (NEFL) levels, a clinically relevant biomarker, were also ameliorated in fully treated mice. Intrathecal gene delivery after the onset of peripheral neuropathy offers a significant therapeutic benefit in this disease model, providing a proof of principle for treating patients with CMT1X at different ages.
Quality of life in patients with mild Alzheimer disease: the mediator role of mindfulness and spirituality

Abstract Objectives This study examined the mediator role of mindfulness and spirituality in the relationship between psychological morbidity, awareness of the disease, functionality, social support, family satisfaction, and quality of life (QoL) in patients with mild AD. Method The sample consisted of 128 patients who answered the Cognitive and Affective Mindfulness Scale-Revised (CAMS-R), the Assessment Scale of Psychosocial Impact of the Diagnosis of Dementia (ASPIDD), the Hospital Anxiety and Depression Scales (HADS), the Satisfaction with Social Support Scale (SSSS), the Family Satisfaction Scale (FSS), the Spiritual and Religious Attitudes in Dealing with Illness (SpREUK), the Index of Barthel, and the Quality of Life-Alzheimer's Disease (QoL-AD). Results Mindfulness and spirituality mediated the relationship between functionality, awareness of the disease, family satisfaction and QoL. Psychological morbidity had a direct negative impact on QoL and was negatively associated with awareness of the disease, family satisfaction and social support. Mindfulness was negatively associated with spirituality and the latter was negatively associated with QoL. More social support was associated with greater awareness of the disease and family satisfaction. More functionality, awareness of the disease and family satisfaction contributed to more QoL and this relationship was mediated by mindfulness and spirituality. Conclusion Interventions directed at the promotion of the QoL of patients with mild AD should focus on the promotion of mindfulness skills in AD patients, in addition to the reduction of psychological morbidity and the promotion of functionality, awareness of the disease, family relationships and social support.
PMR5, an acetylation protein at the intersection of pectin biosynthesis and defense against fungal pathogens.

Powdery mildew (Golovinomyces cichoracearum), one of the most prolific obligate biotrophic fungal pathogens worldwide, infects its host by penetrating the plant cell wall while avoiding the activation of the plant's innate immune system. The Arabidopsis mutant powdery mildew resistant5 (pmr5) carries a mutation in a putative pectin acetyltransferase gene, which confers enhanced resistance to powdery mildew. Here, we show that heterologously expressed PMR5 protein transfers acetyl groups from [14 C]- acetyl-CoA to oligogalacturonides. Through site-directed mutagenesis, we show that three amino acids within a highly conserved esterase domain in putative PMR5 orthologs are necessary for PMR5 function. A suppressor screen of mutagenized pmr5 seed selecting for increased powdery mildew susceptibility identified two previously characterized genes affecting acetylation of plant cell wall polysaccharides, RWA2 and TBR. The rwa2 and tbr mutants also suppress powdery mildew disease resistance in pmr6, a mutant defective in a putative pectate lyase gene. Cell wall analysis of pmr5, pmr6, and their rwa2 and tbr suppressor mutants, demonstrates minor shifts in cellulose and pectin composition. In direct contrast to their increased powdery mildew resistance, both pmr5 and pmr6 plants are highly susceptibility to multiple strains of the generalist necrotroph Botrytis cinerea and have decreased camalexin production upon B. cinerea infection. These results illustrate that cell wall composition is intimately connected to fungal disease resistance, and outline a potential route for engineering powdery mildew resistance into susceptible crop species. This article is protected by copyright. All rights reserved.
Systematic FTIR Spectroscopy Study of the Secondary Structure Changes in Human Serum Albumin under Various Denaturation Conditions

Human serum albumin (HSA) is the most abundant protein in blood plasma. HSA is involved in the transport of hormones, fatty acids, and some other compounds, maintenance of blood pH, osmotic pressure, and many other functions. Although this protein is well studied, data about its conformational changes upon different denaturation factors are fragmentary and sometimes contradictory. This is especially true for FTIR spectroscopy data interpretation. Here, the effect of various denaturing agents on the structural state of HSA by using FTIR spectroscopy in the aqueous solutions was systematically studied. Our data suggest that the second derivative deconvolution method provides the most consistent interpretation of the obtained IR spectra. The secondary structure changes of HSA were studied depending on the concentration of the denaturing agent during acid, alkaline, and thermal denaturation. In general, the denaturation of HSA in different conditions is accompanied by a decrease in α-helical conformation and an increase in random coil conformation and the intermolecular β-strands. Meantime, some variation in the conformational changes depending on the type of the denaturation agent were also observed. The increase of β-structural conformation suggests that HSA may form amyloid-like aggregates upon the denaturation.
The Antitumor Activity of TCR-Mimic Antibody-Drug Conjugates (TCRm-ADCs) Targeting the Intracellular Wilms Tumor 1 (WT1) Oncoprotein

Wilms tumor 1 (WT1) oncoprotein is an intracellular oncogenic transcription factor which is barely expressed in normal adult tissues but over expressed in a variety of leukemias and solid cancers. WT1-derived HLA-A*02:01 T cell epitope, RMFPNAPYL (RMF), is a validated target for T cell-based immunotherapy. We generated two T cell receptor mimic antibody-drug conjugates (TCRm-ADCs), ESK-MMAE, and Q2L-MMAE, against WT1 RMF/HLA-A*02:01 complex with distinct affinities, which mediate specific antitumor activity. Although ESK-MMAE showed higher tumor growth inhibition ratio in vivo, the efficacy of them was not so promising, which might be due to low expression of peptide/HLA targets. Therefore, we explored a bispecific TCRm-ADC that exerted more potent tumor cytotoxicity compared with TCRm-ADCs. Hence, our findings validate the feasibility of the presenting intracellular peptides as the targets of ADCs, which broadens the antigen selection range of antibody-based drugs and provides new strategies for precision medicine in tumor therapy.
Transcriptomic Analysis of the Influence of Methanol Assimilation on the Gene Expression in the Recombinant Pichia pastoris Producing Hirudin Variant 3

Hirudin and its variants, as strong inhibitors against thrombin, are present in the saliva of leeches and are recognized as potent anticoagulants. However, their yield is far from the clinical requirement up to now. In this study, the production of hirudin variant 3 (HV3) was successfully realized by cultivating the recombinant Pichia pastoris GS115/pPIC9K-hv3 under the regulation of the promoter of AOX1 encoding alcohol oxidase (AOX). The antithrombin activity in the fermentation broth reached the maximum value of 5000 ATU/mL. To explore an effective strategy for improving HV3 production in the future, we investigated the influence of methanol assimilation on the general gene expression in this recombinant by transcriptomic study. The results showed that methanol was partially oxidized into CO2, and the rest was converted into glycerone-P which subsequently entered into central carbon metabolism, energy metabolism, and amino acid biosynthesis. However, the later metabolic processes were almost all down-regulated. Therefore, we propose that the up-regulated central carbon metabolism, energy, and amino acid metabolism should be beneficial for methanol assimilation, which would accordingly improve the production of HV3.
Immune evasion by Salmonella: exploiting the VPAC1/VIP axis in human monocytes

Immune evasion is a critical survival mechanism for bacterial colonization of deeper tissues and may lead to life‐threatening conditions such as endotoxaemia and sepsis. Understanding these immune evasion pathways would be an important step for the development of novel anti‐microbial therapeutics. Here, we report a hitherto unknown mechanism by which Salmonella exploits an anti‐inflammatory pathway in human immune cells to obtain survival advantage. We show that Salmonella enterica serovar Typhimurium strain 4/74 significantly (P < 0·05) increased expression of mRNA and surface protein of the type 1 receptor (VPAC1) for anti‐inflammatory vasoactive intestinal peptide (VIP) in human monocytes. However, we also show that S. Typhimurium induced retrograde recycling of VPAC1 from early endosomes to Rab11a‐containing sorting endosomes, associated with the Golgi apparatus, and anterograde trafficking via Rab3a and calmodulin 1. Expression of Rab3a and calmodulin 1 were significantly increased by S. Typhimurium infection and W‐7 (calmodulin antagonist) decreased VPAC1 expression on the cell membrane while CALP‐1 (calmodulin agonist) increased VPAC1 expression (P < 0·05). When infected monocytes were co‐cultured with VIP, a significantly higher number of S. Typhimurium were recovered from these monocytes, compared with S. Typhimurium recovered from monocytes cultured only in cell media. We conclude that S. Typhimurium infection exploits host VPAC1/VIP to gain survival advantage in human monocytes.
One stone with two birds: functional gold nanostar for targeted combination therapy of drug resistant Staphylococcus aureus infection.

The development of new antibacterial agents to deal with the emergence and spread of antibiotic resistance in Gram-positive bacterial pathogens has become an increasing problem. Here, a new strategy is developed for the effective targeting and killing of Gram-positive bacteria based on Vancomycin (Van) modified gold nanostars (AuNSs). Our work has demonstrated that Van-modified AuNSs (AuNSs@Van ) can not only selectively recognize MRSA, but also kill MRSA under NIR laser irradiation in vitro. Additionally, the AuNSs@Van shows satisfactory biocompatibility and antibacterial activity in treating bacterial infection in vivo. The attractive trait of AuNSs@Van is attributed to the physical effect of its antibacterial activity, with less potential for resistance development. The aforementioned advantages indicate the potential of AuNSs@Van as a photothermal antibacterial agent for effectively combating Gram-positive bacteria in the field of healthcare.
Twenty Years of BRCA1 and BRCA2 Molecular Analysis at MMCI - Current Developments for the Classification of Variants.

BACKGROUND Deleterious mutations in the BRCA1 and BRCA2 genes account for a considerable proportion of dominantly inherited breast and ovarian cancer susceptibility. The laboratory interpretation has always been dependent on the information available at the time of the report conclusion. The aim of this study has been to review the results from the BRCA testing at Masaryk Memorial Cancer Institute (MMCI). PATIENTS AND METHODS Patients with suspected hereditary predisposition to breast/ovarian cancer, belonging to 7,400 families, were referred by genetic counsellors for BRCA1 and BRCA2 mutation testing at the MMCI from 1999 to the beginning of 2018. Various methods have been used over 20 years of laboratory practice - starting with the Protein Truncation Test and Heteroduplex Analysis via the High Resolution Melting analysis and Sanger sequencing up to Next Generation Sequencing. RESULTS BRCA1 and BRCA2 mutation screening resulted in the identification of 1,021 families with a germline high-risk BRCA1 mutation and 497 families carrying a high-risk BRCA2 mutation, representing a mutation detection rate of 20.5%. A broad spectrum of unique mutations classified as pathogenic or likely pathogenic has been detected in both genes - 124 in the BRCA1 and 123 in the BRCA2 gene. Other sequence variants (96 unique variants in the BRCA1 and 126 in the BRCA2 gene) have been revised and classified as benign or likely benign. The other 82 unique variants remain classified as of uncertain significance mainly due to a lack of information for inclusion in other groups. All the results are summarised in the tables, including the reasons for their classification. CONCLUSION The clinical classification of rare sequence variants identified in the high-risk breast cancer susceptibility genes BRCA1 and BRCA2 is essential for appropriate genetic counselling. Here we present an overview of BRCA mutation frequencies in our region and the retrospective evaluation and eventually reclassification of previously reported rare variants in light of recent findings.
Prevalence of shift work disorder among hospital personnel: A cross‐sectional study using objective working hour data

The prevalence of shift work disorder (SWD) has been studied using self‐reported data and the International Classification of Sleep Disorders, Second Edition (ICSD‐2) criteria. We examined the prevalence in relation to ICSD‐2 and ICSD‐3 criteria, work schedules and the number of non‐day shifts (work outside 06:00–18:00 hours) using objective working‐hours data. Secondly, we explored a minimum cut‐off for the occurrence of SWD symptoms. Hospital shift workers without (n = 1,813) and with night shifts (n = 2,917) and permanent night workers (n = 84) answered a survey (response rate 69%) on SWD and fatigue on days off. The prevalence of SWD was calculated for groups with ≥1, ≥3, ≥5 and ≥7 monthly non‐day shifts utilizing the working hours registry. ICSD‐3‐based SWD prevalence was 2.5%–3.7% (shift workers without nights), 2.6%–9.5% (shift workers with nights) and 6.0% (permanent night workers), depending on the cut‐off of non‐day shifts (≥7–1/month, respectively). The ICSD‐2‐based prevalence was higher: 7.1%–9.2%, 5.6%–33.5% and 16.7%, respectively. The prevalence was significantly higher among shift workers with than those without nights (p‐values <.001) when using the cut‐offs of ≥1–3 non‐day shifts. Shift workers with nights who had ≥3 days with ICSD‐3‐based SWD symptoms/month more commonly had fatigue on days off (49.3%) than those below the cut‐off (35.8%, p < .05). The ICSD‐3 criteria provided lower estimates for SWD prevalence than ISCD‐2 criteria, similarly to exclusion of employees with the fewest non‐day shifts. The results suggest that a plausible cut‐off for days with ICSD‐3‐based SWD symptoms is ≥3/month, resulting in 3%–6% prevalence of SWD.
Ruminally protected and unprotected Saccharomyces cerevisiae fermentation products as alternatives to antibiotics in finishing beef steers.

The objectives of this study were to assess the effects of Saccharomyces cerevisiae fermentation products (SCFP; NaturSafe®, SCFPns; and Original XPC™, XPC; Diamond V) on growth performance, carcass traits, immune response and antimicrobial resistance in beef steers fed high-grain diets. Ninety Angus steers (initial body weight [BW], 533 ± 9.8 kg) were assigned to a randomized complete design with 6 treatments (n = 15/treatment): 1) control, 2) low (12 g SCFPns·steer-1·d-1), 3) medium (15 g SCFPns·steer-1·d-1), 4) high SCFP (18 g SCFPns·steer-1·d-1), 5) encapsulated XPC (eXPC; 7 g XPC·steer-1·d-1 encapsulated with 9 g capsule material), and 6) antibiotics (ANT; 330 mg monensin + 110 mg tylosin·steer-1·d-1). Steers were fed ad libitum a diet containing 10% barley silage and 90% barley grain concentrate mix (dry matter basis) for 105 d. Increasing SCFPns tended (P < 0.09) to linearly increase feed efficiency. Average daily gain (ADG) tended (P < 0.10) to be greater in steers supplemented with eXPC than control. The SCFPns also tended (P < 0.10) to linearly increase marbling score. Proportion of severely abscessed livers tended (P < 0.10) to be lower in steers supplemented with medium and high SCFPns, eXPC or ANT. A treatment × days on feed interaction were noticed (P < 0.01) for blood glucose, blood urea nitrogen (BUN) and acute phase proteins. The concentration of blood glucose responded quadratically (P < 0.05) on d 28 and 56, whereas BUN linearly (P < 0.01) increased on d 105 with increasing SCFPns dose. The SCFPns linearly increased haptoglobin (P < 0.03) and serum amyloid A (SAA; P < 0.05) concentrations on d 105, and lipopolysaccharide binding protein (LBP; P < 0.01) on d 56 and 105. The percentage of erythromycin resistant and erythromycin + tetracycline resistant enterococci was greater (P < 0.05) with ANT than control, SCFPns and eXPC, while no difference was observed among control, SCFPns and eXPC. No treatment effect was detected on the percentage of tetracycline resistant enterococci. These results indicate that feeding SCFPns and eXPC were beneficial in improving ADG, feed efficiency and decreasing liver abscesses in a manner comparable to ANT. Unlike antibiotics, SCFPns or eXPC did not increase antimicrobial resistance. Both SCFPns and eXPC are potential alternatives to in-feed antibiotics.
Effect of a dialogue-based intervention on psychosocial well-being 6 months after stroke in Norway: A randomized controlled trial.

OBJECTIVE To evaluate the effect of a dialogue-based intervention on psychosocial well-being 6 months after stroke. DESIGN Multicentre, prospective, randomized controlled trial. SUBJECTS Adults (aged ≥≥18 years) who had their first or recurrent stroke within the last month, were medically stable, had sufficient cognitive functioning to participate and understood and spoke Norwegian. METHODS A total of 322 participants were randomly assigned to the intervention (n = 166) or control (n = 156) group. Participants in the intervention group received up to 8 individual sessions aimed at supporting the coping and life skills of stroke survivors in addition to usual care. The primary outcome was mood (General Health Questionnaire-28; GHQ-28). The secondary outcomes included health-related quality of life (Stroke and Aphasia Quality of Life Scale; SAQOL-39g), depression (Yale-Brown single-item questionnaire; Yale) and sense of coherence (SOC-13). RESULTS After controlling for the baseline values, no significant benefit was found in the intervention group over the control group (odds ratio (OR): 0.916: 95% confidence interval (95% CI): 0.54-1.54, p = 0.742) 6 months post-stroke. CONCLUSION Psychosocial well-being improved during the first 6 months after stroke in both arms of the trial, but no statistically significant benefit of the dialogue-based intervention was found compared with usual care.
The effects of copper on photosynthesis and biomolecules yield in Chlorolobion braunii

Our knowledge of the effects of copper on microalgal physiology is largely based on studies conducted with high copper concentrations; much less is known when environmentally relevant copper levels come into question. Here, we evaluated the physiology of Chlorolobion braunii exposed to free copper ion concentrations between 5.7 × 10−9 and 5.0 × 10−6 mol · L−1, thus including environmentally relevant values. Population growth and maximum photosynthetic quantum yield of PSII were determined daily during the 96 h laboratory controlled experiment. Exponentially‐growing cells (48 h) were analyzed for effective quantum yield and rapid light curves (RLC), and total lipids, proteins, carbohydrates, chlorophyll a and carotenoids were determined. The results showed that growth rates and population density decreased gradually as copper increased in experiment, but the photosynthetic parameters (maximum and effective quantum yields) and photochemical quenching (qP) decreased only at the highest free copper concentration tested (5.0 × 10−6 mol · L−1); nonphotochemical quenching (NPQ) increased gradually with copper increase. The RLC parameters Ek and rETRmax were inversely proportional to copper concentration, while α and Im decreased only at 5.0 × 10−6 mol · L−1. The effects of copper in biomolecules yield (mg · L−1) varied depending on the biomolecule. Lipid yield increased at free copper concentration as low as 2.5 × 10−8 mol · L−1, but proteins and carbohydrates were constant throughout.