Miracle-dz/UniFAR-FTUs huggingface dataset:
Early-onset liver mtDNA depletion and late-onset proteinuric nephropathy in Mpv17 knockout mice

In humans, MPV17 mutations are responsible for severe mitochondrial depletion syndrome, mainly affecting the liver and the nervous system. To gain insight into physiopathology of MPV17-related disease, we investigated an available Mpv17 knockout animal model. We found severe mtDNA depletion in liver and, albeit to a lesser extent, in skeletal muscle, whereas hardly any depletion was detected in brain and kidney, up to 1 year after birth. Mouse embryonic fibroblasts did show mtDNA depletion, but only after several culturing passages, or in a serumless culturing medium. In spite of severe mtDNA depletion, only moderate decrease in respiratory chain enzymatic activities, and mild cytoarchitectural alterations, were observed in the Mpv17−/− livers, but neither cirrhosis nor failure ever occurred in this organ at any age. The mtDNA transcription rate was markedly increased in liver, which could contribute to compensate the severe mtDNA depletion. This phenomenon was associated with specific downregulation of Mterf1, a negative modulator of mtDNA transcription. The most relevant clinical features involved skin, inner ear and kidney. The coat of the Mpv17−/− mice turned gray early in adulthood, and 18-month or older mice developed focal segmental glomerulosclerosis (FSGS) with massive proteinuria. Concomitant degeneration of cochlear sensory epithelia was reported as well. These symptoms were associated with significantly shorter lifespan. Coincidental with the onset of FSGS, there was hardly any mtDNA left in the glomerular tufts. These results demonstrate that Mpv17 controls mtDNA copy number by a highly tissue- and possibly cytotype-specific mechanism.
Muscle size and arterial stiffness after blood flow‐restricted low‐intensity resistance training in older adults

Previous studies have shown that blood flow‐restricted low‐intensity resistance training (BFR‐RT) causes muscle hypertrophy while maintaining arterial function in young adults. We examined the effects of BFR‐RT on muscle size and arterial stiffness in older adults. Healthy subjects (ages 61–84 years) were divided into BFR‐RT (n = 9) or non‐training control (CON; n = 10) groups. The BFR‐RT group performed 20% and 30%, respectively, of one‐repetition maximal (1‐RM) knee extension and leg press exercises, 2 days/wk for 12 weeks. The BFR‐RT group wore elastic cuffs (120–270 mmHg) on both legs during training. Magnetic resonance imaging‐measured muscle cross‐sectional area (CSA), 1‐RM strength, chair stand (CS) test, and cardio‐ankle vascular index testing (CAVI), an index of arterial stiffness, were measured before and 3–5 days after the final training session. Muscle CSA of the quadriceps (8.0%), adductors (6.5%), and gluteus maximus (4.4%), leg extension and leg press 1‐RM strength (26.1% and 33.4%), and CS performance (18.3%) improved (P < 0.05) in the BFR‐RT group, but not in the CON group. In CAVI testing, there were no changes in both two groups. In conclusion, BFR‐RT improves muscle CSA as well as maximal muscle strength, but does not negatively affect arterial stiffness or humeral coagulation factors in older adults.
Retinoic acid‐mediated growth inhibition of small cell lung cancer cells is associated with reduced myc and increased p27Kip1 Expression

Human lung cancer cells, including small cell lung carcinoma (SCLC), frequently lose expression of retinoic acid receptor β (RAR‐β) and are resistant to the growth inhibitory activity of all‐trans retinoic acid (RA). To elucidate the role of RAR‐β in the growth regulation of SCLC by retinoids, we restored RAR‐β expression in RAR‐β‐negative H209 SCLC cells by retroviral transduction (H209‐RAR‐β). We found that H209‐RAR‐β, but not parental H209 cells, underwent growth inhibition upon RA treatment. RA‐treated H209‐RAR‐β cells arrested in G1 and displayed reduced L‐myc expression and cyclin‐dependent kinase 2 (cdk2) activity compared with untreated cells. RA treatment of H209‐RAR‐β cells was also accompanied by increased expression of the cdk inhibitor p27Kip1, whereas no differences in the expression of L‐myc or p27Kip1 were detected upon RA treatment of parental H209 cells. The RA‐induced growth arrest of H82 SCLC cells, which express endogenous RAR‐β, was also associated with reduced c‐myc and increased p27Kip1 expression. We found that ectopic expression of p27Kip1 induced growth inhibition in both H209 and H82 cells, and that sustained myc expression in H209‐RAR‐β cells promoted the induction of apoptosis upon RA addition. Our observations indicate that RAR‐β gene transfer can restore RA sensitivity in SCLC cells and suggest that myc and p27Kip1 may represent critical mediators of the RA‐induced cell cycle arrest in SCLC cells expressing RAR‐β. Int. J. Cancer 80:935–943, 1999. © 1999 Wiley‐Liss, Inc.
INHIBITION OF KETO ACID OXIDATION BY PLAGUE TOXIN

The major objective of this work has been to learn the effect of plague toxin on several enzymatic systems in vitro. The availability of purified preparations of plague toxin (Ajl et al., 1955) permitted us to carry out these investigations. In this report, experiments are described in which purified plague toxin has been added to actively respiring cell-free extracts and crude mouse liver homogenates. It has been found that the toxin inhibits the oxidation of a-keto acids by these enzymatic preparations.
Determinants of Human Immunodeficiency Virus Type 1 Resistance to gp41-Derived Inhibitory Peptides

ABSTRACT A synthetic peptide, DP178, containing amino acids 127 to 162 of the human immunodeficiency virus type 1 (HIV-1) gp41 Env glycoprotein, is a potent inhibitor of virus infection and virus mediated cell-to-cell fusion (C. Wild, T. Greenwell, and T. Matthews, AIDS Res. Hum. Retroviruses 9:1051–1053, 1993). In an effort to understand the mechanism of action of this peptide, we derived resistant variants of HIV-1IIIB and NL4-3 by serial virus passage in the presence of increasing doses of the peptide. Sequence analysis of the resistant isolates suggested that a contiguous 3-amino-acid sequence within the amino-terminal heptad repeat motif of gp41 was associated with resistance. Site-directed mutagenesis studies confirmed this observation and indicated that changes in two of these three residues were necessary for development of the resistant phenotype. Direct binding of DP178 to recombinant protein and synthetic peptide analogs containing the wild-type and mutant heptad repeat sequences revealed a strong correlation between DP178 binding and the biological sensitivity of the corresponding virus isolates to DP178. The results are discussed from the standpoints of the mechanism of action of DP178 and recent crystallographic information for a core structure of the gp41 ectodomain.
Reflecting Disaster Risk in Development Indicators

Disasters triggered by hazards, such as floods, earthquakes, droughts, and cyclones, pose significant impediments to sustainable development efforts in the most vulnerable and exposed countries. Mainstreaming disaster risk is hence seen as an important global agenda as reflected in the Sustainable Development Goals (SDGs) and the Sendai Framework for Disaster Risk Reduction (SFDRR) 2015–2030. Yet, conventional development indicators remain largely negligent of the potential setbacks that may be posed by disaster risk. This article discusses the need to reflect disaster risk in development indicators and proposes a concept disaster risk-adjusted human development index (RHDI) as an example. Globally available national-level datasets of disaster risk to public and private assets (including health, educational facilities, and private housing) is combined with an estimate of expenditure on health, education, and capital formation to construct an RHDI. The RHDI is then analyzed across various regions and HDI groups, and contrasted with other HDI variants including inequality-adjusted HDI (IHDI) and the gender-specific female HDI (FHDI) to identify groups of countries where transformational disaster risk reduction (DRR) approaches may be necessary.
Moving beyond pain scores: Multidimensional pain assessment is essential for adequate pain management after surgery

Background Clinical experience teaches us that patients are willing to accept postoperative pain, despite high pain intensity scores. Nevertheless, relationships between pain scores and other methods of pain assessment, e.g. acceptability of pain or its interference with physical functioning, are not fully established. Our aims were to examine these relationships. Methods A cross-sectional study was conducted on patients who underwent major surgery between January 2008 and August 2013. Using logistic regression, we quantified the relationships between movement-evoked pain scores on the numerical rating scale (NRS-MEP) and three dichotomous dependent variables: patient’s opinion on acceptability of pain (PO: acceptable or unacceptable pain); nurses’ observation of patient’s performance of necessary activities to expedite recovery (NO: good or bad performance); a compound measure judging the presence of the clinically desirable situation of acceptable pain associated with good patients’ performance (PONO: present or not). Using Receiver Operating Characteristics (ROC) analysis, NRS cut-off points were determined such that they best discriminate between patients having one versus the other outcome for PO, NO and PONO. Results 15,394 assessments were obtained in 9,082 patients in the first three postoperative days. Nine percent of the patients had unacceptable pain while having an NRS-MEP of 0–4. An estimated 47% (95%CI = 45%-49%) of patients with an NRS-MEP of 7 described their pain as acceptable on day one. Moreover, 33% (31%-35%) performed all required physical activities, and 22% (21%-24%) combined acceptable pain with appropriate movement. NRS cut-off points for PO, NO and PONO were five, four and four, respectively, but had insufficient discriminatory power. Conclusions Our results suggest pain management should be guided by the many dimensions of the patient’s pain experience, not solely by NRS cut-off points. Future research should evaluate the impact of such multidimensional pain assessment on patients’ functional outcome.
Osteopontin Enhances Phagocytosis through a Novel Osteopontin Receptor, the αXβ2 Integrin1

Osteopontin (OPN) is a cytokine with multiple functions, including immune defense mechanisms against invading microorganisms. OPN-deficient mice are impaired in clearing intracellular pathogens, suggesting an important role of OPN during phagocytosis, but it remains to be defined how OPN may enhance this innate immune process. Here, we demonstrate that OPN binds to monocytes, but not resting T cells, NK cells, or B cells, and mediates chemoattraction of IL-1-activated human monocytes. Moreover, OPN binds in a specific manner to all known serotypes of the two bacterial species Streptococcus agalactiae and Staphylococcus aureus and opsonizes these bacteria for phagocytosis. We identify the integrin αXβ2 (CD11c/CD18), which is highly expressed on the cell surface of monocytes, as a novel OPN receptor. To eliminate the contribution from other molecular interactions between the bacteria and the phagocyte, we show that OPN-coated synthetic beads are phagocytosed in an αXβ2 integrin-dependent manner. The ligand recognition does not involve the RGD motif previously reported to support binding of OPN to integrins. Taken together, these data identify the αXβ2 integrin as a novel OPN receptor that is required for OPN-mediated phagocytosis, thereby elucidating an important mechanism of an innate immune function of OPN.
Virtual environment navigation with look-around mode to explore new real spaces by people who are blind

Abstract Background: This paper examines the ability of people who are blind to construct a mental map and perform orientation tasks in real space by using Nintendo Wii technologies to explore virtual environments. The participant explores new spaces through haptic and auditory feedback triggered by pointing or walking in the virtual environments and later constructs a mental map, which can be used to navigate in real space. Methods: The study included 10 participants who were congenitally or adventitiously blind, divided into experimental and control groups. The research was implemented by using virtual environments exploration and orientation tasks in real spaces, using both qualitative and quantitative methods in its methodology. Results: The results show that the mode of exploration afforded to the experimental group is radically new in orientation and mobility training; as a result 60% of the experimental participants constructed mental maps that were based on map model, compared with only 30% of the control group participants. Conclusions: Using technology that enabled them to explore and to collect spatial information in a way that does not exist in real space influenced the ability of the experimental group to construct a mental map based on the map model. Implications for rehabilitation The virtual cane system for the first time enables people who are blind to explore and collect spatial information via the look-around mode in addition to the walk-around mode. People who are blind prefer to use look-around mode to explore new spaces, as opposed to the walking mode. Although the look-around mode requires users to establish a complex collecting and processing procedure for the spatial data, people who are blind using this mode are able to construct a mental map as a map model. For people who are blind (as for the sighted) construction of a mental map based on map model offers more flexibility in choosing a walking path in a real space, accounting for changes that occur in the space.
Applying a highly specific and reproducible cDNA RDA method to clone garlic up-regulated genes in human gastric cancer cells.

AIM To develop and optimize cDNA representational difference analysis (cDNA RDA) method and to identify and clone garlic up-regulated genes in human gastric cancer (HGC) cells. METHODS We performed cDNA RDA method by using abundant double-stranded cDNA messages provided by two self-constructed cDNA libraries (Allitridi-treated and paternal HGC cell line BGC823 cells cDNA libraries respectively). Bam H I and Xho I restriction sites harbored in the library vector were used to select representations. Northern and Slot blots analyses were employed to identify the obtained difference products. RESULTS Fragments released from the cDNA library vector after restriction endonuclease digestion acted as good marker indicating the appropriate digestion degree for library DNA. Two novel expressed sequence tags (ESTs) and a recombinant gene were obtained. Slot blots result showed a 8-fold increase of glia-derived nexin/protease nexin 1 (GDN/PN1) gene expression level and 4-fold increase of hepatitis B virus x-interacting protein (XIP) mRNA level in BGC823 cells after Allitridi treatment for 72h. CONCLUSION Elevated levels of GDN/PN1 and XIP mRNAs induced by Allitridi provide valuable molecular evidence for elucidating the garlic's efficacies against neurodegenerative and inflammatory diseases. Isolation of a recombinant gene and two novel ESTs further show cDNA RDA based on cDNA libraries to be a powerful method with high specificity and reproducibility in cloning differentially expressed genes.
Preparation and ectopic osteogenesis in vivo of scaffold based on mineralized recombinant human-like collagen loaded with synthetic BMP-2-derived peptide

The ideal bone graft material must be biocompatible, biodegradable, osteoconductive and osteoinductive. In this study, a new biomimetic scaffold based on mineralized recombinant collagen, nano-hydroxyapatite/recombinant human-like collagen/poly(lactic acid) (nHA/RHLC/PLA), was prepared and the synthetic P24 peptide derived from BMP-2 was introduced into the porous nHA/RHLC/PLA scaffold to improve its osteoinductive property. The nHA/RHLC/PLA implants loaded with 3 mg, 2 mg, 1 mg and 0 mg P24 peptide were implanted subcutaneously into rats. At the 4th, 8th and 12th weeks after implantation, the rats were sacrificed in batch and the samples were harvested. Their osteogenic capability was detected by CT scan and histological observation. The results indicated that the osteogenic capability of 3 mg, 2 mg and 1 mg of the P24 peptide was superior to the implants without the P24 peptide. There was no significant difference between implants with 3 mg and 2 mg P24 peptide, but the osteogenic capability of the two dosage groups was significantly better than that of the 1 mg group. It was concluded that BMP-2-derived peptide can increase the osteoinduction of nHA/RHLC/PLA scaffold and the P24 peptide induced new bone formation in a dose-dependent manner. The nHA/RHLC/PLA scaffold loaded with the synthetic BMP-2-derived peptide is a kind of ideal scaffold material for bone tissue engineering.
Polysomnographic Findings in Dementia With Lewy Bodies

Introduction:The clinical features of dementia with Lewy bodies (DLB) during wakefulness are well known. Other than rapid eye movement (REM) sleep behavior disorder, only limited data exists on other sleep disturbances and disorders in DLB. We sought to characterize the polysomnographic (PSG) findings in a series of DLB patients with sleep-related complaints. Methods:Retrospective study of patients with DLB who underwent clinical PSG at Mayo Clinic, Rochester or Mayo Clinic, Jacksonville over an almost 11-year span for evaluation of dream enactment behavior, excessive nocturnal movements, sleep apnea, hypersomnolence, or insomnia. The following variables were analyzed: respiratory disturbance index (RDI) in disordered breathing events/hour, periodic limb movement arousal index, arousals for no apparent reason (AFNAR), total arousal index, presence of REM sleep without atonia, and percent sleep efficiency. Results:Data on 78 patients (71 male, 7 female) were analyzed. The mean age was 71±8 years. Seventy-five (96%) patients had histories of recurrent dream enactment during sleep with 83% showing confirmation of REM sleep without atonia±dream enactment during PSG. Mean RDI=11.9±5.8, periodic limb movement arousal index =5.9±8.5, arousals for no apparent reason index=10.7±12.0, and total arousal index=26.6±17.4. Sleep efficiency was <80% in 72% of the sample, <70% in 49%, and <60% in 24%. In patients who did not show evidence of significant disordered breathing (23 with RDI<5), 62% of arousals were AFNARs. In those patients who had significant disordered breathing (55 with RDI≥5), 36% of arousals were AFNARs. Six patients underwent evaluations with PSG plus multiple sleep latency test. Two patients had mean initial sleep latencies of <5 minutes, and both had RDI<5. No patient had any sleep onset REM periods. Nineteen patients have undergone neuropathologic examination, and 18 have had limbic-predominant or neocortical-predominant Lewy body pathology. One had progressive supranuclear palsy, but no REM sleep was recorded in prior PSG. Conclusions:In patients with DLB and sleep-related complaints, several sleep disturbances in addition to REM sleep behavior disorder are frequently present. In this sample, about 3/4 had a significant number of arousals not accounted for by a movement or breathing disturbance, and the primary sleep disorders do not seem to entirely account for the poor sleep efficiency in DLB, especially in those without a significant breathing disorder. Further studies are warranted to better understand the relationship between disturbed sleep, arousal, and DLB; such characterization may provide insights into potential avenues of treatment of symptoms that could impact quality of life.
Epidemiology, Production Losses, and Control Measures Associated with an Outbreak of Avian Influenza Subtype H7N2 in Pennsylvania (1996–98)

Abstract An outbreak of H7N2 low-pathogenicity (LP) avian influenza (AI) occurred in a two-county area in Pennsylvania from December of 1996 through April of 1998. The outbreak resulted in infection of 2,623,116 commercial birds on 25 premises encompassing 47 flocks. Twenty-one (one premise with infection twice) of the twenty-five infected premises housed egg-laying chickens and one premise each had turkeys, layer pullets, quail, and a mixed backyard dealer flock. Despite close proximity of infected flocks to commercial broiler flocks, no infected broilers were identified. Experimentally, when market age broilers were placed on an influenza-infected premise they seroconverted and developed oviduct lesions. The outbreak was believed to have originated from two separate introductions into commercial layer flocks from premises and by individuals dealing in sales of live fowl in the metropolitan New York and New Jersey live-bird markets. Source flocks for these markets are primarily in the northeast and mid-Atlantic areas, including Pennsylvania. Mixed fowl sold include ducks, geese, guinea hens, quail, chukar partridges, and a variety of chickens grown on perhaps hundreds of small farms. Infections with the H7N2 AI virus were associated with variable morbidity and temporary decreases in egg production ranging from 1.6% to 29.1% in commercial egg-laying chickens. Egg production losses averaged 4.0 weeks duration. Mortality ranged from 1.5 to 18.3 times normal (mean of 4.3 times normal). Duration of mortality ranged from 2 to 13 weeks (average of 3.9 weeks) in flocks not depopulated. Lesions observed were primarily oviducts filled with a mucous and white gelatinous exudates and atypical egg yolk peritonitis. Quarantine of premises and complete depopulation were the early measures employed in control of this outbreak. Epidemiological studies suggested that depopulation furthered the spread of influenza to nearby flocks. Thereafter, later control measures included quarantine, strict biosecurity, and controlled marketing of products.
Weibel‐Palade Body Membrane Proteins Exhibit Differential Trafficking After Exocytosis in Endothelial Cells

Weibel‐Palade bodies, the secretory granules of endothelial cells, possess two different membrane proteins. However, P‐selectin is seen only in Weibel‐Palade bodies in HUVECs, whereas CD63 is also seen in late endosomes/lysosomes. Since P‐selectin is targeted to lysosomes in heterologous expression studies, we have determined whether a lysosomal targeting signal also operates within HUVECs. We have also examined the trafficking of CD63 to its two different intracellular locations. By following antibodies bound at the plasma membrane during stimulation, we have discovered that while half of the P‐selectin recycles to the WPBs, 50% is rapidly delivered to a lamp‐1‐positive compartment. Thus, the lysosomal targeting signal of this protein also operates in HUVECs. CD63 is found constitutively at the cell surface of HUVECs and most of it is delivered to the late endosomes/lysosomes after internalisation. However, stimulation causes both a rise in the CD63 plasma membrane level and in the amount that recycles to the WPBs. Our data strongly suggest that the CD63 that originates in the WPB preferentially recycles to the granule rather than being delivered to the late endosome/lysosome, and that there are, therefore, two separate pools of this protein within HUVECs. Our findings indicate that although P‐selectin and CD63 are both targeted to the same compartments from the PM, the kinetics and the ratio of their targeting to Weibel‐Palade bodies versus lysosomes are very different.