Miracle-dz/UniFAR-FTUs huggingface dataset:
Thermal stability: a means to assure tertiary structure in therapeutic proteins.

To be both safe and effective, a therapeutic product must have the correct chemical structure and be free of harmful contaminants. Structure in protein therapeutic products, however, implies not only the correct sequence of amino acids (primary structure) but also the proper folding of that amino acid chain in three-dimensional space (tertiary structure). This work is part of a general strategy to develop a battery of physico-chemical methods that could give assurances of structure (and hence function) in formulated therapeutic proteins in the absence of in vivo data. It focuses on recombinant human growth hormone (rhGH), a well-characterized therapeutic protein, and examines the utility of thermodynamic parameters in assessing its tertiary structure. Resistance of solutions of formulated rhGH to thermal denaturation was followed using Fourier Transform Infrared Spectroscopy (FTIR) by observing decreases in total helicity and increases in intermolecular beta-sheet formation. Under conditions known to induce changes in the intra-molecular ionic and H-bonding patterns stabilizing the tertiary structure but not affecting the protein's secondary structure or global fold, we have observed upwards of a 12 degrees C shift in the melting temperature of the protein. Furthermore, our results indicated that the T(m) of unfolding of rhGH was sensitive to much more subtle changes in the protein structure. Thus, resistance to thermal denaturation may well be a useful means to measure structure in formulations of well-characterized therapeutic proteins.
Low Back Pain Among Endurance Athletes With and Without Specific Back Loading—A Cross-Sectional Survey of Cross-Country Skiers, Rowers, Orienteerers, and Nonathletic Controls

Study Design. Cross-sectional survey among athletes competing at the national elite level in cross-country skiing, rowing, and orienteering, as well as a matched nonathletic control group. Objective. To compare the prevalence of symptoms of low back pain between endurance sports with different loading characteristics on the lumbar region: cross-country skiing, rowing, and orienteering, as well as a nonathletic control group. Summary of Background Data. Although it is claimed that back pain is a frequent problem in endurance sports loading the lower spine such as rowing or cross-country skiing, the prevalence of low back problems in such sports has not been compared with relevant control groups. Methods. Self-reported questionnaire on low back pain adapted for sports based on standardized Nordic questionnaires for musculoskeletal symptoms. Responders were 257 cross-country skiers (response rate: 100%), 199 rowers (99.5%), and 278 orienteerers (99.3%), and 197 control subjects (66%). Results. Low back pain was reported to be somewhat more common among cross-country skiers and rowers than orienteerers and nonathletic controls. The prevalence among cross-country skiers of reported low back pain ever (65.4%) and low back pain during the previous 12 months (63.0%) was higher than nonathletic controls (OR [95% CI]: 1.94 [1.29–2.92]). Rowers (25.6%) reported missing training because of low back pain more frequently than orienteerers did (13.7%, OR: 2.16 [1.25–3.74]). The athletes reported more low back pain during periods when training and competition load was higher, and cross-country skiers more frequently reported having low back problems using classic than freestyle skiing techniques. Conclusions. Low back pain appears to be somewhat more common in endurance sports that specifically load the low back during training and competition. The relationship between seasonal training patterns and specific skiing techniques indicate that there is a relationship between low back pain and the specific loading patterns of skiing and rowing.
A gradient of BMP activity specifies dorsal-ventral fates in early Xenopus embryos.

BMP-4 is an extracellular signalling molecule belonging to the TGF-beta superfamily that plays a central role in dorsoventral patterning in vertebrate gastrulae. We review the evidence indicating that BMP-4 acts as a morphogen, specifying dorsoventral positional values in a concentration-dependent manner. An activity gradient of BMP-4 is established not by simple diffusion from a localised source, but by diffusion of inhibitory binding proteins that act on a uniform level of BMP-4 protein. These in turn are regulated by the activity of tolloid-related metalloproteases, such as Xenopus xolloid and zebrafish tolloid.
Molecular Pathobiology of Gastric Cancer

Gastric carcinogenesis is a multistep process, during which numerous genetic and epigenetic alterations accumulate: there are abnormalities of growth factors/receptors, angiogenic factors, cell cycle regulators, DNA mismatch repair genes etc. These abnormalities define, at the same time, the biological character of the cancer cell and may thus serve as therapeutic targets. Genetic instability may cause accumulation of genetic abnormalities. The most important epigenetic alterations are DNA methylation, histone modification and chromatin remodeling. Some of these changes are common in gastric cancer, regardless of subtype, and some differ by histological type or (gastric or intestinal) mucin phenotype. Genetic polymorphism is a crucial endogenous cause and fundamental aspect of cancer risk. Importantly, genetic polymorphisms are also associated with the therapeutic efficacy and toxicity of anti-cancer drugs. Genomic science and technology such as Serial Analysis of Gene Expression (SAGE) allows the identification of novel genes and molecules specifically up-regulated or down-regulated in gastric cancer, e.g., RegIV and claudin-18 can be identified. Advances in our understanding of the genetic and molecular bases lead to improved diagnosis, personalised medicine and prevention of gastric cancer.
Misdiagnosis of multidrug-resistant tuberculosis possibly due to laboratory-related errors.

OBJECTIVE To describe 9 cases where a misdiagnosis of multidrug-resistant tuberculosis (MDR TB) was made, possibly due to laboratory-related errors. DESIGN Case series. SETTING Public and private hospitals, outpatient clinics, and mycobacteriology laboratories serving those institutions in Los Angeles County, Calif. PATIENTS Consecutive sample of 70 patients diagnosed with MDR TB who were identified between August 1993 and August 1994 by the Multidrug-Resistant Unit within TB Control in Los Angeles County. OUTCOME MEASURE Detection of laboratory-related diagnostic errors. RESULTS Pulmonary MDR TB was misdiagnosed in 9 (13%) of 70 patients. Reasons why the diagnoses appeared to be erroneous are as follows: growth of MDR TB from an old tuberculous lesion in a patient who was never treated for TB and whose diagnosis predated anti-TB drugs (1 case), documented contamination with Mycobacterium avium complex (1 case), suspected cross-contamination (1 case), suspected specimen mislabeling (1 case), successful treatment using drugs to which the isolate was reportedly resistant (4 cases), discrepant susceptibility test results on additional sputum specimens submitted by the patient (2 cases), and no clinical evidence of TB (3 cases). CONCLUSIONS These cases emphasize the diagnostic errors that can occur if mycobacterial susceptibility results are not correlated with all clinical data including other laboratory results for a given patient. We conclude that susceptibility results alone are not enough to dictate treatment, and that careful clinical correlation is necessary in making the diagnosis of MDR TB.
Partially Occluded Leaf Recognition via Subgraph Matching and Energy Optimization

We present an approach to match partially occluded plant leaves with databases of full plant leaves. Although contour based 2D shape matching has been studied extensively in the last couple of decades, matching occluded leaves with full leaf databases is an open and little worked on problem. Classifying occluded plant leaves is even more challenging than full leaf matching because of large variations and complexity of leaf structures. Matching an occluded contour with all the full contours in a database is an NP-hard problem [Su et al. ICCV2015], so our algorithm is necessarily suboptimal.
SEROEPIDEMIOLOGY OF CHLAMYDIAL INFECTIONS OF WILD RUMINANTS IN SPAIN

Chlamydial infections were determined serologically among wild ruminants in the Nature Park of the Sierras de Cazorla, Segura y Las Villas (CNP; Spain). Sampling was done during the period from 1990–95. There were 1,244 blood samples collected, consisting of 490 from fallow deer (Dama dama), 343 from mouflon (Ovis mussimon), 283 from red deer (Cervus elaphus) and 128 from Spanish ibex (Capra pyrenaica). Specific complement-fixing antibodies of Chlamydia spp. were detected by means of microtechnique, using lipopolysaccharide antigen. The relationship of biological (species, sex, age), temporal (year) and territorial (central and peripheral areas) factors to seropositive prevalence was examined, and preliminary data were collected on whether or not sheep and goat herds grazing in the peripheral areas of the park also were infected with Chlamydia spp. Chlamydiosis was common in the four species of wild ruminants in the CNP in all the years studied. The prevalence of Chlamydia sp. in mouflon (37%) was significantly greater than in fallow deer (30%), and both had a significantly higher prevalence rate than Spanish ibex and red deer (both 24%). The four species of wild ruminants were similar in that they act as reservoirs of Chlamydia spp. , although their receptivity may be different, and the infection can certainly be maintained among these animals by intra-group transmission. The differences in prevalences and geometric mean titers (GMT), both between the sexes (male versus female) and between different ages (adult versus juvenile), were insignificant in all four species. For all species of wild ruminants both prevalence rates and GMTs were greater in populations occupying the peripheral areas of the park than in those inhabiting the central area. Herds of sheep and goats had a high prevalence of chlamydiosis. Intertransmission of Chlamydia sp. between wild and domestic ruminants occurred through grazing on the same pastures. The highest mean prevalence (44%) of patent infections (CFT titers of ≥1:80) was detected in red deer, although this frequency was not significantly different from those observed in mouflon (39%), Spanish ibex (38%), and fallow deer (37%). The proportion of patent infection was higher in females than in males, and none of the juveniles (<2-yr-old) showed patent infections. The prevalence of predicted patent chlamydial infections was always higher in the peripheral areas of the park, although only among mouflon and fallow deer were the differences statistically significant.
Nonfoodborne Vibrio infections: an important cause of morbidity and mortality in the United States, 1997-2006.

BACKGROUND Infections due to Vibrio species cause an estimated 8000 illnesses annually, often through consumption of undercooked seafood. Like foodborne Vibrio infections, nonfoodborne Vibrio infections (NFVI) also result in serious illness, but awareness of these infections is limited. METHODS We analyzed illnesses occuring during the period 1997-2006 that were reported to the Centers for Disease Control and Prevention's Cholera and Other Vibrio Illness Surveillance system. The diagnosis of NFVI required isolation of Vibrio species from a patient with contact with seawater. RESULTS Of 4754 Vibrio infections reported, 1210 (25%) were NFVIs. Vibrio vulnificus infections were the most common (accounting for 35% of NFVIs), with 72% of V. vulnificus infections reported from residents of Gulf Coast states. Infections due to V. vulnificus resulted in fever (72% of cases), cellulitis (85%), amputation (10%), and death (17%). V. vulnificus caused 62 NFVI-associated deaths (78%). Recreational activities accounted for 70% of exposures for patients with NFVIs associated with all species. Patients with liver disease were significantly more likely to die as a result of infection (odds ratio, 7.8; 95% confidence interval, 2.8-21.9). Regardless of pre-existing conditions, patients were more likely to die when hospitalization occurred >2 days after symptom onset (odds ratio, 2.9; 95% confidence interval, 1.8-4.8). CONCLUSION NFVIs, especially those due to V. vulnificus, demonstrate high morbidity and mortality. Persons with liver disease should be advised of the risks associated with seawater exposure if a wound is already present or is likely to occur. Clinicians should consider Vibrio species as an etiologic agent in infections occurring in persons with recent seawater exposure, even if the individual was only exposed during recreational marine activities. Immediate antibiotic treatment with aggressive monitoring is advised in suspected cases.
Tetraacylated Lipid A and Paclitaxel-Selective Activation of TLR4/MD-2 Conferred through Hydrophobic Interactions

LPS exerts potent immunostimulatory effects through activation of the TLR4/MD-2 receptor complex. The hexaacylated lipid A is an agonist of mouse (mTLR4) and human TLR4/MD-2, whereas the tetraacylated lipid IVa and paclitaxel activate only mTLR4/MD-2 and antagonize activation of the human receptor complex. Hydrophobic mutants of TLR4 or MD-2 were used to investigate activation of human embryonic kidney 293 cells by different TLR4 agonists. We show that each of the hydrophobic residues F438 and F461, which are located on the convex face of leucine-rich repeats 16 and 17 of the mTLR4 ectodomain, are essential for activation of with lipid IVa and paclitaxel, which, although not a structural analog of LPS, activates cells expressing mTLR4/MD-2. Both TLR4 mutants were inactive when stimulated with lipid IVa or paclitaxel, but retained significant activation when stimulated with LPS or hexaacylated lipid A. We show that the phenylalanine residue at position 126 of mouse MD-2 is indispensable only for activation with paclitaxel. Its replacement with leucine or valine completely abolished activation with paclitaxel while preserving the responsiveness to lipid IVa and lipid A. This suggests specific interaction of paclitaxel with F126 because its replacement with leucine even augmented activation by lipid A. These results provide an insight into the molecular mechanism of TLR4 activation by two structurally very different agonists.
Markers of bone turnover in prostate cancer.

Prostate cancer is the most common malignancy in elderly men and is often associated with bone metastases. Although bone metastases are osteosclerotic, histological and biochemical studies clearly indicate an increase of both bone formation and bone resorption, providing the rational for using bisphosphonate as a palliative treatment in these patients. The recent development of specific and sensitive biochemical markers, reflecting the overall rate of bone formation and bone resorption, has improved the non-invasive assessment of bone turnover abnormalities in patients with prostate cancer. The immunoassays for bone-specific alkaline phosphatase and type I collagen propeptides are currently the most sensitive markers to assess bone, formation. The best indices of bone resorption are the immunoassay for the pyridinoline cross-links and the related peptides that can be measured in urine and more recently in serum. A better knowledge of the biochemistry, especially of the age-related post-translational modifications of type I collagen in the abnormal bone matrix, associated with bone metastases from prostate cancer may lead to markers of increased sensitivity. A recent example is the demonstration that the isomerization and racemization of the aspartic acid residue in C-telopeptides of type I collagen is impaired in patients with prostate cancer and bone metastases, a pattern than can be detected with specific conformational antibodies. The most sensitive markers of bone formation and bone resorption are markedly increased in patients with bone metastases compared with patients with cancer but without metastases, the levels correlating with the extent of the bone involvement. However, their sensitivity remains limited, suggesting that the currently available biochemical markers cannot be used as a surrogate for bone scintigraphy in the diagnosis of bone involvement. A few studies have suggested that the measurement of bone markers may be useful in the assessment of response to anti-endocrine therapy, although available data indicate a lower sensitivity than with prostates specific antigen. Additional longitudinal studies are required to assess the potential use of bone markers, especially to identify patients who relapse during the course of the treatment and, more specifically 3 those that result from the progression in bone metastases.Clearly, the established use of bone markers is for monitoring effects of bisphosphonate treatment. Several studies have shown a rapid decrease of bone resorption markers in patients with prostate cancer and bone metastases, the magnitude of the decrease correlating with the efficacy of the treatment in reducing bone pain. Thus, bone markers are likely to become a useful and objective tool to monitor bisphosphonate treatment and individual the therapy scheme.
Arrhythmogenic mechanisms of non‐sedating antihistamines

Antihistamines (H1‐receptor antagonists) are amongst the most frequently prescribed drugs worldwide for the treatment of allergic conditions. Recently, there have been reports that certain non‐sedating antihistamines, mainly terfenadine and astemizole, might be associated with the risk of rare but severe arrhythmias, namely torsades de pointes, particularly in overdosage, concomitant ingestion of imidazole or macrolide antibiotics and in patients with underlying cardiac or liver diseases. It has now been shown that the molecular target in human ventricle for the potassium channel blockade of antihistamine is HERG gene located in chromosome 7 that expresses the delayed rectifier IKr and appears to be involved in the congenital long QT syndrome. Mechanistic studies showed that blockade of IKr channels by these drugs leads to prolongation of the monophasic action potential (QT interval on surface electrocardiogram) which may then induce the development of early after‐depolarization and dispersion of repolarisation leading to torsades de pointes through re‐entry mechanism. There are still many questions that need to be answered such as the roles of other potassium channels (IKs, Ito, and Iped) and the relative expression of various potassium channels in different individuals which may be important in the pathogenesis of torsades de pointes with non‐sedating antihistamines. There is also a lack of information on the cardiac actions of newer non‐sedating antihistamines. It is hoped that with a better understanding of the arrhythmogenic mechanism of non‐sedating antihistamines, one will be able to identify those at risk patients and prevent any cardiac toxicity associated with antihistamines and ultimately death.
Infectious in vitro transcripts from cowpea chlorotic mottle virus cDNA clones and exchange of individual RNA components with brome mosaic virus

Complete cDNA copies of genomic RNA1, RNA2, and RNA3 of cowpea chlorotic mottle virus (CCMV) were cloned 1 base downstream from a T7 RNA polymerase promoter. The mixture of capped in vitro transcripts from all three clones produced normal CCMV infections in barley protoplasts and cowpea plants. By using transcripts from these clones and from a similar set of biologically active clones of the related brome mosaic virus (BMV), all possible single component exchanges between the BMV and CCMV tripartite genomes were tested. Viral RNA replication was not observed with any heterologous combination of RNA1 and RNA2, which encode trans-acting viral RNA replication factors. However, substitution of the heterologous RNA3 into either genome produced viable hybrid viruses, both of which replicated in barley protoplasts and produced lesions on Chenopodium hybridum, a local lesion host for both parent viruses. In hybrid infections, BMV and CCMV coat proteins each readily packaged RNAs from the heterologous virus, but BMV RNAs were replicated to a higher level than CCMV RNAs, even when trans-acting RNA replication factors were provided by CCMV genes. Neither hybrid systemically infected the natural host of either parent virus, suggesting that host specificity determinants in BMV and CCMV are encoded by RNA3 and at least one other genomic RNA.
Accessing the China A-Shares Market via Minimum-Variance Investing

As the China A-shares market is receiving more attention from international investors because of its expanding market size and improved access, means of accessing the market have become an important topic. The authors suggest the use of minimum variance investing as an alternative to the traditional market cap approach for accessing the China A-shares market. Their portfolio construction method takes into account the stock suspension features of the China A-shares market, and the simulated results show that China A-shares minimum variance investing is capable of achieving volatility reduction. The study also observes return enhancement from the minimum variance strategies for the 2007–2017 period. The authors compare minimum variance investing in different markets and find that the volatility reduction in the China A-shares market is lower compared with other major equity markets despite its superior historical return. This can be attributed to its smaller ex ante volatility reduction and forecastability of the ex post volatility. The authors investigate two methods of applying factor exposure control of the minimum variance portfolio. The results show that a value and quality factor overlay does not affect the volatility reduction capability and helps to enhance the return of the China A-shares minimum variance portfolio through the capture of factor risk premium.
Transplant Glomerulopathy: Subclinical Incidence and Association with Alloantibody

Transplant glomerulopathy (TG) usually has been described as part of a constellation of late chronic histologic abnormalities associated with proteinuria and declining function. The current study used both protocol and clinically‐indicated biopsies to investigate clinical and subclinical TG, their prognosis and possible association with alloantibody. We retrospectively studied 582 renal transplants with a negative pre‐transplant T‐cell complement dependent cytotoxicity crossmatch. TG was diagnosed in 55 patients, 27 (49%) based on protocol biopsy in well‐functioning grafts. The cumulative incidence of TG increased over time to 20% at 5 years. The prognosis of subclinical TG was equally as poor as TG diagnosed with graft dysfunction, with progressive worsening of histopathologic changes and function. Although TG was associated with both acute and chronic histologic abnormalities, 14.5% of TG biopsies showed no interstitial fibrosis or tubular atrophy, while 58% (7/12) of biopsies with severe TG showed only minimal abnormalities. TG was associated with acute rejection, pretransplant hepatitis C antibody positivity and anti‐HLA antibodies (especially anti‐Class II), with the risk increasing if the antibodies were donor specific. We suggest that subclinical TG is an under‐recognized cause of antibody‐mediated, chronic renal allograft injury which may be mechanistically distinct from other causes of nephropathy.