Miracle-dz/UniFAR-FTUs huggingface dataset:
Amide Hydrogen Exchange Reveals Conformational Changes in Hsp70 Chaperones Important for Allosteric Regulation*

Hsp70 chaperones assist protein folding processes by a nucleotide-driven cycle of substrate binding and release. Although structural information is available for the isolated nucleotide-binding (NBD) and substrate-binding domains (SBD) in the high affinity conformation, the low affinity conformations and the conformational changes associated with mutual allosteric regulation remained largely enigmatic. By using amide hydrogen exchange in combination with mass spectrometry, we analyzed the Escherichia coli Hsp70 homologue DnaK as full-length protein and its individual domains in the nucleotide-free and ATP-bound conformation. We found a surprising degree of flexibility in both domains. The comparison of the full-length protein with the isolated domains demonstrates a mutual stabilization of both domains. This protection from solvent was most pronounced and in addition was nucleotide-dependent in the lowerβ-sheet of the SBD and the loop that connects the last β-strand with helix αA. Interestingly, the linker region, which connects NBD and SBD and which is close to the protected loop in the SBD, is solvent-exposed in the absence of nucleotide and completely protected from hydrogen exchange in the presence of ATP. Peptide binding to DnaK·ATP reverts the ATP-induced conformational changes in the linker and selected parts of the NBD. Our data outline a pathway for allosteric interdomain control and suggest an important role of the linker and the base of helix αA.
Predictive Control Based on Recurrent Neural Network and Application to Plastic Injection Molding Processes

This paper presents a predictive control based on recurrent neural network (RNN) for a class of nonlinear systems and investigates its application to temperature control of plastic injection molding processes. The RNN is used as a model identifier for approximating the nonlinear discrete-time systems and the multivariable predictive control based on the RNN is derived from a generalized predictive performance criterion. The adaptive learning rates of the RNN model and the controller are investigated via the discrete Lyapunov stability theorem, which are respectively used to guarantee the convergences of both the RNN model and the predictive controller. Finally, numerical simulations and experimental results are provided to demonstrate the effectiveness of the proposed control strategy under setpoint changes and bounded disturbances.
Successful Treatment of All-Trans Retinoic Acid Resistant and Chemotherapy Naive Acute Promyelocytic Patients with Arsenic Trioxid-e - Two Case Reports

Arsenic trioxide(As2O3) has proved highly effective in treating both refractory or primary cases of acute promyelocytic leukemia (APL). The role of arsenic trioxide in APL treatment has been confirmed by study groups in China and in the USA. However, what is the role of As2O3 in treating APL? Should it be used as first line therapy, or should it be used as a second line drug. This still remains to be defined. Here, we report two cases of APL, who were treated successfully with As2O3 when they relapsed. Initially, both received all-trans retinoic acid (ATRA) for primary remission induction therapy, and obtained a complete remission. For ethical or personal reasons, they did not receive chemotherapy as consolidation therapy and when they relapsed at 23 months and 12 months later respectively, they both received As2O3 therapy after being resistant to ATRA treatment. Two courses of As2O3 were given and both reached complete remission. There were very few adverse reactions to the drug, only mild abdominal cramps, mild fluid retention, and transient elevation of transarninases. They both had rather good quality of life throughout the treatment and both remain in remission for 32 months and 10 months since therapy, respectively.
Spatial analysis of the participation in agri-environment measures for organic farming

Abstract Support for organic farming is a key strategy of rural development policies in several countries. This paper studied the spatial pattern of participation in agro-environmnetal policy the policies designing to foster diffusion of organic farming. The ultimate goal is to investigate the impact of local factors for improving the policy targeting. Indicators of spatial association and a spatial econometrics model were performed for the analysis. The results show regional agglomeration effects of the rate of participants to the measures adopted to promote organic farming. In addition, a spatial relation among the farms that obtain public support is found, highlighting that the diffusion of participation is driven mainly by imitation process and external economies of scale.
Zygomatic bone shape in intentional cranial deformations: a model for the study of the interactions between skull growth and facial morphology

Intentional cranial deformations (ICD) were obtained by exerting external mechanical constraints on the skull vault during the first years of life to permanently modify head shape. The repercussions of ICD on the face are not well described in the midfacial region. Here we assessed the shape of the zygomatic bone in different types of ICDs. We considered 14 non‐deformed skulls, 19 skulls with antero‐posterior deformation, nine skulls with circumferential deformation and seven skulls with Toulouse deformation. The shape of the zygomatic bone was assessed using a statistical shape model after mesh registration. Euclidian distances between mean models and Mahalanobis distances after canonical variate analysis were computed. Classification accuracy was computed using a cross‐validation approach. Different ICDs cause specific zygomatic shape modifications corresponding to different degrees of retrusion but the shape of the zygomatic bone alone is not a sufficient parameter for classifying populations into ICD groups defined by deformation types. We illustrate the fact that external mechanical constraints on the skull vault influence midfacial growth. ICDs are a model for the study of the influence of epigenetic factors on craniofacial growth and can help to understand the facial effects of congenital skull malformations such as single or multi‐suture synostoses, or of external orthopedic devices such as helmets used to correct deformational plagiocephaly.
The Biology and Control of Leishmaniasis Vectors

Vector control remains a key component of many anti-leishmaniasis programs and probably will remain so until an effective vaccine becomes available. Technologies similar to those used for control of adult mosquitoes, specifically interior residual sprays and insecticide-treated nets, are currently at the forefront as disease control measures. This article provides a review of literature on the biology and control of sand fly vectors of leishmaniasis in the context of changing disease risks and the realities of modern vector control. The Literature Retrieval System of the Armed Forces Pest Management Board, Washington, DC, was the primary search engine used to review the literature.
Patterns of personality disorder comorbidity in early-onset versus late-onset major depression.

OBJECTIVE This study tested the hypothesis that in a population of adult outpatients with major depression, those with an early onset of depression would have a greater prevalence of personality disorders than those with a late onset of depression. METHOD The 404 subjects were patients participating in depression treatment studies at the Massachusetts General Hospital. They were administered the Structured Clinical Interview for DSM-III-R-Patient Version to assess the current presence of major depression and the age at onset of the initial depressive episode. The subjects were then divided into two groups: those with early onset (before 18 years of age) and those with late onset (at age 18 or later). The prevalence of personality disorders was determined through use of the physician-rated Structured Clinical Interview for DSM-III-R Personality Disorders (SCID-II) and the patient-rated Personality Diagnostic Questionnaire-Revised (PDQ-R). RESULTS The patients with early onset of major depression had a significantly higher prevalence of avoidant, histrionic, narcissistic, and borderline personality disorders according to the SCID-II. The PDQ-R scores indicated that avoidant, dependent, passive-aggressive, histrionic, narcissistic, borderline, and antisocial personality disorders were significantly more prevalent among the patients with early onset of major depression. CONCLUSIONS Overall, the results are consistent with the view that early-onset depressive illness is distinguished from late-onset major depression by more frequent association with persistent disturbances in behaviors and attitudes.
Importance of Cerebral Blood Flow to the Recognition of and Physiological Responses to Hypoglycemia

During hypoglycemia, cerebral blood flow (CBF) does not increase significantly until peripheral glucose levels are very low (2.0 nmol/l), that is, well below the blood glucose threshold for impairment of cognitive function (3.0 nmol/l). Because increased rates of cerebral blood flow will increase glucose transport, a failure of flow to rise earlier, before brain function is threatened, might be considered maladaptive. To examine the influence of inducing an earlier rise in CBF during hypoglycemia, eight healthy volunteers participated in three studies using a randomized, placebo-controlled design. In all three studies, a hyperinsulinemic (60 mU · m2 · min−1) clamp was used to maintain blood glucose levels at 4.5 nmol/l for 60 min. Thereafter, for EUGACZ, blood glucose was maintained at 4.5 nmol/l from 60 to 170 min and at 90 min from the start of this study, and 1-g acetazolamide i.v. was given to induce an early rise in CBF; for HYPO-ACZ, glucose was lowered over 20 min to 2.8 mmol/l and kept at that level for 90 min, and acetazolamide was given 90 min from the start of this study; and for HYPO-CON, glucose was treated as in HYPO-ACZ, and matching placebo was given in place of acetazolamide. Injection of acetazolamide was associated with a 30% rise in right (95% CI24–34%) and left (20–32%) middle cerebral artery velocity (an index of CBF) during euglycemia without any change in hypoglycemia awareness or counterregulatory hormone levels. When glucose was lowered to 2.8 nmol/l, acetazolamide caused a similar rise in middle cerebral artery velocity in the HYPO-ACZ study. However, all subjects were less “aware” of hypoglycemia, had fewer adrenergic symptoms (sweating, palpitations, tremors; all P < 0.05), and had lower plasma epinephrine levels (1,026 vs. 1,790 pmol/l; –764 [437 to 1,097] pmol/l, point estimate of difference [95% CI]; P < 0.001), compared with the HYPO-CON study, whereas levels of other counterregulatory hormones and norepinephrine were similar. Cognitive function (latency of the P300 evoked response) was unaffected by increasing CBF. In conclusion, enhanced rates of cerebral blood flow at the onset of systemic hypoglycemia are associated with diminished perception of low blood glucose levels and attenuation of the epinephrine counterregulatory response. These findings suggest that augmenting cerebral blood flow leads to an enhanced rate of substrate delivery to the central nervous system.
Detection and identification of Toscana and other phleboviruses by RT‐nested‐PCR assays with degenerated primers

Phleboviruses are a large and widespread group of viruses that are transmitted by arthropods. Toscana virus is one of the principal agents that causes meningitis in humans during the summer in Italy and, possibly, in other Mediterranean countries. Rift Valley Fever virus can cause serious illness in both animals and humans, leading to high morbidity and mortality, and is considered to be a potential agent for epizootics and human epidemics. Since information on this group of viruses is still scant, reliable laboratory tools for diagnosis and epidemiological surveillance must be developed, in order to ascertain their real impact on Public Health. Sequence data obtained from Spanish isolates of Toscana virus and other phleboviruses confirmed that natural genome variability may hamper the diagnosis of these agents by molecular methods, so this must be borne in mind when developing reliable assays. In view of the above, a novel and useful protocol has been developed for the detection and specific identification of every member of the phlebovirus genus present in a sample, including Toscana virus, based on a generic RT‐nested‐PCR, followed by sequencing of the amplified fragment. A change in this method also allowed specific direct detection and identification of wild isolates of Toscana virus of different geographical origin, using newly designed primers. Testing clinical samples with these assays confirmed the role of Toscana virus as an agent that causes acute aseptic meningitis in the central region of Spain. J. Med. Virol. 71:140–149, 2003. © 2003 Wiley‐Liss, Inc.
Characterization of Prenylcysteines That Interact with P-glycoprotein and Inhibit Drug Transport in Tumor Cells (*)

Prenylcysteine methyl esters that represent the C-terminal structures of prenylated proteins demonstrate specific substrate-like interactions with P-glycoprotein (Zhang, L., Sachs, C. W., Fine, R. L., and Casey, P. J.(1994) J. Biol. Chem. 269, 15973-15976). The simplicity of these compounds provides a unique system for probing the structural specificity of P-glycoprotein substrates. We have further assessed the structural elements of prenylcysteines involved in the interaction with P-glycoprotein. Carboxyl group methylation, a modification in many prenylated proteins, plays an essential role of blocking the negative charge at the free carboxylate. Substitution of the methyl ester with a methyl amide or simple amide does not change the ability of the molecule to stimulate P-glycoprotein ATPase activity, but substitution with a glycine is not tolerated unless the carboxyl group of glycine is methylated. The presence of a nitrogen atom, which is found in many P-glycoprotein substrates and modifiers, is also essential for prenylcysteines to interact with P-glycoprotein. The structure at the nitrogen atom can, however, influence the type of interaction. Acetylation of the free amino group of prenylcysteine results in a significant loss in the ability of prenylcysteines to stimulate P-glycoprotein ATPase activity. Instead, certain acetylated prenylcysteines behave as inhibitors of this activity. In studies using MDR1-transfected human breast cancer cells, the acetylated prenylcysteine analogs inhibit P-glycoprotein-mediated drug transport and enhance the steady-state accumulation of [H]vinblastine, [H]colchicine, and [H]taxol. These inhibitors do not, however, affect drug accumulation in parental cells. These studies provide a novel approach for designing P-glycoprotein inhibitors that could prove effective in reversing the phenotype of multidrug resistance in tumor cells.
Larvicidal and oviposition-altering activity of monoterpenoids, trans-anithole and rosemary oil to the yellow fever mosquito Aedes aegypti (Diptera: Culicidae).

BACKGROUND Aedes aegypti L. is the major vector of dengue fever and dengue hemorrhagic fever. In an effort to find effective tools for control programs to reduce mosquito populations, the authors assessed the acute toxicities of 14 monoterpenoids, trans-anithole and the essential oil of rosemary against different larval stages of Ae. aegypti. The potential for piperonyl butoxide (PBO) to act as a synergist for these compounds to increase larvicidal activity was also examined, and the oviposition response of gravid Ae. aegypti females to substrates containing these compounds was evaluated in behavioral bioassays. RESULTS Pulegone, thymol, eugenol, trans-anithole, rosemary oil and citronellal showed high larvicidal activity against all larval stages of Ae. aegypti (LC(50) values 10.3-40.8 mg L(-1)). The addition of PBO significantly increased the larvicidal activity of all test compounds (3-250-fold). Eugenol, citronellal, thymol, pulegone, rosemary oil and cymene showed oviposition deterrent and/or repellent activities, while the presence of borneol, camphor and beta-pinene increased the number of eggs laid in test containers. CONCLUSIONS This study quantified the lethal and sublethal effects of several phytochemical compounds against all larval stages of Aedes aegypti, providing information that ultimately may have potential in mosquito control programs through acute toxicity and/or the ability to alter reproductive behaviors.
Active suppression of low-frequency disturbances on AC side of traction active current-source rectifier

This paper deals with traction active current-source rectifier (ACSR) developed within the research into a new generation of main traction converters employing medium-frequency transformer dedicated for suburban units operating on both ac electrification systems of 25kV/50 Hz and 15kV/16⅔ Hz. The new control strategy able to operate under distorted trolley-wire voltage and actively suppress (i) low-frequency disturbances in trolley-wire current caused by distorted trolley-wire voltage, and (ii) input LC filter oscillations is presented. Proper function of proposed control strategy has been verified by simulations and large experimental study made on designed small-scale prototype of ACSR of rated power of 7kVA.
Elderly suicide rates: cross-national comparisons and association with sex and elderly age-bands

Suicide rates generally increase with age. Examination of cross-national variations in elderly suicide rates may allow the generation of aetiological hypotheses. Suicide rates for males and females in the age-bands 65-74 years and 75+ years were ascertained from the World Health Organisation website for all the listed countries. Cross-national variations were examined by segregating different countries into four quartiles of elderly suicide rates. Suicide rates between males and females and between the two age-bands were compared across different countries. The main findings were: (i) there is wide cross-national variation in elderly suicide rates; (ii) elderly suicide rates were the lowest in Caribbean, central American and Arabic countries, and the highest in central and eastern European, some oriental and some west European countries; (iii) suicide rates were higher in men compared to women for both the age-bands; and, (iv) suicide rates were higher in the age-band 75+ years compared to the age-band 65-74 years for males and females. Potential explanations for regional and cross-national variations in elderly suicide rates include cross-national differences in genetic and environmental factors, prevalence of mental illness in the elderly, life expectancy, socio-economic deprivation, social fragmentation, cultural factors, the availability of appropriate healthcare services, and public health initiatives to improve the detection and treatment of mental illness, mental health and suicide prevention.
The Novel α7β2-Nicotinic Acetylcholine Receptor Subtype Is Expressed in Mouse and Human Basal Forebrain: Biochemical and Pharmacological Characterization

We examined α7β2-nicotinic acetylcholine receptor (α7β2-nAChR) expression in mammalian brain and compared pharmacological profiles of homomeric α7-nAChRs and α7β2-nAChRs. α-Bungarotoxin affinity purification or immunoprecipitation with anti-α7 subunit antibodies (Abs) was used to isolate nAChRs containing α7 subunits from mouse or human brain samples. α7β2-nAChRs were detected in forebrain, but not other tested regions, from both species, based on Western blot analysis of isolates using β2 subunit–specific Abs. Ab specificity was confirmed in control studies using subunit-null mutant mice or cell lines heterologously expressing specific human nAChR subtypes and subunits. Functional expression in Xenopus oocytes of concatenated pentameric (α7)5-, (α7)4(β2)1-, and (α7)3(β2)2-nAChRs was confirmed using two-electrode voltage clamp recording of responses to nicotinic ligands. Importantly, pharmacological profiles were indistinguishable for concatenated (α7)5-nAChRs or for homomeric α7-nAChRs constituted from unlinked α7 subunits. Pharmacological profiles were similar for (α7)5-, (α7)4(β2)1-, and (α7)3(β2)2-nAChRs except for diminished efficacy of nicotine (normalized to acetylcholine efficacy) at α7β2- versus α7-nAChRs. This study represents the first direct confirmation of α7β2-nAChR expression in human and mouse forebrain, supporting previous mouse studies that suggested relevance of α7β2-nAChRs in Alzheimer disease etiopathogenesis. These data also indicate that α7β2-nAChR subunit isoforms with different α7/β2 subunit ratios have similar pharmacological profiles to each other and to α7 homopentameric nAChRs. This supports the hypothesis that α7β2-nAChR agonist activation predominantly or entirely reflects binding to α7/α7 subunit interface sites.
Identification of a Ribavirin‐resistant NS5B mutation of hepatitis C virus during ribavirin monotherapy

Ribavirin (RBV), a guanosine analogue, has been suggested to exert an antiviral action against hepatitis C virus (HCV) by causing lethal mutations and suppressing RNA polymerase in vitro, but the mechanism of its clinical therapeutic effects is currently unknown. To test the hypothesis that RBV could act both as an RNA mutagen and inhibit viral RNA synthesis in vivo, we studied the evolution of the nucleotide sequences of HCV RNA at the nonstructural (NS) 5B region in patients receiving RBV, placebo, or interferon alfa (IFN‐α) monotherapy. The RBV group showed a slightly more accelerated evolution rate of HCV RNA quasispecies than either the IFN‐α or placebo group. RBV caused preferentially A‐to‐G and U‐to‐A mutations. Interestingly, an NS5B amino acid 415 Phe‐to‐Tyr (F415Y) mutation emerged in all (5 of 5) patients infected with HCV genotype 1a during the RBV treatment. Subsequently, the parental 415F strain reemerged in some patients after the treatment was discontinued. The effect of the amino acid substitution at NS5B415 on HCV RNA replication was then investigated using an HCV subgenomic replicon in Huh7 cells. We showed that treatment of replicon cells with RBV reduced the HCV RNA level of NS5B415F replicon, but not NS5B415Y, in a dose‐dependent manner. Thus, NS5B F415Y mutation represents an RBV‐resistant variant. The 3‐dimensional modeling and structure analysis of NS5B protein revealed that the 415th amino acid is located at the P helix region of the thumb subdomain, which may interact with the minor groove of the template‐primer duplex in the putative RNA‐binding cleft. In conclusion, RBV could work as a weak mutagen for HCV RNA in HCV‐infected patients. Furthermore, the selection of an RBV‐resistant variant with a single amino acid substitution in NS5B suggested that RBV may directly interact with HCV RNA polymerase, thus interfering with its enzymatic activity. (Hepatology 2003;38:869–878).
A novel locus for autosomal dominant hereditary gingival fibromatosis, GINGF3, maps to chromosome 2p22.3‐p23.3

Hereditary gingival fibromatosis (HGF) is a rare, benign disorder characterized by slowly progressive fibrous overgrowth of the gingiva. To date, two loci have been mapped in familial cases with autosomal dominant non‐syndromic HGF: GINGF (MIM 135300) on chromosome 2p21‐p22 and GINGF2 (MIM 605544) on chromosome 5q13‐q22. Of the two loci, only SOS1 (son of sevenless one, MIM 182530) gene underlying GINGF locus has been identified. Ascertainment of a large Chinese family has allowed the mapping of a novel locus to 2p22.3‐p23.3, GINGF3. Haplotype construction and analysis localized the new locus to an 11.4‐cM interval between markers D2S2221 (telomeric) and D2S1788 (centromeric). The maximum two‐point limit of detection (LOD) score of 3.45 (θ = 0) and multipoint LOD score of 5.00 for marker D2S390 strongly supported linkage to this region. Thus, this genetic interval is distal to and does not overlap with the previously described locus, GINGF, on 2p21‐p22.