Miracle-dz/UniFAR-FTUs huggingface dataset:
Anti-MDA5 antibody, ferritin and IL-18 are useful for the evaluation of response to treatment in interstitial lung disease with anti-MDA5 antibody-positive dermatomyositis.

OBJECTIVE The aim of this study was to investigate the precise clinical characteristics and to analyse the association between the anti-MDA5 antibody (anti-MDA5ab) titre and disease status in patients with anti-MDA5ab-positive DM. METHODS Twenty-seven patients who presented with DM and were positive for the anti-MDA5ab were enrolled. The association between the clinical manifestations and the clinical parameters, including the anti-MDA5ab, was analysed. RESULTS The complication of rapidly progressive interstitial lung disease (RP-ILD) occurred in 20 (74%) patients. The frequencies of fatal outcome, relapse and malignancy were 33, 4 and 4%, respectively. Remarkably, a fatal outcome occurred within the first 6 months. Compared with six non-RP-ILD patients, elderly age at onset, severely involved pulmonary function and high levels of serum ferritin were present in 20 RP-ILD patients with anti-MDA5ab. Alveolar-arterial oxygen difference (AaDO(2)) ≥32 mmHg and ferritin ≥828 ng/ml at admission were poor prognostic factors in RP-ILD patients with anti-MDA5ab-positive DM. The median value of the anti-MDA5ab titre on admission was higher in patients who later died than in those who survived. The efficacy of treatment was indicated by the anti-MDA5ab, ferritin and IL-18 concentrations. The decline index of the anti-MDA5ab titre after treatment was lower in the subset of patients who died than in the subset of patients who lived. Sustained high levels of anti-MDA5ab, ferritin and IL-18 were present in the patients who died. CONCLUSION Anti-MDA5ab titre and ferritin and IL-18 concentrations are useful for the evaluation of the response to treatment and the status of ILD in patients with anti-MAD5ab-positive DM.
Metastatic Eccrine Porocarcinoma Respond to Combination Chemotherapy Docetaxel, Cisplatin and Infusion 5 FU with Long Disease Control

Introduction : Eccrine porocarcinoma (EPC) is a rare tumor. It develops from the intraepidermal ductal portion of the eccrine sweat gland. Many chemotherapeutic agents were reported to have efficacy in treatment of metastatic EPC; two of very effective agents were docetaxel and 5FU. Case Presentation : We are reporting a case of 60 years old female who was diagnosed as metastatic eccrine porocarcinoma to mediastinum which was treated by systemic chemotherapy in the form of DCF: docetaxel 75 mg/m2 D1, cisplatin 75 mg/m2 D1 and continues infusion 5FU 750 mg/m2 from D1 to D4, and this regimen was repeated every 28 days for 6 cycles. Conclusion : DCF regimen can be one of the best options for stage IV EPC with long overall survival and best response rate.
Noxa/Bcl-2 Protein Interactions Contribute to Bortezomib Resistance in Human Lymphoid Cells*

Previous studies have suggested that the BH3 domain of the proapoptotic Bcl-2 family member Noxa only interacts with the anti-apoptotic proteins Mcl-1 and A1 but not Bcl-2. In view of the similarity of the BH3 binding domains of these anti-apoptotic proteins as well as recent evidence that studies of isolated BH3 domains can potentially underestimate the binding between full-length Bcl-2 family members, we examined the interaction of full-length human Noxa with anti-apoptotic human Bcl-2 family members. Surface plasmon resonance using bacterially expressed proteins demonstrated that Noxa binds with mean dissociation constants (KD) of 3.4 nm for Mcl-1, 70 nm for Bcl-xL, and 250 nm for wild type human Bcl-2, demonstrating selectivity but not absolute specificity of Noxa for Mcl-1. Further analysis showed that the Noxa/Bcl-2 interaction reflected binding between the Noxa BH3 domain and the Bcl-2 BH3 binding groove. Analysis of proteins expressed in vivo demonstrated that Noxa and Bcl-2 can be pulled down together from a variety of cells. Moreover, when compared with wild type Bcl-2, certain lymphoma-derived Bcl-2 mutants bound Noxa up to 20-fold more tightly in vitro, pulled down more Noxa from cells, and protected cells against killing by transfected Noxa to a greater extent. When killing by bortezomib (an agent whose cytotoxicity in Jurkat T-cell leukemia cells is dependent on Noxa) was examined, apoptosis was enhanced by the Bcl-2/Bcl-xL antagonist ABT-737 or by Bcl-2 down-regulation and diminished by Bcl-2 overexpression. Collectively, these observations not only establish the ability of Noxa and Bcl-2 to interact but also identify Bcl-2 overexpression as a potential mechanism of bortezomib resistance.
Exploiting Cross-reactivity to Neutralize Two Different Scorpion Venoms with One Single Chain Antibody Fragment*

We report the optimization of a family of human single chain antibody fragments (scFv) for neutralizing two scorpion venoms. The parental scFv 3F recognizes the main toxins of Centruroides noxius Hoffmann (Cn2) and Centruroides suffusus suffusus (Css2), albeit with low affinity. This scFv was subjected to independent processes of directed evolution to improve its recognition toward Cn2 (Riaño-Umbarila, L., Juárez-González, V. R., Olamendi-Portugal, T., Ortíz-León, M., Possani, L. D., and Becerril, B. (2005) FEBS J. 272, 2591–2601) and Css2 (this work). Each evolved variant showed strong cross-reactivity against several toxins, and was capable of neutralizing Cn2 and Css2. Furthermore, each variant neutralized the whole venoms of the above species. As far as we know, this is the first report of antibodies with such characteristics. Maturation processes revealed key residue changes to attain expression, stability, and affinity improvements as compared with the parental scFv. Combination of these changes resulted in the scFv LR, which is capable of rescuing mice from severe envenomation by 3 LD50 of freshly prepared whole venom of C. noxius (7.5 μg/20 g of mouse) and C. suffusus (26.25 μg/20 g of mouse), with surviving rates between 90 and 100%. Our research is leading to the formulation of an antivenom consisting of a discrete number of human scFvs endowed with strong cross-reactivity and low immunogenicity.
Loop L5 Acts as a Conformational Latch in the Mitotic Kinesin Eg5*

All members of the kinesin superfamily of molecular motors contain an unusual structural motif consisting of an α-helix that is interrupted by a flexible loop, referred to as L5. We have examined the function of L5 in the mitotic kinesin Eg5 by combining site-directed mutagenesis of L5 with transient state kinetics, molecular dynamics simulations, and docking using cryo electron microscopy density. We find that mutation of a proline residue located at a turn within this loop profoundly slows nucleotide-induced structural changes both at the catalytic site as well as at the microtubule binding domain and the neck linker. Molecular dynamics simulations reveal that this mutation affects the dynamics not only of L5 itself but also of the switch I structural elements that sense ATP binding to the catalytic site. Our results lead us to propose that L5 regulates the rate of conformational change in key elements of the nucleotide binding site through its interactions with α3 and in so doing controls the speed of movement and force generation in kinesin motors.
The Yb Body, a Major Site for Piwi-associated RNA Biogenesis and a Gateway for Piwi Expression and Transport to the Nucleus in Somatic Cells*

Despite exciting progress in understanding the Piwi-interacting RNA (piRNA) pathway in the germ line, less is known about this pathway in somatic cells. We showed previously that Piwi, a key component of the piRNA pathway in Drosophila, is regulated in somatic cells by Yb, a novel protein containing an RNA helicase-like motif and a Tudor-like domain. Yb is specifically expressed in gonadal somatic cells and regulates piwi in somatic niche cells to control germ line and somatic stem cell self-renewal. However, the molecular basis of the regulation remains elusive. Here, we report that Yb recruits Armitage (Armi), a putative RNA helicase involved in the piRNA pathway, to the Yb body, a cytoplasmic sphere to which Yb is exclusively localized. Moreover, co-immunoprecipitation experiments show that Yb forms a complex with Armi. In Yb mutants, Armi is dispersed throughout the cytoplasm, and Piwi fails to enter the nucleus and is rarely detectable in the cytoplasm. Furthermore, somatic piRNAs are drastically diminished, and soma-expressing transposons are desilenced. These observations indicate a crucial role of Yb and the Yb body in piRNA biogenesis, possibly by regulating the activity of Armi that controls the entry of Piwi into the nucleus for its function. Finally, we discovered putative endo-siRNAs in the flamenco locus and the Yb dependence of their expression. These observations further implicate a role for Yb in transposon silencing via both the piRNA and endo-siRNA pathways.
Protein-Protein Interactions in Assembly of Lipoic Acid on the 2-Oxoacid Dehydrogenases of Aerobic Metabolism*

Lipoic acid is a covalently attached cofactor essential for the activity of 2-oxoacid dehydrogenases and the glycine cleavage system. In the absence of lipoic acid modification, the dehydrogenases are inactive, and aerobic metabolism is blocked. In Escherichia coli, two pathways for the attachment of lipoic acid exist, a de novo biosynthetic pathway dependent on the activities of the LipB and LipA proteins and a lipoic acid scavenging pathway catalyzed by the LplA protein. LipB is responsible for octanoylation of the E2 components of 2-oxoacid dehydrogenases to provide the substrates of LipA, an S-adenosyl-l-methionine radical enzyme that inserts two sulfur atoms into the octanoyl moiety to give the active lipoylated dehydrogenase complexes. We report that the intact pyruvate and 2-oxoglutarate dehydrogenase complexes specifically copurify with both LipB and LipA. Proteomic, genetic, and dehydrogenase activity data indicate that all of the 2-oxoacid dehydrogenase components are present. In contrast, LplA, the lipoate protein ligase enzyme of lipoate salvage, shows no interaction with the 2-oxoacid dehydrogenases. The interaction is specific to the dehydrogenases in that the third lipoic acid-requiring enzyme of Escherichia coli, the glycine cleavage system H protein, does not copurify with either LipA or LipB. Studies of LipB interaction with engineered variants of the E2 subunit of 2-oxoglutarate dehydrogenase indicate that binding sites for LipB reside both in the lipoyl domain and catalytic core sequences. We also report that LipB forms a very tight, albeit noncovalent, complex with acyl carrier protein. These results indicate that lipoic acid is not only assembled on the dehydrogenase lipoyl domains but that the enzymes that catalyze the assembly are also present “on site. ”
Shift work and cancer screening: do females who work alternative shifts undergo recommended cancer screening?

BACKGROUND Alternative shift work is classified as a probable human carcinogen. Certain cancer screening tests reduce cancer mortality. METHODS The 2010 National Health Interview Survey was used to examine associations between adherence to breast, cervical, and colon cancer screening recommendations and alternative shift work among female workers. RESULTS Workers on alternative shifts, compared to workers on daytime shifts, were more likely to be non-adherent to screening recommendations for breast (34% vs. 23%) and colorectal (55% vs. 48%) cancer (P < 0.05). Workers on alternative shifts in two industries ("Manufacturing" and "Accommodation/Food Services") and three occupations ("Food Preparation/Serving," "Personal Care Services," and "Production") were more likely to be non-adherent to screening recommendations for at least two cancers (P < 0.05). CONCLUSIONS The Affordable Care Act eliminates out-of-pocket screening expenses for these three cancers. Greater efforts are needed to promote this benefit, particularly among workers with demonstrated non-adherence. Am. J. Ind. Med. 57:265-275, 2014. Published 2013. This article is a U.S. Government work and is in the public domain in the USA.
Using injury severity to improve occupational injury trend estimates.

BACKGROUND Hospitalization-based estimates of trends in injury incidence are also affected by trends in health care practices and payer coverage that may differentially impact minor injuries. This study assessed whether implementing a severity threshold would improve occupational injury surveillance. METHODS Hospital discharge data from four states and a national survey were used to identify traumatic injuries (1998-2009). Negative binomial regression was used to model injury trends with/without severity restriction, and to test trend divergence by severity. RESULTS Trend estimates were generally biased downward in the absence of severity restriction, more so for occupational than non-occupational injuries. Restriction to severe injuries provided a markedly different overall picture of trends. CONCLUSIONS Severity restriction may improve occupational injury trend estimates by reducing temporal biases such as increasingly restrictive hospital admission practices, constricting workers' compensation coverage, and decreasing identification/reporting of minor work-related injuries. Injury severity measures should be developed for occupational injury surveillance systems.
Genome‐wide analysis of genes related to ovary activation in worker honey bees

A defining characteristic of eusocial animals is their division of labour into reproductive and nonreproductive specialists. Here, we used a microarray study to identify genes associated with functional sterility in the worker honey bee Apis mellifera. We contrasted gene expression in workers from a functionally sterile wild‐type strain with that in a mutant (anarchist) strain selected for high rates of ovary activation. We identified a small set of genes from the brain (n = 7) and from the abdomen (n = 5) that are correlated in their expression with early stages of ovary activation. Sterile wild‐type workers up‐regulated two unknown genes and a homologue of Drosophila CG6004. By contrast, reproductive anarchist workers up‐regulated genes for the yolk protein vitellogenin, venom peptides and a member of the AdoHycase superfamily, among others. The differentially expressed genes identified are likely to be involved in early differentiation into sterile and reproductive worker phenotypes and may therefore form part of the gene networks associated with the regulation of honey bee worker sterility. Our study may have lacked sufficient power to detect all but a minority of biologically relevant changes taking place; however, the differential expression of vitellogenin and a putative AdoHycase suggests that our screen has captured core reproductive genes and that ovary activation may involve an epigenetic mechanism.
Genomic structure and promoter analysis of pathogen‐induced repat genes from Spodoptera exigua

The repat gene family encodes midgut proteins overexpressed in response to pathogen infection in the lepidopteran Spodoptera exigua. Up‐regulation of repat genes has been observed after challenging the larvae with both Bacillus thuringiensis toxins and after infection with the baculovirus Autographa californica multiple nucleopolyhedrovirus. In our study, PCR amplification of the genomic region and genome walking were used to obtain the genomic structure and the sequence of the 5′‐upstream region of repat1 and repat2, two of the most phylogenetically distant members of the repat family. A similar gene structure between repat1 and repat2 has been found, with conserved exon‐intron positions and junction sequences, suggesting a common origin for these genes. Recombinant baculoviruses carrying the firefly luciferase gene under the control of different 5′‐upstream regions of the repat1 gene were constructed to elucidate the influence of these regions in gene expression. Infection of Helicoverpa zea gut‐derived cells with the recombinant baculoviruses revealed the upstream regions of the repat1 gene which are involved in gene transcription and demonstrated the role of an intron located in the 5′‐untranslated region in the enhancement of gene expression.
Septic injury‐inducible genes in medicinal maggots of the green blow fly Lucilia sericata

Lucilia sericata maggots are used world‐wide in biosurgery for the medical treatment of nonhealing wounds because they ingest necrotic tissues and significantly promote healing. To gain further insight into interdependencies between ecological adaptation and molecular evolution of innate immunity in Diptera, we used the suppression subtractive hybridization method to screen for genes that are differentially expressed in response to septic wounding of sterile second instar larvae of L. sericata. This approach resulted in the identification of 65 novel Lucilia genes including potential signalling proteins (e.g. inhibitor of apoptosis 2 protein) and a number of digestive enzymes including lipases and proteinases. Additionally, we found numerous putative antimicrobial peptides (AMPs), such as a potential Lucilia defensin, diptericin and three novel proline‐rich AMPs. The identified genes may facilitate access to both peptides and proteins within the beneficial excretions, secretions and haemolymph of medicinal maggots and provide novel insights into the evolution of innate immunity in Diptera.
Molecular characterization and expression of three heat shock protein70 genes from the carmine spider mite, Tetranychus cinnabarinus (Boisduval)

Three heat shock protein 70 (Hsp70) cDNAs were isolated from the carmine spider mite, Tetranychus cinnabarinus. They were tentatively named as TCHsp70‐1, TCHsp70‐2 and TCHsp70‐3. Structural analyses showed that all of the three TCHsp70 cDNAs held the full open reading frame (ORF). Putative protein sequences and a phylogenetic tree suggested that TCHsp70‐1 and TCHsp70‐3 were cytoplasm HSP70 and TCHsp70‐2 was endoplasmic reticulum HSP70. Comparison of deduced amino acid sequences of TCHsp70‐1 and TCHsp70‐3 showed 84.78% identity, TCHsp70‐1 and TCHsp70‐2 showed 57.33% identity, TCHsp70‐2 and TCHsp70‐3 showed 58.26% identity. Real‐time comparative quantitative PCR revealed that the relative expression of TCHsp70‐2 was lower than TCHsp70‐1 and TCHsp70‐3 at each temperature tested. TCHsp70‐1 and TCHsp70‐3 shared a similar expression pattern after cold and heat shock compared with their expression at normal temperature (26 °C), but the mRNA expression of TCHsp70‐1 was significantly higher and lower than that of TCHsp70‐3 at cold and heat shock temperatures (except for 34 °C), respectively. This result possibly indicated the expression patterns of TCHsp70 were affected by their location in different cellular compartments. The results also indicated that three TCHsp70s, especially TCHsp70‐1 and TCHsp70‐3, may play an important role in mediating tolerance to cold, thermal stress for Tetranychus cinnabarinus.
Identification of pyrethroid resistance associated mutations in the para sodium channel of the two‐spotted spider mite Tetranychus urticae (Acari: Tetranychidae)

We investigated pyrethroid resistance mechanisms in Tetranychus urticae strains from Greece. Combined bioassay, biochemical and synergistic data indicated that although P450 mono‐oxygenase activities were associated with the trait, target site insensitivity was the major resistance component. A 3.3 kb cDNA fragment of the T. urticae para sodium channel gene encompassing segment 4 of domain II to segment 6 of domain IV was obtained by a degenerate PCR strategy. The T. urticae sequence showed highest identity (56%) to the scabies mite, Sarcoptes scabiei, and was phylogenetically classified within the divergent group of Arachnida. Comparison of resistant and susceptible strains identified the point mutation F1538I in segment 6 of domain III, which is known to confer strong resistance to pyrethroids, along with a second mutation (A1215D) in the intracellular linker connecting domains II and III with an unknown role. Three transcripts were identified corresponding to the k and l alternative exons. The mode of inheritance of resistance was confirmed as incompletely recessive, which is consistent with a target site mechanism for pyrethroids.
Expression of the Hsp83 gene in response to diapause and thermal stress in the moth Sesamia nonagrioides

A full‐length Hsp83, named SnoHsp83, cDNA from the corn stalk borer, Sesamia nonagrioides, was cloned and sequenced. Genomic analysis showed that the SnoHsp83 gene is unique. The size of the SnoHsp83 cDNA was found to be approximately 2.6 kb. The deduced polypeptide comprised 717 amino acid residues, with a molecular mass of 82.6 kDa. It contained all the highly conserved amino acid motifs that characterize the cytosolic members of the hsp90 family. We investigated the expression of SnoHsp83 gene in response to diapause and heat/cold stress. SnoHsp83 is constitutively expressed in non‐diapausing larvae and is induced 15‐fold by heat. SnoHsp83 displays a similar pattern to SnoHsc70 under diapause conditions, when extra larval moults occur. Our results indicate that the SnoHsp83 gene could be involved in the developmental process that occurs between two moults.
Potent and Selective Inhibitors of the Inositol-requiring Enzyme 1 Endoribonuclease

Inositol-requiring enzyme 1 (IRE1) is the most highly conserved signaling node of the unfolded protein response (UPR) and represents a potential therapeutic target for a number of diseases associated with endoplasmic reticulum stress. IRE1 activates the XBP-1 transcription factor by site-specific cleavage of two hairpin loops within its mRNA to facilitate its nonconventional splicing and alternative translation. We screened for inhibitors using a construct containing the unique cytosolic kinase and endoribonuclease domains of human IRE1α (hIRE1α-cyto) and a mini-XBP-1 stem-loop RNA as the substrate. One class compounds was salicylaldehyde analogs from the hydrolyzed product of salicylaldimines in the library. Salicylaldehyde analogs were active in inhibiting the site-specific cleavage of several mini-XBP-1 stem-loop RNAs in a dose-dependent manner. Salicyaldehyde analogs were also active in inhibiting yeast Ire1 but had little activity inhibiting RNase L or the unrelated RNases A and T1. Kinetic analysis revealed that one potent salicylaldehyde analog, 3-ethoxy-5,6-dibromosalicylaldehyde, is a non-competitive inhibitor with respect to the XBP-1 RNA substrate. Surface plasmon resonance studies confirmed this compound bound to IRE1 in a specific, reversible and dose-dependent manner. Salicylaldehydes inhibited XBP-1 splicing induced pharmacologically in human cells. These compounds also blocked transcriptional up-regulation of known XBP-1 targets as well as mRNAs targeted for degradation by IRE1. Finally, the salicylaldehyde analog 3-methoxy-6-bromosalicylaldehyde strongly inhibited XBP-1 splicing in an in vivo model of acute endoplasmic reticulum stress. To our knowledge, salicylaldehyde analogs are the first reported specific IRE1 endoribonuclease inhibitors.
Vitellogenin gene expression in autogenous Culex tarsalis

Autogeny, the ability of a mosquito to mature an initial batch of eggs without blood feeding, is an alternative reproductive strategy with important implications for vector‐borne disease transmission. Regulation of the major yolk protein (vitellogenin; Vg) genes during bloodmeal‐induced oogenesis is well studied, but little is known about regulation of vitellogenesis in autogenous mosquitoes. We characterized the expression of four vitellogenin genes (Vg1a, Vg1b, Vg2a and Vg2b) in an autogenous strain of the West Nile Virus vector, Culex tarsalis. All vitellogenin genes were expressed during autogenous reproduction and following a bloodmeal, although the intensity and duration of expression varied amongst genes. Quantitative PCR analysis of vitellogenin transcription during autogeny revealed a similar temporal pattern to known vitellogenin expression profiles in anautogenous Aedes aegypti. Vitellogenin transcript, primarily produced from the Vg1b gene, was also detected in the larval and pupal stages of development, but no detectable vitellogenin protein was produced during this time period.