Miracle-dz/UniFAR-FTUs huggingface dataset:
Neonatal Programming by Neuroimmune Challenge: Effects on Responses and Tolerance to Septic Doses of Lipopolysaccharide in Adult Male and Female Rats

A mild immune challenge experienced during the neonatal period leads to attenuated febrile responses to a similar challenge experienced later in life. However, the immune response to an endotoxin differs depending upon the severity of the challenge and it is not clear whether a neonatal immune challenge will also affect responses to a severe, potentially life‐threatening stimulus, such as sepsis. In the present study, we examined the effects of a neonatal immune challenge with lipopolysaccharide (LPS) on adult sickness responses, as well as the development of endotoxin tolerance, to a septic dose (1 or 3 mg/kg) of the same LPS in male and female rats. We demonstrate significant differences, particularly in males, in the fever profiles of neonatally LPS‐treated rats compared to neonatally saline‐treated controls. Specifically, male rats treated neonatally with LPS have reduced hypothermic and enhanced hyperthermic responses to both septic doses of LPS in adulthood. A somewhat different profile is seen in females, with neonatally LPS‐treated females having reduced hypothermia and enhanced hyperthermia compared to controls with 1 mg/kg but no differences with 3 mg/kg LPS. The results obtained demonstrate that alterations in innate immune responses previously reported for low doses of LPS can, for the most part, also be observed after severe immune challenge in later life.
Mitochondrial haplotype analysis for differentiation of isolates of Phytophthora cinnamomi.

Although Phytophthora cinnamomi is heterothallic, there are few instances of successful crossing in laboratory experiments, and analysis of field populations indicates a clonally reproducing population. In the absence of sexual recombination, the ability to monitor mitochondrial haplotypes may provide an additional tool for identification of clonal isolates and analysis of population structure. To determine mitochondrial haplotypes for this species, seven mitochondrial loci spanning a total of 6,961 bp were sequenced for 62 isolates representing a geographically diverse collection of isolates with A1 and A2 mating type. Three of the regions were primarily intergenic regions between trnG and rns, rns and nad3, and nad6 and cox1, while the remaining loci spanned cox2, nad9, rps10, and secY coding regions and some of the flanking spacer regions. In total, 45 mitochondrial haplotypes were identified (75% of the total isolates examined) with differences due to single-nucleotide polymorphisms (SNPs, totaling 152 bp) and length mutations (17 indels >2 bp representing a total of 910 bp in length). SNPs were the predominate mutation in the four coding regions and their flanking intergenic regions, while both SNPs and length mutations were observed in the three primarily intergenic regions. Some of the length mutations in these regions were due to addition or loss of unique sequences while others were due to variable numbers of subrepeats (in the trnG-rns region, there were 3 to 12 copies of a 24-bp subrepeat sequence that differentiated 17 haplotypes). Network analysis of the haplotypes identified eight primary clades, with the most divergent clade representing primarily A1 isolates collected from Papua New Guinea. The isolate grouping in the network corresponded to mating type and previously published isozyme classifications, with three exceptions: a haplotype representing an A1 mating type (H29) was placed well within the A2 mating type haplotype grouping, one haplotype (H26) had isolates with two isozyme classifications, and one isozyme group was represented on separate network clades, suggesting that recombination has occurred in the past. Among the 62 isolates examined, several examples were identified of isolates recovered from different geographic regions having the same mitochondrial haplotype, suggesting movement of isolates via plant material. Analysis of the data set to determine whether fewer loci could be sequenced to classify haplotypes indicated that the trnG-rns and rns-nad6 loci would classify 87% of the haplotypes identified in this study, while additional sequencing of the nad9 or secY loci would further differentiate the remaining six haplotypes. Based on conservation of gene order in Phytophthora spp. , the trnG-rns locus should be useful for mitochondrial haplotype classification in other species, as should the cox2, nad9, rps10, and secY loci. However, the rns-nad3 and nad6-cox1 loci span regions that can have a different gene order in some Phytophthora spp.
How Periplasmic Thioredoxin TlpA Reduces Bacterial Copper Chaperone ScoI and Cytochrome Oxidase Subunit II (CoxB) Prior to Metallation*♦

Background: α-Proteobacteria, extant relatives of mitochondria, are model organisms for studying assembly of bacterial and mitochondrial metalloenzymes. Results: Periplasmic thioredoxin TlpA is a specific reductant for copper chaperone ScoI and cytochrome oxidase subunit II (CoxB). Conclusion: Cysteines in the copper-binding sites of ScoI and CoxB must be reduced prior to metallation. Significance: Structures of TlpA-ScoI and TlpA-CoxB intermediates reveal mechanistic details of the reduction process. Two critical cysteine residues in the copper-A site (CuA) on subunit II (CoxB) of bacterial cytochrome c oxidase lie on the periplasmic side of the cytoplasmic membrane. As the periplasm is an oxidizing environment as compared with the reducing cytoplasm, the prediction was that a disulfide bond formed between these cysteines must be eliminated by reduction prior to copper insertion. We show here that a periplasmic thioredoxin (TlpA) acts as a specific reductant not only for the Cu2+ transfer chaperone ScoI but also for CoxB. The dual role of TlpA was documented best with high-resolution crystal structures of the kinetically trapped TlpA-ScoI and TlpA-CoxB mixed disulfide intermediates. They uncovered surprisingly disparate contact sites on TlpA for each of the two protein substrates. The equilibrium of CoxB reduction by TlpA revealed a thermodynamically favorable reaction, with a less negative redox potential of CoxB (E′0 = −231 mV) as compared with that of TlpA (E′0 = −256 mV). The reduction of CoxB by TlpA via disulfide exchange proved to be very fast, with a rate constant of 8.4 × 104 m−1 s−1 that is similar to that found previously for ScoI reduction. Hence, TlpA is a physiologically relevant reductase for both ScoI and CoxB. Although the requirement of ScoI for assembly of the CuA-CoxB complex may be bypassed in vivo by high environmental Cu2+ concentrations, TlpA is essential in this process because only reduced CoxB can bind copper ions.
Prothrombin and factor X are elevated in multiple sclerosis patients

Animal models have implicated an integral role for coagulation factors in neuroinflammatory diseases such as multiple sclerosis (MS) beyond their role in hemostasis. However, their relevance in humans requires further elucidation. This study aimed to determine whether levels of coagulation factors differ between patients with neuroimmunological disorders and respective controls. Individuals suffering from relapsing–remitting and secondary progressive MS had significantly higher prothrombin and factor X levels than healthy donors, whereas levels were unchanged in primary progressive MS and neuromyelitis optica patients. Our study demonstrates that coagulation factors may be key mediators in neuroinflammation and may therefore provide future targets for therapeutic strategies. Ann Neurol 2016;80:946–951
Comparison of Refractive Stability After Non-toric Versus Toric Intraocular Lens Implantation During Cataract Surgery

PURPOSE: To compare refractive state changes in eyes implanted with toric intraocular lenses (IOLs) vs nontoric IOLs, after cataract extraction. DESIGN: Retrospective, comparative. METHODS: In a single institution, 121 eyes underwent phacoemulsification and implantation with either nontoric IOLs or toric IOLs. The spherical value, cylindrical value, spherical equivalent (SE) of refractive error, and visual acuity were measured preoperatively and 1, 3, and 6 months after surgery. Main outcome measures were the pattern of changes of spherical, cylindrical, and SE values based on postoperative time, between different IOL types. RESULTS: The groups, which included patients who underwent surgery with SN60WF (Group I), SA6AT3 (Group II-3), SA6AT4 (Group II-4), and SA6AT5 lenses (Group II-5), contained 37, 29, 23, and 32 eyes, respectively. The cylindrical value was significantly decreased in all groups (P < .05). Before surgery, the SE of refractive errors was estimated as L0.21, L0.10, L0.20, andL0.22 in the respective groups. The actual remaining SE values were L0.19, L0.24, L0.42, and L0.56 at 1month;L0.17,L0.26,L0.57, andL0.64 at 3months; andL0.17,L0.26,L0.70, andL0.74 at 6 months postoperatively, respectively.The follow-upSEvalues in groups I and II-3 were similar (P> .05 in both groups); however, significant myopic changes were observed in Groups II-4 and II-5 after surgery, vs Group I (P< .05). CONCLUSION: Selection of toric IOLs for cataract surgery requires a refined formula to precisely determine necessary IOL power, especially in cases with high levels of astigmatism, to reliably and accurately prevent myopic outcomes. (Am J Ophthalmol 2014;157:658–665. 2014 by Elsevier Inc. All rights reserved.)
UJI KEKERASAN, KEREGASAN, DAN WAKTU HANCUR BEBERAPA TABLET RANITIDIN

Salah satu bentuk sediaan obat yang paling sering digunakan adalah tablet karena bentuknyayang efisien, sangat praktis, dan ideal untuk pemberian zat aktif terapi secara oral. Untuk dapatmenghasilkan efek terapi, tablet harus hancur dan melepaskan zat aktif ke dalam cairan tubuh untukdilarutkan dan tersedia untuk diabsorpsi. Selain persyaratan waktu hancur, tablet juga harus mempunyaikekerasan dan keregasan yang sesuai dengan persyaratan agar tablet dapat bertahan terhadap guncanganpada saat pembuatan dan pengepakan. Penelitian ini bertujuan untuk mengetahui apakah beberapa tabletranitidin memenuhi persyaratan kekerasan, keregasan, dan waktu hancur sesuai dengan persyaratan yangada. Jenis penelitian yang digunakan adalah penelitian deskriptif. Sampel yang digunakan dalampenelitian adalah tablet ranitidin generik produksi Landson, OGB Dexa, Hexpharm Jaya dan produkgenerikbermerek produksi Sanbe (Acran), Gracia Pharmindo (Ratinal), dan Kalbe Farma (Rantin). Pengujian yang dilakukan yaitu, uji kekerasan, uji keregasan dan uji waktu hancur. Hasil penelitianmenunjukkan bahwa tablet ranitidin yang digunakan dalam penelitian baik produk generik ataupungenerik bermerek telah memenuhi persyaratan untuk uji keregasan dan waktu hancur, tetapi tidakmemenuhi persyaratan untuk uji kekerasan tablet.
Axonal components of nerves innervating the human arm

Axons traveling within the brachial plexus are responsible for the dexterous control of human arm and hand movements. Despite comprehensive knowledge on the topographical anatomy of nerves innervating the human upper limbs, the definite quantity of sensory and motor axons within this neural network remains elusive. Our aim was to perform a quantitative analysis of the axonal components of human upper limb nerves based on highly specific molecular features from spinal cord level to the terminal nerves at wrist level.
The Influenza Hemagglutinin Fusion Domain Is an Amphipathic Helical Hairpin That Functions by Inducing Membrane Curvature*

Background: The influenza hemagglutinin fusion peptide is responsible for fusion of viral and endosomal membranes upon infection. Results: Negatively induced curvature and fusion activity were significantly reduced by changing the shape of the fusion peptide. Conclusion: The hemagglutinin fusion peptide structure promotes negative membrane curvature. Significance: This work enables elucidates how a crucial component of influenza infection functions and can be targeted. The highly conserved N-terminal 23 residues of the hemagglutinin glycoprotein, known as the fusion peptide domain (HAfp23), is vital to the membrane fusion and infection mechanism of the influenza virus. HAfp23 has a helical hairpin structure consisting of two tightly packed amphiphilic helices that rest on the membrane surface. We demonstrate that HAfp23 is a new class of amphipathic helix that functions by leveraging the negative curvature induced by two tightly packed helices on membranes. The helical hairpin structure has an inverted wedge shape characteristic of negative curvature lipids, with a bulky hydrophobic region and a relatively small hydrophilic head region. The F3G mutation reduces this inverted wedge shape by reducing the volume of its hydrophobic base. We show that despite maintaining identical backbone structures and dynamics as the wild type HAfp23, the F3G mutant has an attenuated fusion activity that is correlated to its reduced ability to induce negative membrane curvature. The inverted wedge shape of HAfp23 is likely to play a crucial role in the initial stages of membrane fusion by stabilizing negative curvature in the fusion stalk.
Conformational Activation of Antithrombin by Heparin Involves an Altered Exosite Interaction with Protease*

Background: Exosites are known to mediate heparin allosteric activation of antithrombin. Results: Mutagenesis revealed that an exosite differentially contributes to antithrombin reactivity with factors Xa/IXa in unactivated and heparin-activated states. Conclusion: Heparin allosteric activation of antithrombin results from alterations in an exosite interaction with protease induced by core conformational changes. Significance: The findings support our recently proposed model of antithrombin allosteric activation. Heparin allosterically activates antithrombin as an inhibitor of factors Xa and IXa by enhancing the initial Michaelis complex interaction of inhibitor with protease through exosites. Here, we investigate the mechanism of this enhancement by analyzing the effects of alanine mutations of six putative antithrombin exosite residues and three complementary protease exosite residues on antithrombin reactivity with these proteases in unactivated and heparin-activated states. Mutations of antithrombin Tyr253 and His319 exosite residues produced massive 10–200-fold losses in reactivity with factors Xa and IXa in both unactivated and heparin-activated states, indicating that these residues made critical attractive interactions with protease independent of heparin activation. By contrast, mutations of Asn233, Arg235, Glu237, and Glu255 exosite residues showed that these residues made both repulsive and attractive interactions with protease that depended on the activation state and whether the critical Tyr253/His319 residues were mutated. Mutation of factor Xa Arg143, Lys148, and Arg150 residues that interact with the exosite in the x-ray structure of the Michaelis complex confirmed the importance of all residues for heparin-activated antithrombin reactivity and Arg150 for native serpin reactivity. These results demonstrate that the exosite is a key determinant of antithrombin reactivity with factors Xa and IXa in the native as well as the heparin-activated state and support a new model of allosteric activation we recently proposed in which a balance between attractive and repulsive exosite interactions in the native state is shifted to favor the attractive interactions in the activated state through core conformational changes induced by heparin binding.
L'abolition sélective du paiement direct en Afrique subsaharienne : une opportunité pour le renforcement des systèmes de santé ?

En Afrique, nombreux sont ceux qui recommandent l’abolition ciblee du paiement direct des soins de sante pour les femmes et les enfants de moins de cinq ans. Mais des difficultes de mise en œuvre sont apparues au cours d’experiences menees par quelques pays precurseurs d’Afrique de l’Ouest. De nombreux goulots d’etranglement du systeme de sante sont apparus et cet article permet d’en mettre au jour un certain nombre. Mais en meme temps, nous croyons qu’ils constituent autant d’opportunites de renforcement des systemes de sante, si l’on envisage de proceder notamment aux changements suivants : accroitre de maniere significative le financement de la sante et en ameliorer la fiabilite, adopter des politiques de sante erigeant l’equite au rang de priorite, mettre en œuvre des reformes alignees sur les principes de la « Nouvelle Gestion Publique », assurer l’apport en intrants de qualite, renforcer les differentes composantes du secteur de la sante, et realiser davantage d’evaluations dans ce meme secteur.
MYRF is associated with encephalopathy with reversible myelin vacuolization

Reversible myelin vacuolization is associated with variable conditions including mild encephalitis/encephalopathy with a reversible splenial lesion (MERS), which is characterized by mildly impaired consciousness and transient splenial lesion. Familial and/or recurrent cases with a clinical diagnosis of MERS suggest the presence of genetic factors.
Exposure of Neutralizing Epitopes in the Carboxyl-terminal Domain of TcdB Is Altered by a Proximal Hypervariable Region*

Background: TcdB from 027 strains is not as sensitive to antibody neutralization as TcdB from 012 strains, although neutralizing epitopes are present on both forms. Results: Sequence alterations in strain-specific TcdB influence intramolecular protein-protein interactions and exposure of neutralizing epitopes. Conclusion: Our work uncovers a mechanism used by TcdB to shield neutralizing epitopes. Significance: This study demonstrates how strain-specific TcdB can avoid antibody targeting. The sequence, activity, and antigenicity of TcdB varies between different strains of Clostridium difficile. As a result, ribotype-specific forms of TcdB exhibit different toxicities and are not strongly cross-neutralized. Using a combination of biochemical and immunological approaches, we compared two important variants of TcdB (TcdB012 and TcdB027) to identify the mechanisms through which sequence differences alter epitopes and activity of the toxin. These analyses led to the discovery of a critical variation in the 1753–1851 (B2′) region of TcdB, which affects the exposure of neutralizing epitopes in the toxin. Sequence comparisons found that the B2′ region exhibits only 77% identity and is the most variable sequence between the two forms of TcdB. A combination of biochemical, analytical, and mutagenesis experiments revealed that the B2′ region promotes protein-protein interactions. These interactions appear to shield neutralizing epitopes that would otherwise be exposed in the toxin, an event found to be less prominent in TcdB012 due to sequence differences in the 1773–1780 and 1791–1798 regions of the B2′ domain. When the carboxyl-terminal domains of TcdB012 and TcdB027 are swapped, neutralization experiments suggest that the amino terminus of TcdB interacts with the B2′ region and impacts the exposure of neutralizing epitopes in the carboxyl terminus. Collectively, these data suggest that variations in the B2′ region affect protein-protein interactions within TcdB and that these interactions influence the exposure of neutralizing epitopes.
Ligand Binding Pocket Formed by Evolutionarily Conserved Residues in the Glucagon-like Peptide-1 (GLP-1) Receptor Core Domain*

Background: Little is known about the interaction between GLP-1 and the heptahelical core domain of GLP1R. Results: GLP-1 Asp9 and Gly4 interact with the evolutionarily conserved residues in extracellular loop 3. Conclusion: Ligand binding pocket formed by evolutionarily conserved residues in the GLP1R core domain. Significance: This study highlights the mechanism underlying high affinity interaction between GLP-1 and the binding pocket of the receptor. Glucagon-like peptide-1 (GLP-1) plays a pivotal role in glucose homeostasis through its receptor GLP1R. Due to its multiple beneficial effects, GLP-1 has gained great attention for treatment of type 2 diabetes and obesity. However, little is known about the molecular mechanism underlying the interaction of GLP-1 with the heptahelical core domain of GLP1R conferring high affinity ligand binding and ligand-induced receptor activation. Here, using chimeric and point-mutated GLP1R, we determined that the evolutionarily conserved amino acid residue Arg380 flanked by hydrophobic Leu379 and Phe381 in extracellular loop 3 (ECL3) may have an interaction with Asp9 and Gly4 of the GLP-1 peptide. The molecular modeling study showed that Ile196 at transmembrane helix 2, Met233 at ECL1, and Asn302 at ECL2 of GLP1R have contacts with His1 and Thr7 of GLP-1. This study may shed light on the mechanism underlying high affinity interaction between the ligand and the binding pocket that is formed by these conserved residues in the GLP1R core domain.
The use of telecare for people with chronic obstructive pulmonary disease: implications for management.

AIM To evaluate the telecare service offered by Home Care teams to patients with chronic obstructive pulmonary disease (COPD). BACKGROUND The use of telecare aims to support older people in remaining independent at home, reducing hospital admissions and improving the quality of life for older people and their informal carers. In the redesign of managed care for people with COPD using telecare, an evaluation of the implementation process is necessary. METHOD A focus group with Home Care teams and social care staff was conducted. Six case studies identified by nursing staff were used to examine key issues relating to telecare implementation. FINDINGS The experience and expectation in telecare, the usability of equipment, and changes in practice can impact on COPD care. Case studies highlight that the rapid access to care, an increased sense of personal safety and security, and the continuity of care are perceived as benefits. However, the equipment was perceived as not 'user friendly' and bulky. CONCLUSION It is important that any service redesign to include telecare is evaluated and targeted at its specific role. IMPLICATIONS FOR NURSING MANAGEMENT Partnership working has to be negotiated, and leadership roles include addressing tensions and motivation within the team.