Molecular biology of amitraz resistance in cattle ticks of the genus Rhipicephalus

Amitraz is an important product for the control of cattle ticks around the world. In comparison with other products for the control of ticks, it is quite affordable and it has a rapid knock-down effect. It binds with and activates adrenergic neuro-receptors of animals and it inhibits the action of monoamine oxidases (MAO). Resistance to amitraz has been documented in Rhipicephalus microplus, R. decoloratus and R. appendiculatus. Four mechanisms of resistance have been proposed, each of which is supported by evidence but none of which has been definitively confirmed as the cause of resistance in the field. The proposed mechanisms include genetic target site insensitivity in two G protein-coupled receptors, the beta-adrenergic octopamine receptor (BAOR) and the octopamine/tyramine receptor (OCT/Tyr), increased expression or activity of monoamine oxidases and increased expression or activity of the ATP binding cassette transporter

Improving IQ measurement in intellectual disabilities using true deviation from population norms

BackgroundIntellectual disability (ID) is characterized by global cognitive deficits, yet the very IQ tests used to assess ID have limited range and precision in this population, especially for more impaired individuals.MethodsWe describe the development and validation of a method of raw z-score transformation (based on general population norms) that ameliorates floor effects and improves the precision of IQ measurement in ID using the Stanford Binet 5 (SB5) in fragile X syndrome (FXS; n = 106), the leading inherited cause of ID, and in individuals with idiopathic autism spectrum disorder (ASD; n = 205). We compared the distributional characteristics and Q-Q plots from the standardized scores with the deviation z-scores. Additionally, we examined the relationship between both scoring methods and multiple criterion measures.ResultsWe found evidence that substantial and meaningful variation in cognitive ability on standardized IQ tests among individuals with ID is lost when converting raw scores to standardized scaled, index and IQ scores. Use of the deviation z- score method rectifies this problem, and accounts for significant additional variance in criterion validation measures, above and beyond the usual IQ scores. Additionally, individual and group-level cognitive strengths and weaknesses are recovered using deviation scores.ConclusionTraditional methods for generating IQ scores in lower functioning individuals with ID are inaccurate and inadequate, leading to erroneously flat profiles. However assessment of cognitive abilities is substantially improved by measuring true deviation in performance from standardization sample norms. This work has important implications for standardized test development, clinical assessment, and research for which IQ is an important measure of interest in individuals with neurodevelopmental disorders and other forms of cognitive impairment

DNA repair deficiency biomarkers and the 70-gene ultra-high risk signature as predictors of veliparib/carboplatin response in the I-SPY 2 breast cancer trial.

Veliparib combined with carboplatin (VC) was an experimental regimen evaluated in the biomarker-rich neoadjuvant I-SPY 2 trial for breast cancer. VC showed improved efficacy in the triple negative signature. However, not all triple negative patients achieved pathologic complete response and some HR+HER2- patients responded. Pre-specified analysis of five DNA repair deficiency biomarkers (BRCA1/2 germline mutation; PARPi-7, BRCA1ness, and CIN70 expression signatures; and PARP1 protein) was performed on 116 HER2- patients (VC: 72 and concurrent controls: 44). We also evaluated the 70-gene ultra-high risk signature (MP1/2), one of the biomarkers used to define subtype in the trial. We used logistic modeling to assess biomarker performance. Successful biomarkers were combined using a simple voting scheme to refine the 'predicted sensitive' group and Bayesian modeling used to estimate the pathologic complete response rates. BRCA1/2 germline mutation status associated with VC response, but its low prevalence precluded further evaluation. PARPi-7, BRCA1ness, and MP1/2 specifically associated with response in the VC arm but not the control arm. Neither CIN70 nor PARP1 protein specifically predicted VC response. When we combined the PARPi-7 and MP1/2 classifications, the 42% of triple negative patients who were PARPi7-high and MP2 had an estimated pCR rate of 75% in the VC arm. Only 11% of HR+/HER2- patients were PARPi7-high and MP2; but these patients were also more responsive to VC with estimated pathologic complete response rates of 41%. PARPi-7, BRCA1ness and MP1/2 signatures may help refine predictions of VC response, thereby improving patient care

Resolution of the taxonomic status of Rhipicephalus (Boophilus) microplus

Rhipicepahlus (Boophilus) microplus is an obligate feeding, hard tick of great economical importance in the cattle industry. Every year billions of dollars of loss is attributed to R.(B) microplus, mainly through loss of cattle due to pathogens transmitted such as Babesia and Anaplasma, but also through damage to hides from blood-feeding. There is conflicting evidence regarding the taxonomic status of R.(B) microplus, however the most recent published research has been in support of the reinstatement of R.(B) australis as a species distinct from R.(B) microplus. The way in which some members of the scientific community have responded to the designation of separate species has implications for vaccine and acaricide research. In this study, we aimed to resolve the taxonomic status of Rhipicephalus (Boophilus) microplus, using morphological and phylogenetic approaches. 1,650 Rhipicephalus (Boophilus) microplus ticks from Australia, Thailand, South Africa, North and Central America and South America were used in this study. 340 specimens consisting of 170 R.(B) annulatus (USA) and 170 R.(B) decoloratus (South Africa) were also used. To maximize the information obtained from morphological observations, three methods were used; a binary scoring system based on previously described features, a standard morphometric method, and the more novel approach of geometric morphometrics. For the phylogenetic analysis three genes were used; the mitochondrial gene COX1 and two functional nuclear genes; Bm86 and βAOR. Morphological scoring is the process of assigning a binary value to any feature as being present or absent, or satisfying a logical comparator. For this study the scoring matrix was based on previously described sets of morphological criteria used for discriminating among species. Each of the populations for which samples were obtained was tested using four two-way analyses, each of which was designed to test whether a sample should be classified as one of two possible species: R.(B) australis versus R.(B) microplus; R.(B) microplus versus R.(B) annulatus; R.(B) microplus versus R.(B) decoloratus; and R.(B) annulatus versus R.(B) decoloratus. The scoring system was highly repeatable for the differentiation of males and females of R. (B) annulatus and R.(B) decoloratus from both of R.(B) microplus and R.(B) decoloratus. However, in the case of R.(B) australis and R.(B) microplus, clear differentiation was not achieved for either male or female ticks. Among females, the Australian population were classified almost evenly as R.(B) australis and R.(B) microplus, with 8 individuals showing a mixture of features and therefore not able to be classified. Ticks from the rest of the regions were mainly classified as R.(B) microplus, which is to be expected as R.(B) australis is reported in Australia. However, only the Mozo isolates were classified as solely R.(B) microplus. The remaining regions included several ticks with mixed features. Six ticks from South Africa, and four of the Juarez isolate were classified as R.(B) australis. Among the males an entirely different pattern emerged. Most male ticks from all geographical locations were classified as either R.(B) australis or showed a mixture of both features, with only a small number scoring as R.(B) microplus. Morphometrics is the linear measurement from one anatomical landmark to another and is a widely-used technique for quantifying phenotypic variation. Twelve features based on previous morphometric work were used. The results obtained from this study varied according to stage and sex. For the larvae, the Fisher Pairwise comparison showed that the Australian ticks tended to have a shorter body length, idiosoma length and narrower scutum width. Among the remaining morphological features, there were no consistent patterns in the different populations and species. A principal components analysis (PCA) was undertaken and in PC1 the strongest feature was scutum length and hypostome length. In PC2 the strongest feature was idiosoma length. The PCA of larval stage ticks didn’t provide conclusive evidence that R.(B) australis is a distinct species from R.(B) microplus, and there was no obvious grouping based on region at all, even when including R.(B) decoloratus and R.(B) annulatus. In relation to the male ticks studied, the Fisher Pairwise comparison and the PCA showed that Australian males (presumed R.(B) australis) were significantly different from the other isolates. As with the larvae, no patterns were seen in the other populations, based on species or region. In PC1 palpal length measures were the strongest features for differentiation and in PC2 the length of the ventral basis capituli had the strongest effect. The adult female samples yielded a mixed result. There was no real trend in the size of Australian ticks observed from the Fisher Pairwise comparison. However, R.(B) decoloratus tended to be smaller for most of the morphological features tested and R.(B) annulatus tended to be larger. This observation was inconsistent with the results from the PCA, in which there was grouping of Australian ticks. Measures of palpal length, width of the basis capituli and the length of the dorsal basis capituli were the strongest for differentiation in PC1. In PC2 the length of the ventral basis capituli was the strongest feature for differentiating populations. Geometric morphometrics is the quantitative representation of shape using coordinates in the form of landmarks, instead of measurements and is intended to give the shape of the feature independent of size. Hence it is useful for eliminating the effect of size distortion occurring with physiological changes. Geometric morphometric analysis did not clearly and consistently enable the differentiation of any of the populations of ticks in this study. Each feature differed among samples in different sets of pairwise relationships. Mitochondrial cytochrome oxidase subunit I gene (COX1) has been presented as a suitable mitochondrial gene to clarify complex groupings that were not resolved when using other mitochondrial genes. COX1 has also been proposed to be the main gene for differentiating between R.(B) microplus and R.(B) australis. The aims of this study were to confirm whether COX1 can be used to resolve complex relationships within the R.(B) microplus clade and to determine whether there is justification for the view that R.(B) australis is a distinct species from R.(B) microplus. Maximum likelihood trees were constructed with a Bootstrap analysis. A relaxed clock Bayesian analysis was then undertaken to estimate topology and divergence timings, using three ticks found in amber covering three genera: Amblyomma, Hyalomma and Ixodes to calibrate the clock. These analyses suggest that R.(B) microplus is a clade, containg five subspecies including R.(B) annulatus, R.(B) australis, and three, regionally based clades of R.(B) microplus: 1. All the South and Central American isolates together with isolates from Cambodia, Thailand, and some of those from Malaysia; 2. Indian and the remaining Malaysian isolates; 3. Most of the Chinese isolates. R.(B) decoloratus shares a common ancestor with R.(B) microplus and R.(B) annulatus however it is clearly divergent, appearing to be more related to R. bursa. All proposed groups of R.(B) microplus also appear to have evolved within the same time scale (within the last 20 million years). Bm86 is the name given to a midgut glycoprotein that is the target antigen of the only commercially available vaccine against ticks. All the prior work on this gene has been conducted using cDNA and suggests a high degree of sequence variation and the presence of different isoforms. The aim was to use genomic DNA to examine the regional variation in the Bm86 sequences and to determine whether Bm86 variation segregated according to the recently proposed taxonomic re-classification of R.(B) microplus and R.(B) australis. After extensive optimization, it was found that all primer sets, including those previously published and those designed in this project, failed on the extracted genomic DNA from all isolates. High variability in the published cDNA sequences indicated an extremely high mutation rate, which could potentially be linked to variation in the function of the protein and its utility as a vaccine immunogen. Analysis of sequence alignments from publicly available databases did not allow grouping of samples by either geographical location or proposed taxon. These findings are in apparent contradiction to claims by other researchers that regional variation in the efficacy of the vaccine is associated with regional variation in sequence. Beta-adrenergic octopamine receptor (βAOR) is a G-protein coupled receptor (GPCR) located on the neuronal cell surface and believed to be the main target of the acaricide amitraz. Polymorphism in βAOR has been associated with amitraz resistance. 121 samples from our isolates were sequenced for a length of 183 base pairs in position 95-277, among which eight SNPs were identified, five of which had not been previously described. It was found that geographical populations did not group based on the βAOR gene. Six of the SNPs were non-synonymous. When the 2-D structure of the putative βAOR protein was predicted, it was found that all non-synonymous single nucleotide polymorphisms (SNPs) caused a change to a residue in the βAOR cytoplasmic pore. Chi-square analysis showed that populations that are known to be resistant to amitraz were significantly more likely to have one of the non-synonymous SNPs, regardless of geographical location. In summary, when using the morphological analyses alone, it is not possible to consistently differentiate R.(B) microplus from the proposed R.(B) australis. Analysis of the COX1 gene supports the differentiation of R.(B) australis from R.(B) microplus, however when the gene is analyzed across all isolates, COX1 also showed support for R.(B) microplus being a species complex made up of three regional groups, R.(B) australis and R.(B) annulatus. The Bm86 gene was not amenable to analysis of gDNA and the analysis of published cDNA sequence was not informative and showed no clear regional or taxonomic variation. The shared SNPs between the previously documented Australian amitraz-resistant population and our South American amitraz-resistant isolates provide support for a role of βAOR in amitraz resistance. The presence of the same SNP arising independently in resistant isolates on two continents suggests strong selection at this locus. The three novel SNPs that were found in amitraz-resistant populations, having amino acid residues located on the intracellular loop 1, provide further support for the link between genotype and functional resistance

Roadmap on structured light

Structured light refers to the generation and application of custom light fields. As the tools and technology to create and detect structured light have evolved, steadily the applications have begun to emerge. This roadmap touches on the key fields within structured light from the perspective of experts in those areas, providing insight into the current state and the challenges their respective fields face. Collectively the roadmap outlines the venerable nature of structured light research and the exciting prospects for the future that are yet to be realized

Comparing Large Language Model AI and Human-Generated Coaching Messages for Behavioral Weight Loss

Automated coaching messages for weight control can save time and costs, but their repetitive, generic nature may limit their effectiveness compared to human coaching. Large language model (LLM) based artificial intelligence (AI) chatbots, like ChatGPT, could offer more personalized and novel messages to address repetition with their data-processing abilities. While LLM AI demonstrates promise to encourage healthier lifestyles, studies have yet to examine the feasibility and acceptability of LLM-based BWL coaching. 87 adults in a weight-loss trial rated ten coaching messages' helpfulness (five human-written, five ChatGPT-generated) using a 5-point Likert scale, providing additional open-ended feedback to justify their ratings. Participants also identified which messages they believed were AI-generated. The evaluation occurred in two phases: messages in Phase 1 were perceived as impersonal and negative, prompting revisions for Phase 2 messages. In Phase 1, AI-generated messages were rated less helpful than human-written ones, with 66 percent receiving a helpfulness rating of 3 or higher. However, in Phase 2, the AI messages matched the human-written ones regarding helpfulness, with 82% scoring three or above. Additionally, 50% were misidentified as human-written, suggesting AI's sophistication in mimicking human-generated content. A thematic analysis of open-ended feedback revealed that participants appreciated AI's empathy and personalized suggestions but found them more formulaic, less authentic, and too data-focused. This study reveals the preliminary feasibility and acceptability of LLM AIs, like ChatGPT, in crafting potentially effective weight control coaching messages. Our findings also underscore areas for future enhancement.Comment: 29 pages, 5 figure

New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism.

Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood. Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits. In an expanded genome-wide association meta-analysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism

Penilaian Kinerja Keuangan Koperasi di Kabupaten Pelalawan

This paper describe development and financial performance of cooperative in District Pelalawan among 2007 - 2008. Studies on primary and secondary cooperative in 12 sub-districts. Method in this stady use performance measuring of productivity, efficiency, growth, liquidity, and solvability of cooperative. Productivity of cooperative in Pelalawan was highly but efficiency still low. Profit and income were highly, even liquidity of cooperative very high, and solvability was good

Measurements of the pp → ZZ production cross section and the Z → 4ℓ branching fraction, and constraints on anomalous triple gauge couplings at √s = 13 TeV

Four-lepton production in proton-proton collisions, pp -> (Z/gamma*)(Z/gamma*) -> 4l, where l = e or mu, is studied at a center-of-mass energy of 13 TeV with the CMS detector at the LHC. The data sample corresponds to an integrated luminosity of 35.9 fb(-1). The ZZ production cross section, sigma(pp -> ZZ) = 17.2 +/- 0.5 (stat) +/- 0.7 (syst) +/- 0.4 (theo) +/- 0.4 (lumi) pb, measured using events with two opposite-sign, same-flavor lepton pairs produced in the mass region 60 4l) = 4.83(-0.22)(+0.23) (stat)(-0.29)(+0.32) (syst) +/- 0.08 (theo) +/- 0.12(lumi) x 10(-6) for events with a four-lepton invariant mass in the range 80 4GeV for all opposite-sign, same-flavor lepton pairs. The results agree with standard model predictions. The invariant mass distribution of the four-lepton system is used to set limits on anomalous ZZZ and ZZ. couplings at 95% confidence level: -0.0012 < f(4)(Z) < 0.0010, -0.0010 < f(5)(Z) < 0.0013, -0.0012 < f(4)(gamma) < 0.0013, -0.0012 < f(5)(gamma) < 0.0013

Non-collinear 2k antiferromagnetism in the Zintl semiconductor Eu5_5In2_2Sb6_6

Eu$_5$In$_2$Sb$_6$ is an orthorhombic non-symmorphic small band gap semiconductor with three distinct Eu$^{2+}$ sites and two low-temperature magnetic phase transitions. The material displays one of the greatest (negative) magnetoresistances of known stoichiometric antiferromagnets and belongs to a family of Zintl materials that may host an axion insulator. Using single crystal neutron diffraction, we show that the $T_{\mathrm{N1}}=14\mathrm{~K}$ second-order phase transition is associated with long-range antiferromagnetic order within the chemical unit cell $\left( k_1 = (000) \right)$. Upon cooling below $T_{\mathrm{N1}}$, the relative sublattice magnetizations of this structure vary until a second-order phase transition at $T_{\mathrm{N2}}=7\mathrm{~K}$ that doubles the unit cell along the $\hat{c}$ axis $\left( k_2 = \left(00\frac{1}{2}\right) \right)$. We show the anisotropic susceptibility and our magnetic neutron diffraction data are consistent with magnetic structures described by the $\Gamma_3$ irreducible representation with the staggered magnetization of the $k_1$ and $k_2$ components polarized along the $\hat{b}$ and $\hat{a}$ axis, respectively. As the $k_2$ component develops, the amplitude of the $k_1$ component is reduced, which indicates a 2k non-collinear magnetic structure. Density functional theory is used to calculate the energies of these magnetic structures and to show the $k_1$ phase is a metal so $T_{\mathrm{N1}}$ is a rare example of a unit-cell-preserving second-order phase transition from a paramagnetic semiconductor to an antiferromagnetic metal. DFT indicates the transition at $T_{\mathrm{N2}}$ to a doubled unit cell reduces the carrier density of the metal, which is consistent with resistivity data.Comment: 13 pages, 9 figure