Miracle-dz/UniFAR-FTUs huggingface dataset:
Latanoprostene Bunod 0.024% in Subjects With Open-angle Glaucoma or Ocular Hypertension: Pooled Phase 3 Study Findings

Purpose: To compare the diurnal intraocular pressure (IOP)-lowering effect of latanoprostene bunod (LBN) 0.024% with timolol maleate 0.5% in subjects with open-angle glaucoma (OAG) or ocular hypertension (OHT). Patients and Methods: Pooled analysis of two phase 3, randomized, multicenter, double-masked, parallel-group, noninferiority trials (APOLLO and LUNAR), each with open-label safety extension phases. Adults with OAG or OHT were randomized 2:1 to double-masked treatment with LBN once daily (qd) or timolol twice daily (bid) for 3 months followed by open-label LBN treatment for 3 (LUNAR) or 9 (APOLLO) months. IOP was measured at 8 AM, 12 PM, and 4 PM at week 2, week 6, and months 3, 6, 9, and 12. Results: Of the 840 subjects randomized, 774 (LBN, n=523; timolol crossover to LBN, n=251) completed the efficacy phase, and 738 completed the safety extension phase. Mean IOP was significantly lower with LBN versus timolol at all 9 evaluation timepoints during the efficacy phase (P<0.001). A significantly greater proportion of LBN-treated subjects attained a mean IOP ⩽18 mm Hg and IOP reduction ≥25% from baseline versus timolol-treated subjects (P<0.001). The IOP reduction with LBN was sustained through the safety phase; subjects crossed over from timolol to LBN experienced additional significant IOP lowering (P⩽0.009). Both treatments were well tolerated, and there were no safety concerns with long-term LBN treatment. Conclusions: In this pooled analysis of subjects with OAG and OHT, LBN 0.024% qd provided greater IOP-lowering compared with timolol 0.5% bid and maintained lowered IOP through 12 months. LBN demonstrated a safety profile comparable to that of prostaglandin analogs.
Tackling Maori Masculinity: A Colonial Genealogy of Savagery and Sport

The primary aim of this paper is to deconstruct one of the dominant discourses surrounding Maori men—a discourse that was constructed to limit, homogenize, and reproduce an acceptable and imagined Maori masculinity, and one that has also gained hegemonic consent from many tane. I use a genealogical approach to outline the historical underpinnings of the image of the Maori man as naturally physical, and the mechanisms, including the confiscation of land and a racist state education system, that served to propound and perpetuate this construction. The contemporary portrayal of the natural Maori sportsman has evolved from these historical roots in what has become a largely subconscious but no less insidious pattern of subjugation through positively framed sporting images.
Mitochondrial DNA and the origins of the domestic horse

The place and date of the domestication of the horse has long been a matter for debate among archaeologists. To determine whether horses were domesticated from one or several ancestral horse populations, we sequenced the mitochondrial D-loop for 318 horses from 25 oriental and European breeds, including American mustangs. Adding these sequences to previously published data, the total comes to 652, the largest currently available database. From these sequences, a phylogenetic network was constructed that showed that most of the 93 different mitochondrial (mt)DNA types grouped into 17 distinct phylogenetic clusters. Several of the clusters correspond to breeds and/or geographic areas, notably cluster A2, which is specific to Przewalski's horses, cluster C1, which is distinctive for northern European ponies, and cluster D1, which is well represented in Iberian and northwest African breeds. A consideration of the horse mtDNA mutation rate together with the archaeological timeframe for domestication requires at least 77 successfully breeding mares recruited from the wild. The extensive genetic diversity of these 77 ancestral mares leads us to conclude that several distinct horse populations were involved in the domestication of the horse.
Prisoners' families and offender management: Mobilizing social capital

Interest in prisoners' families has grown considerably in recent years as the link between family support and reduced recidivism is increasingly recognized. This article explores the potential role of prisoners' families in reducing re-offending by reviewing the research literature to assess the contribution that family ties can make to effective resettlement and desistance from crime. Like other commentators, such as Farrall (2004) and Wolff and Draine (2004), the authors draw on the concept of `social capital' to provide key insights into the importance of family relationships for encouraging desistance. Potential ways to mobilize this social capital are considered and the article concludes with reflections on the likelihood of such measures being deployed by offender managers in the current penal context, and assesses whether the shift to offender management is likely to boost recognition of prisoners' family relationships.
A Vaccinia Virus-Driven Interplay between the MKK4/7-JNK1/2 Pathway and Cytoskeleton Reorganization

ABSTRACT Viral manipulation of transduction pathways associated with key cellular functions such as survival, response to microbial infection, and cytoskeleton reorganization can provide the supportive milieu for a productive infection. Here, we demonstrate that vaccinia virus (VACV) infection leads to activation of the stress-activated protein kinase (SAPK)/extracellular signal-regulated kinase (ERK) 4/7 (MKK4/7)–c-Jun N-terminal protein kinase 1/2 (JNK1/2) pathway; further, the stimulation of this pathway requires postpenetration, prereplicative events in the viral replication cycle. Although the formation of intracellular mature virus (IMV) was not affected in MKK4/7- or JNK1/2-knockout (KO) cells, we did note an accentuated deregulation of microtubule and actin network organization in infected JNK1/2-KO cells. This was followed by deregulated viral trafficking to the periphery and enhanced enveloped particle release. Furthermore, VACV infection induced alterations in the cell contractility and morphology, and cell migration was reduced in the JNK-KO cells. In addition, phosphorylation of proteins implicated with early cell contractility and cell migration, such as microtubule-associated protein 1B and paxillin, respectively, was not detected in the VACV-infected KO cells. In sum, our findings uncover a regulatory role played by the MKK4/7-JNK1/2 pathway in cytoskeleton reorganization during VACV infection.
A crosslinguistic analysis of Binding in Down syndrome.

This chapter reports an investigation of the knowledge of binding in young adults with Down syndrome (DS), speakers of Serbo-Croatian, and compares it to that of English-speaking individuals with DS and typically developing controls. In line with data reported for English, Serbo-Croatian speakers with DS showed difficulties interpreting anaphoric elements. It is argued that these results point to a specific deficit in the grammar of DS: an inability to establish a syntactic relationship of binding between an anaphor and its antecedent. These results present evidence against the characterisation of language development in DS as delayed, since the pattern observed in this population cross-linguistically has not been observed during any stage of typical language development.
In much smaller things forgotten: a case for microartifact analysis in cultural resource management

The past several decades have seen a shift in archaeology from the exclusive analysis of “interesting” artifacts, such as diagnostic lithics and ceramics, towards a more holistic examination that includes the smaller, less obvious, “forgotten” artifacts. These micro-sized artifacts are a focus for archaeologists because many studies show their utility in documenting activity areas and site formation processes. As early as the 1970s, researchers recognized the value of microartifacts and academic archaeologists increasingly included them in their studies over the subsequent decades. In this paper, we argue that microartifact analysis is also of interest to those working in cultural resource management (CRM), albeit for different reasons. By analyzing both macro- and microartifacts recovered from an Archaic-period lithic scatter in Meade County, KY, we explore the contribution microartifacts, specifically microdebitage, can make to our understanding of lithic scatters within CRM. The results of this exploratory case study suggest that data derived from microartifacts may alter assessments of National Register of Historic Places (NRHP) eligibility of some lithic scatters that otherwise might be deemed insignificant and, therefore, ineligible for the NRHP.
Morphology of seminal and swim‐up spermatozoa and the outcome of in vitro fertilization and embryo transfer

Summary Tubal infertility was treated by in vitro fertilization‐embryo transfer (IVF‐ET) in 112 couples. Twenty‐eight pregnancies were obtained in 140 treatment cycles. Couples are accepted for treatment in our IVF‐ET programme if previous semen samples fulfil the inclusion criteria: ejaculate volume > 1.5 ml, concentration of spermatozoa > 15 × 106 ml‐1, > 40% motile spermatozoa, and > 25% spermatozoa with normal morphology. In order to determine to which extent IVF‐ET treatment results are influenced by sperm morphology, within this selected group of patients, we have retrospectively analysed the data from both original semen samples and swim‐up preparations. The sperm morphology was not related to the outcome of treatment in terms of fertilization (ovum cleavage rate), early embryo development, or pregnancy. Nor was any relationship detected between early embryo development or pregnancy and the degree of improvement in morphology resulting from the swim‐up procedure. However, if improvement in morphology by swim‐up was high, ovum cleavage rate was low. Sperm morphology within the limits set by our inclusion criteria could not predict the outcome of IVF‐ET treatment. It is further concluded that the presence of abnormal spermatozoa at the site of fertilization may be without harm if only the number of normal sperms is high enough.
Interpreting a Pumping Test Influenced by Another Well in an Anisotropic Aquifer

In confined aquifers the influence of neighboring active wells is often neglected when interpreting a pumping test. This can, however, lead to an erroneous interpretation of the pumping test data. This article presents simple methods to evaluate the transmissivity tensor and storativity of an anisotropic confined aquifer when there is an interfering well in the neighborhood of the tested well. Two methods have been developed depending on whether the tested well or the interfering well is the first in operation. These new methods yield better estimates of the hydraulic parameters than when the influence of the interfering well is neglected. These methods have then been used on data obtained from numerical models with an interfering well and the results have been compared to an analytical method that neglects the influence of the interfering well. The methods require knowledge of the pumping rate of the interfering well and the time elapsed since the pumping started in each well. If the interfering well started pumping before the tested well, the method does not require knowledge of the aquifer piezometric level at the beginning of the test, which is often unknown in this case. As for the method without interference, at least three monitoring wells (MWs) are needed, the position of which influences the accuracy of the estimated parameters. Some recommendations concerning MWs position have been given to get more accurate results according to the sought parameter.
The mechanisms of generation and propagation of synchronized bursting in developing networks of cortical neurons

The characteristics and mechanisms of synchronized firing in developing networks of cultured cortical neurons were studied using multisite recording through planar electrode arrays (PEAs). With maturation of the network (from 3 to 40 d after plating), the frequency and propagation velocity of bursts increased markedly (approximately from 0.01 to 0.5 Hz and from 5 to 100 mm/sec, respectively), and the sensitivity to extracellular magnesium concentration (0–10 mM) decreased. The source of spontaneous bursts, estimated from the relative delay of onset of activity between electrodes, varied randomly with each burst. Physical separation of synchronously bursting networks into several parts using an ultraviolet laser, divided synchronous bursting into different frequencies and phases in each part. Focal stimulation through the PEA was effective at multiple sites in eliciting bursts, which propagated over the network from the site of stimulation. Stimulated bursts exhibited both an absolute refractory period and a relative refractory period, in which partially propagating bursts could be elicited. Periodic electrical stimulation (at 1 to 30 sec intervals) produced slower propagation velocities and smaller numbers of spikes per burst at shorter stimulation intervals. These results suggest that the generation and propagation of spontaneous synchronous bursts in cultured cortical neurons is governed by the level of spontaneous presynaptic firing, by the degree of connectivity of the network, and by a distributed balance between excitation and recovery processes.
Brain Regions Involved in Fatigue Sensation: Reduced Acetylcarnitine Uptake into the Brain

Fatigue is an indispensable sense for ordering rest. However, the neuronal and molecular mechanisms of fatigue remain unclear. Chronic fatigue syndrome (CFS) with long-lasting fatigue sensation seems to be a good model for studying these mechanisms underlying fatigue sensation. Recently, we found that most patients with CFS showed a low level of serum acetylcarnitine, which well correlated with the rating score of fatigue, and that a considerable amount of acetyl moiety of serum acetylcarnitine is taken up into the brain. Here we show by metabolite analysis of the mouse brain that an acetyl moiety taken up into the brain through acetylcarnitine is mainly utilized for the biosynthesis of glutamate. When we studied the cerebral uptake of acetylcarnitine by using [2-(11)C]acetyl-L-carnitine in 8 patients with CFS and in 8 normal age- and sex-matched controls, a significant decrease was found in several regions of the brains of the patient group, namely, in the prefrontal (Brodmann's area 9/46d) and temporal (BA21 and 41) cortices, anterior cingulate (BA24 and 33), and cerebellum. These findings suggest that the levels of biosynthesis of neurotransmitters through acetylcarnitine might be reduced in some brain regions of chronic fatigue patients and that this abnormality might be one of the keys to unveiling the mechanisms of the chronic fatigue sensation.
Nek2A contributes to tumorigenic growth and possibly functions as potential therapeutic target for human breast cancer

Nek2A (NIMA‐related kinases 2A) has been known as an important centrosome regulatory factor. The aim of this study was to investigate the expression of Nek2A and the role it played in different stages of breast cancer. We detected the expression of Nek2A in both mRNA and protein levels in MCF10 cell lines including MCF‐10A, MCF‐10DCIS.com, MCF‐10CA1a and in human breast samples which contained normal breast tissue (NBT), breast ductal carcinoma in situ (DCIS), and invasive ductal carcinoma (IDC). Our study revealed that the mRNA and protein expression of Nek2A were significantly up‐regulated in MCF‐10DCIS.com and MCF‐10CA1a cell lines as well as in human primary breast cancer tissue (DCIS and IDC). Our study also presented a correlation between Nek2A mRNA expression and some clinic pathological factors. We found that Nek2A mRNA expression was associated with molecular subtypes, ER, PR and Ki‐67 immunoreactivity (P < 0.05) in DCIS and associated with histological grade, lymph node metastasis, molecular subtypes, c‐erbB‐2, and Ki‐67 expression (P < 0.05) in IDC. In addition, we observed that ectopic expression of Nek2A in “normal” immortalized MCF‐10A breast epithelial cell resulted in increased Nek2A which lead to abnormal centrosomes. Furthermore, knockdown of Nek2A in MCF‐10DCIS.com could remarkably inhibit cell proliferation and induce cell cycle arrest in MCF‐10DCIS.com cell line. These data suggested that Nek2A might bear a close relationship with development and progression of breast carcinoma, and highlighted its role as a novel potential biomarker for diagnosis and a possible therapeutic target for human breast cancer especially for DCIS. J. Cell. Biochem. 113: 1904–1914, 2012. © 2012 Wiley Periodicals, Inc.
Good People and Dirty Work

“& une secte est le noyua et le levain de toute foule& . Etudier la foule c'est juger un drame d'aprks ce qu'on voit sur la scene; etudier la secte c'est le juger d'apres ce qu'on voit dans les coulisses. ” Sighele, S. Psychologie des sectes . Paris, 1898. Pp. 62, 63, 65.1
Sociological dimensions in classical/neoclassical economics: Conceptions of social economics and economic sociology

This article posits that traditional economics contains relevant sociological dimensions and that these consist primarily of conceptions and elements of social economics or economic sociology. On this premise, it explores these sociological dimensions in the form of conceptions and elements of social economics and/or economic sociology in classical political economy and neoclassical economics. The article identifies explicit conceptions of social economics such as the proposal for social economy and the idea of economic sociology as well as its implicit versions, including its implications in ‘purest’ economic theory. Alternatively, the article finds no important sociological dimensions in the form of rational choice theory, i.e. the ‘economics of society’, in classical and neoclassical economic science. The article reconsiders economics and sociology in their shared elements or complementary relations as ‘sister’ social sciences.
Chapter 18 Randomness and Structure

Random problems have proved useful in a number of different ways. Firstly, they provide a relatively “unbiased” sample for benchmarking algorithms. In the early days of CP, many algorithms were compared using only a limited sample of problem instances. In some cases, this may have lead to premature conclusions. Random problems, by comparison, permit algorithms to be tested on statistically significant samples of hard problems. However, as we outline in the rest of this chapter, there remain pitfalls waiting the unwary in their use. For example, random problems may not contain structures found in many real world problems, and these structures can make problems much easier or much harder to solve. As a second example, the process of generating random problems may itself be “flawed”, giving problem instances which are not, at least asymptotically, combinatorially hard.
Endothelial Membrane Remodeling Is Obligate for Anti-Angiogenic Radiosensitization during Tumor Radiosurgery

Background While there is significant interest in combining anti-angiogenesis therapy with conventional anti-cancer treatment, clinical trials have as of yet yielded limited therapeutic gain, mainly because mechanisms of anti-angiogenic therapy remain to a large extent unknown. Currently, anti-angiogenic tumor therapy is conceptualized to either “normalize” dysfunctional tumor vasculature, or to prevent recruitment of circulating endothelial precursors into the tumor. An alternative biology, restricted to delivery of anti-angiogenics immediately prior to single dose radiotherapy (radiosurgery), is provided in the present study. Methodology/Principal Findings Genetic data indicate an acute wave of ceramide-mediated endothelial apoptosis, initiated by acid sphingomyelinase (ASMase), regulates tumor stem cell response to single dose radiotherapy, obligatory for tumor cure. Here we show VEGF prevented radiation-induced ASMase activation in cultured endothelium, occurring within minutes after radiation exposure, consequently repressing apoptosis, an event reversible with exogenous C16-ceramide. Anti-VEGFR2 acts conversely, enhancing ceramide generation and apoptosis. In vivo, MCA/129 fibrosarcoma tumors were implanted in asmase+/+ mice or asmase−/− littermates and irradiated in the presence or absence of anti-VEGFR2 DC101 or anti-VEGF G6-31 antibodies. These anti-angiogenic agents, only if delivered immediately prior to single dose radiotherapy, de-repressed radiation-induced ASMase activation, synergistically increasing the endothelial apoptotic component of tumor response and tumor cure. Anti-angiogenic radiosensitization was abrogated in tumors implanted in asmase−/− mice that provide apoptosis-resistant vasculature, or in wild-type littermates pre-treated with anti-ceramide antibody, indicating that ceramide is necessary for this effect. Conclusions/Significance These studies show that angiogenic factors fail to suppress apoptosis if ceramide remains elevated while anti-angiogenic therapies fail without ceramide elevation, defining a ceramide rheostat that determines outcome of single dose radiotherapy. Understanding the temporal sequencing of anti-angiogenic drugs and radiation enables optimized radiosensitization and design of innovative radiosurgery clinical trials.
Molecular testing for somatic cancer mutations: a survey of current and future testing in UK laboratories

Background: Genetics clinical practice has paid limited attention to non-inherited aspects of cancer, namely mutations occurring during carcinogenesis. These somatic mutations are likely to be the primary determinants of cancer behaviour and treatment response, with a recent example being Her2/Neu gene status and response to Herceptin in breast cancer. Aim: To assess the feasibility of widespread testing of tumours by surveying UK histopathology and genetics laboratories. Methods: The questionnaire asked: which of the common cancers or other malignancies are routinely assessed; which molecular and cytogenetic methods are used; who orders and funds testing; what is the future demand for somatic testing; and what are the barriers to widespread testing? Results: Of 50 laboratories surveyed, 33 responded, 22 of which are currently using molecular tests. The survey shows that the most common tests are immunohistochemistry, fluorescence in-situ hybridisation and DNA testing of somatic mutations. Most laboratories predict testing will increase over the next 10 years, particularly for DNA testing using microarrays. Respondents perceived the main barriers to expanding molecular testing were a lack of laboratory funding and scientific evidence and testing not considered an NHS priority. Conclusion: These results provide important information for healthcare commissioners faced with managing demand for molecular testing of cancers.
NUMBER ATTRACTION EFFECTS IN NEAR-NATIVE SPANISH SENTENCE COMPREHENSION

Grammatical agreement phenomena such as verbal number have long been of fundamental interest in the study of second language (L2) acquisition. Previous research from the perspective of sentence processing has documented nativelike behavior among nonnative participants but has also relied almost exclusively on grammar violation paradigms. The present investigation examined the online comprehension of subject-verb number agreement by native and nonnative speakers of Mexican Spanish using the more subtle agreement attraction paradigm, with stimuli grammatical in both conditions, in addition to a nonlocal grammaticality paradigm. The results of a self-paced reading experiment confirmed that nonnatives can acquire nativelike online sensitivity to verbal number agreement, even without grammar errors, and that such sensitivity develops only at very high levels of L2 proficiency.