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Background: High variability in the age at cancer diagnosis in Lynch syndrome (LS) patients is widely observed, even among relatives with the same germline pathogenic variant (PV) in the mismatch repair (MMR) genes. Genetic polymorphisms and lifestyle factors are thought to contribute to this variability. We investigated the influence of previously reported genetic polymorphisms on the age at cancer diagnosis in a homogenous LS cohort with a South African founder germline PV c.1528C>T in the MLH1 gene. Methods: A total of 359 LS variant heterozygotes (LSVH) from 60 different families were genotyped for specific genetic polymorphisms in GSTM1, GSTT1, CYP1A1, CYP17, PPP2R2B, KIF20A, TGFB1, XRCC5, TNF, BCL2, CHFR, CDC25C, ATM, TTC28, CDC25C, HFE, and hTERT genes using Multiplex Polymerase Chain Reaction and MassArray methods. Kaplan–Meier survival analysis, univariate and multivariate Cox proportional hazards gamma shared frailty models adjusted for sex were used to estimate the association between age at cancer diagnosis and polymorphism genotypes. A p-value < 0.05 after correcting for multiple testing using the Benjamini–Hochberg method was considered significant at a 95% confidence interval. Results: We identified three genotypes in the cell-cycle regulation, DNA repair, and xenobiotic-metabolism genes significantly associated with age at cancer diagnosis in this cohort. The CYP1A1 rs4646903 risk (GG) and CDC25C rs3734166 polymorphic (GA+AA) genotypes were significantly associated with an increased risk of a younger age at cancer diagnosis (Adj HR: 2.03 [1.01–4.08], p = 0.034 and Adj HR: 1.53 [1.09–2.14], p = 0.015, respectively). LSVH who were heterozygous for the XRCC5 rs1051685 SNP showed significant protection against younger age at cancer diagnosis (Adj HR: 0.69 [CI, 0.48–0.99], p = 0.043). The risk of a younger age at any cancer diagnosis was significantly high in LS carriers of one to two risk genotypes (Adj HR: 1.49 [CI: 1.06–2.09], corrected p = 0.030), while having one to two protective genotypes significantly reduced the risk of developing any cancer and CRC at a younger age (Adj HR: 0.52 [CI: 0.37–0.73], and Adj HR: 0.51 [CI: 0.36–0.74], both corrected p < 0.001). Conclusions: Polymorphism genotypes in the cell-cycle regulation, DNA repair, and xenobiotic metabolizing genes may influence the age at cancer diagnosis in a homogenous LS cohort with a South African founder germline PV c.1528C>T in the MLH1 gene.

Background The objective of the PERSONAL‐CovidBP (Personalised Electronic Record Supported Optimisation When Alone for Patients With Hypertension: Pilot Study for Remote Medical Management of Hypertension During the COVID‐19 Pandemic) trial was to assess the efficacy and safety of smartphone‐enabled remote precision dosing of amlodipine to control blood pressure (BP) in participants with primary hypertension during the COVID‐19 pandemic. Methods and Results This was an open‐label, remote, dose titration trial using daily home self‐monitoring of BP, drug dose, and side effects with linked smartphone app and telemonitoring. Participants aged ≥18 years with uncontrolled hypertension (5–7 day baseline mean ≥135 mm Hg systolic BP or ≥85 mm Hg diastolic BP) received personalized amlodipine dose titration using novel (1, 2, 3, 4, 6, 7, 8, 9 mg) and standard (5 and 10 mg) doses daily over 14 weeks. The primary outcome of the trial was mean change in systolic BP from baseline to end of treatment. A total of 205 participants were enrolled and mean BP fell from 142/87 (systolic BP/diastolic BP) to 131/81 mm Hg (a reduction of 11 (95% CI, 10–12)/7 (95% CI, 6–7) mm Hg, P

High-latitude (∣ b ∣ > 30°) molecular clouds have virial parameters that exceed 1, but whether these clouds can form stars has not been studied systematically. Using JCMT SCUBA-2 archival data, we surveyed 70 fields that target high-latitude Planck Galactic cold clumps (HLPCs) to find dense cores with density of 10 ^5 –10 ^6 cm ^−3 and size of 1 × 10 ^21 cm ^−2 ). At an average rms of 15 mJy beam ^−1 , we detected Galactic dense cores in only one field, G6.04+36.77 (L183) while also identifying 12 extragalactic objects and two young stellar objects. Compared to the low-latitude clumps, dense cores are scarce in HLPCs. With synthetic observations, the densities of cores are constrained to be n _c ≲ 10 ^5 cm ^−3 should they exist in HLPCs. Low-latitude clumps, Taurus clumps, and HLPCs form a sequence where a higher virial parameter corresponds to a lower dense-core detection rate. If HLPCs were affected by the Local Bubble, the scarcity should favor turbulence-inhibited rather than supernova-driven star formation. Studies of the formation mechanism of the L183 molecular cloud are warranted.

**Background:** Gastro-oesophageal reflux disease (GORD) is a common condition associated with heartburn and regurgitation. Standard of care for GORD patients in the UK involves initial treatment with proton pump inhibitors (PPIs) and laparoscopic antireflux surgery in patients unwilling to continue or intolerant of long-term PPI treatment. Recently, RefluxStop™, a novel, implantable medical device, has proven to be an efficacious and cost-effective treatment for patients with GORD. The current analysis aimed to describe the budget impact of introducing RefluxStop™ within National Health Service (NHS) England and Wales. **Objectives:** To estimate the more immediate, short-term clinical and economic effects of introducing RefluxStop™ as a therapeutic option for patients with GORD treated within NHS England and Wales. **Methods:** A model adherent to international best practice guidelines was developed to estimate the budget impact of introducing RefluxStop™ over a 5-year time horizon, from an NHS perspective. Two hypothetical scenarios were considered, one without RefluxStop™ (comprising PPI treatment, laparoscopic Nissen fundoplication, and magnetic sphincter augmentation using the LINX® system) and one with RefluxStop™ (adding RefluxStop™ to the aforementioned treatment options). Clinical benefits and costs associated with each intervention were included in the analysis. **Results:** Over 5 years, introducing RefluxStop™ allowed the avoidance of 347 surgical failures, 39 reoperations, and 239 endoscopic esophageal dilations. The financial impact of introducing RefluxStop™ was £3 029 702 in year 5, corresponding to a 1.68% increase in annual NHS spending on GORD treatment in England and Wales. **Discussion:** While the time horizon was too short to capture some of the adverse events of PPIs and complications of GORD, such as the development of Barrett’s esophagus or esophageal cancer, the use of RefluxStop™ was associated with a substantial reduction in surgical complications, including surgical failures, reoperations, and endoscopic esophageal dilations. This favorable clinical profile resulted in cost offsets for the NHS and contributed to the marginal budget impact of RefluxStop™ estimated in the current analysis. **Conclusions:** Introducing RefluxStop™ as a treatment option for patients with GORD in England and Wales may be associated with clinical benefits at the expense of a marginal budget impact on the NHS.

The radio transient ASKAP J173608.2–321635, at the position ( ℓ , b ) = (356.°0872, −0.°0390), was serendipitously observed by The H i /OH/Recombination line survey of the Galactic center at three epochs in 2020 March, 2020 April, and 2021 February. The source was detected only on 2020 April 11 with a flux density of 20.6 ± 1.1 mJy at 1.23 GHz and in-band spectral index of α = −3.1 ± 0.2. The commensal Very Large Array Low-band Ionsophere and Transient Experiment simultaneously detected the source at 339 MHz with a flux density of 122.6 ± 20.4 mJy, indicating a spectral break below 1 GHz. The rotation measure (RM) in 2020 April was 63.9 ± 0.3 rad m ^−2 , which almost triples the range of the variable RM observed by Wang et al. to ∼130 rad m ^−2 . The polarization angle, corrected for Faraday rotation, was 97° ± 6°. The 1.23 GHz linear polarization was 76.7% ± 3.9% with wavelength-dependent depolarization, indicating a Faraday depth dispersion of ${\sigma }_{\phi }={4.8}_{-0.7}^{+0.5}\ \mathrm{rad}\ {{\rm{m}}}^{-2}$ . We find an upper limit to the circular polarization of ∣ V ∣/ I < 10.1%. Interpretation of the data in terms of diffractive scattering of radio waves by a plasma near the source indicates an electron density and a line-of-sight magnetic field strength within a factor of 3 of n _e ∼ 2 cm ^−3 and B _∥ ∼ 2 × 10 ^5 μ G . Combined with causality limits to the size of the source, these parameters are consistent with the low-frequency spectral break resulting from synchrotron self-absorption, not free–free absorption. A possible interpretation of the source is a highly supersonic neutron star interacting with a changing environment.

The use of DNA barcoding has revolutionised biodiversity science, but its application depends on the existence of comprehensive and reliable reference libraries. For many poorly known taxa, such reference sequences are missing even at higher-level taxonomic scales. We harvested the collections of the Smithsonian’s National Museum of Natural History (USNM) to generate DNA barcoding sequences for genera of terrestrial arthropods previously not recorded in one or more major public sequence databases. Our workflow used a mix of Sanger and Next-Generation Sequencing (NGS) approaches to maximise sequence recovery while ensuring affordable cost. In total, COI sequences were obtained for 5,686 specimens belonging to 3,737 determined species in 3,886 genera and 205 families distributed in 137 countries. Success rates varied widely according to collection data and focal taxon. NGS helped recover sequences of specimens that failed a previous run of Sanger sequencing. Success rates and the optimal balance between Sanger and NGS are the most important drivers to maximise output and minimise cost in future projects. The corresponding sequence and taxonomic data can be accessed through the Barcode of Life Data System, GenBank, the Global Biodiversity Information Facility, the Global Genome Biodiversity Network Data Portal and the NMNH data portal.

Abstract Exploring the role of changing climates in human evolution is currently impeded by a scarcity of climatic information at the same temporal scale as the human behaviors documented in archaeological sites. This is mainly caused by high uncertainties in the chronometric dates used to correlate long-term climatic records with archaeological deposits. One solution is to generate climatic data directly from archaeological materials representing human behavior. Here we use oxygen isotope measurements of Bos/Bison tooth enamel to reconstruct summer and winter temperatures in the Late Pleistocene when Neandertals were using the site of La Ferrassie. Our results indicate that, despite the generally cold conditions of the broader period and despite direct evidence for cold features in certain sediments at the site, Neandertals used the site predominantly when climatic conditions were mild, similar to conditions in modern day France. We suggest that due to millennial scale climate variability, the periods of human activity and their climatic characteristics may not be representative of average conditions inferred from chronological correlations with long-term climatic records. These results highlight the importance of using direct routes, such as the high-resolution archives in tooth enamel from anthropogenically accumulated faunal assemblages, to establish climatic conditions at a human scale.

We present the continued analysis of polarization and Faraday rotation for the supernova remnants (SNRs) G46.8−0.3 and G39.2−0.3 in L -band (1–2 GHz) radio continuum in The H i /OH/Recombination line (THOR) survey. In this work, we present our investigation of Faraday depth fluctuations from angular scales comparable to the size of the SNRs down to scales less than our 16″ beam (≲0.7 pc) from Faraday dispersion ( σ _ϕ ). From THOR, we find median σ _ϕ of 15.9 ± 3.2 rad m ^−2 for G46.8−0.3 and 17.6 ± 1.6 rad m ^−2 for G39.2−0.3. When comparing to polarization at 6 cm, we find evidence for σ _ϕ ≳ 30 rad m ^−2 in localized regions where we detect no polarization in THOR. We combine Faraday depth dispersion with the rotation measure (RM) structure function (SF) and find evidence for a break in the SF on scales less than the THOR beam. We estimate the RM SF of the foreground interstellar medium using the SF of extragalactic radio sources and pulsars to find that the RM fluctuations we measure originate within the SNRs for all but the largest angular scales.

Pharmacokinetic (PK) predictions of new chemical entities are aided by prior knowledge from other compounds. The development of robust algorithms that improve preclinical and clinical phases of drug development remains constrained by the need to search, curate and standardise PK information across the constantly-growing scientific literature. The lack of centralised, up-to-date and comprehensive repositories of PK data represents a significant limitation in the drug development pipeline.In this work, we propose a machine learning approach to automatically identify and characterise scientific publications reporting PK parameters from in vivo data, providing a centralised repository of PK literature. A dataset of 4,792 PubMed publications was labelled by field experts depending on whether in vivo PK parameters were estimated in the study. Different classification pipelines were compared using a bootstrap approach and the best-performing architecture was used to develop a comprehensive and automatically-updated repository of PK publications. The best-performing architecture encoded documents using unigram features and mean pooling of BioBERT embeddings obtaining an F1 score of 83.8% on the test set. The pipeline retrieved over 121K PubMed publications in which in vivo PK parameters were estimated and it was scheduled to perform weekly updates on newly published articles. All the relevant documents were released through a publicly available web interface (https://app.pkpdai.com) and characterised by the drugs, species and conditions mentioned in the abstract, to facilitate the subsequent search of relevant PK data. This automated, open-access repository can be used to accelerate the search and comparison of PK results, curate ADME datasets, and facilitate subsequent text mining tasks in the PK domain.

The anthelmintic dinitroaniline oryzalin interferes with the formation of microtubules and inhibits meiosis and mitosis in nematodes. Exposure to oryzalin resulted in deterioration in morphology of the oocytes and loss of synaptonemal complexes at meiotic prophase I. The nuclear matrix and envelope were poorly formed, and the central rachis was diminished. These results provide the basis for the loss of fecundity after treatment with the oryzalin resulting in control of parasitic nematodes.

Education for Sustainable Development (ESD) was added to the South African Geography school curriculum when the Curriculum Assessment Policy Statement (CAPS) was implemented from 2012. Many in-service teachers who qualified prior to 2014 did not cover this concept during their initial teacher education qualification because it was not part of the curriculum at that time. To address this deficiency, a teacher professional development (TPD) module was developed by the Fundisa for Change programme and offered to a selection of in-service high school Geography teachers. Transformative learning theory helped to understand the pedagogical practices used by teachers after attending the Fundisa for Change teacher professional development programme, in particular the use of a learner-centred approach. Using a small-scale, qualitative and interpretive case study method, the influence of this short TPD course on the teaching of climate change in the Geography CAPS curriculum on teachers’ pedagogical practices was investigated. Data were collected through semi-structured interviews, document analysis and lesson observations. Data were analysed using both inductive thematic and deductive analysis. Findings from this small sample of five teachers and their practices suggest that despite attending the programme, most of the participating teachers did not sufficiently integrate climate change education in their Geography classroom practices. The majority of the research participants did not implement the learner-centred teaching methods covered in the course. It is therefore recommended that a teacher professional development programme should be incorporated into longer-term and preferably ongoing professional development programmes so as to adequately foster climate change education in classroom practices.

The Countering Violent Extremism (CVE) discourse in Kenya reflects the larger Global War on Terror (GWOT) policy framework. Donor-driven governmental approaches support the top-down efforts to counter violent extremism. CVE initiatives now emerging in response to the rise of homegrown violent extremism in Kenya, in contrast, seek to encourage more community participation in the campaign to limit the activities of Al-Shabaab. This article examines existing countering violent extremism (CVE) initiatives in order to elucidate the effectiveness and shortcomings of CVE interventions. The findings are based on an ethnographic study in the coastal region of Kenya comprising of 249 in-depth interviews with key informants, observations and eight focus group discussions. The article maps existing CVE projects across Kenya’s coast including the prevention framework of primary, secondary and tertiary interventions as modelled on preventative public health approaches. Assessment of existing CVE programs provides information elucidating what works and for whom from a community perspective. Feedback from the community is critical for, facilitating effective measures for mitigating the process of youth radicalization in the coast region. The findings reported here recommend periodic consultation with the intended beneficiaries and other CVE initiatives’ stakeholders to enhance the sustainability of the projects.

This article contains data on clinical endpoints (Peak Flow Expiratory Rate, fractional exhaled nitric oxide and total IgE serum levels) and plasma pharmacokinetic parameters concerning the use of the oral CRTh2 antagonist QAW039 (fevipiprant) in mild to moderate asthma patients. Information on experimental design and methods on how this data was obtained is also described. Further interpretation and discussion of this data can be found in the article “The oral CRTh2 antagonist QAW039 (fevipiprant): a phase II study in uncontrolled allergic asthma” (Erpenbeck et al., in press) [1].

Interpretations and analytical practices surrounding DNA barcoding are examined using a compilation of 3,756 papers (as of December 31, 2018) with “DNA Barcode” in the abstract published since 2004. By examining the rise of DNA barcoding in natural history and biodiversity science over this period, we hope to detect the extent to which its purposes, premises, rationale and application have evolved. The number of studies involving identification, taxonomic decisions and the discovery of cryptic species has grown rapidly and appears to have driven much of the publication activity of DNA barcode studies overall. Forensic studies and papers on biological conservation involving DNA barcodes have loosely tracked the ensemble number of studies but appear to have risen sharply in 2017. Although analytical paradigms have diversified, particularly following the growing availability of tools in BoLD, neighbor-joining and graphic (tree-based) criteria for species delimitation remain preeminent. We conclude that the practices and paradigms of DNA barcoding data are likely to persist and, in groups such as Lepidoptera, remain a widely used tool in taxonomic science.

The Neotropical genus Schacontia Dyar (1914) is reviewed and revised to include eleven species. Schacontia replica Dyar, 1914, syn. n. and S. pfeifferi Amsel, 1956, syn. n. are synonymized with S. chanesalis (Druce, 1899) and eight new species are described: Schacontia umbra, sp. n., S. speciosa, sp. n., S. themis, sp. n., S. rasa, sp. n., S. nyx, sp. n., S. clotho, sp. n., S. lachesis, sp. n., and S. atropos, sp. n. Three species, S. medalba, S. chanesalis, and S. ysticalis, are re-described. An analysis of 64 characters (56 binary, 8 multistate; 5 head, 13 thoracic, 13 abdominal, 25 male genitalic, and 8 female genitalic) scored for all Schacontia and three outgroup species (Eustixia pupula Hübner, 1823, Glaphyria sesquistrialis Hübner, 1823, and Hellula undalis (Fabricius, 1781)) retrieved 8 equally most parsimonious trees (L=102, CI=71, RI=84) of which the strict consensus is: [[[[medalba + umbra] + chanesalis] + speciosa] + [ysticalis + [rasa + themis + [atropos + lachesis + nyx + clotho]]]]. The relevance of male secondary sexual characters to the diagnosis of Schacontia species is discussed.

Using a sociological framework this article explores the emergence and possible consequences of the 2015 U.S. Department of Education’s proposed federal regulatory policy on teacher education programs and alternative route providers. After describing the key features of the policy, we examine the research literature looking for evidence of the merits of accountability policies in improving teacher education and preparation quality and outcomes. Although there is some research evidence that increased accountability measures may indeed contribute to improving the quality and outcomes of teacher education and preparation, the conditions under which this happens are not straightforward. While the stated aim of the regulatory policy, to ultimately advance student learning, finds widespread support in the education community, research evidence points to a number of validity problems with the overall policy. Of particular concern is the policy’s attempts at establishing a direct link between teacher preparation and two of the regulations’ suggested outcomes, namely graduates’ employment and pupil achievement. The policy as conceived could negatively impact program norms and resources and undermine the development of teachers’ human, cultural, and social capital. We discuss the accreditation challenges that the policy is likely to confront and implications for the future of teacher education and preparation accountability.

Given the limited studies conducted within the African continent, the purpose of this study was to investigate the impact of chronic aircraft noise exposure and the moderating effect of home language on the learners′ reading comprehension. The sample comprised 437 (52%) senior primary learners exposed to high levels of aircraft noise (Experimental group) and 337 (48%) learners residing in a quieter area (Control group). Of these, 151 learners in the Experimental group spoke English as a first language (EFL) and 162 spoke English as a second language (ESL). In the Control group, the numbers were similarly divided (EFL n = 191; ESL n = 156). A univariate General Linear Model was used to investigate the effects of aircraft noise exposure and language on reading comprehension, while observing for the possible impact of intellectual ability, gender, and socioeconomic status on the results. A significant difference was observed between ESL and EFL learners in favor of the latter (F 1,419 = 21.95, P =.000). In addition a substantial and significant interaction effect was found between the experimental and control groups for the two language groups. For the EFL speakers there was a strong reduction in reading comprehension in the aircraft noise group. By contrast this difference was not significant for the ESL speakers. Implications of the findings and suggestions for further research are made in the article.

We previously reported the presence of MUC2, MUC5AC and, for the first time, MUC5B in a 58-year-old male with pseudomyxoma peritonei (PMP). This is a report on the biochemical and immunohistochemical characterization of mucin in a 50-year-old female with the same rare illness. A right oophorectomy and appendicectomy and a resection of the involved omentum were performed. Approximately a litre of crude material in the sol and gel phases was obtained from the patient during laparotomy. This was briefly homogenized in 6 M guanidinium hydrochloride and proteolytic inhibitors and purified by density gradient centrifugation in caesium chloride. At laparotomy it was noted that the patient had appendiceal and ovarian masses as well as extensive mucinous deposits in the omentum and peritoneum. A mucinous adenocarcinoma of the appendix and ovary was confirmed on histology. The cells expressed both sulphated and non-sulphated acidic mucins. The presence of MUC2, MUC5AC, MUC5B and α-1-acid glycoprotein was shown by Western blotting and MUC4 by immunohistochemical staining. MUC1 and MUC6 were not detectable in the tissue. The study confirms that MUC2, MUC5AC and MUC5B are produced in the mucus of patients with PMP. The expression of MUC4 in this disease has not been previously reported.

Various studies have presented clinical or in vitro evidence linking bacteria to colorectal cancer, but these bacteria have not previously been concurrently quantified by qPCR in a single cohort. We quantify these bacteria (Fusobacterium spp., Streptococcus gallolyticus, Enterococcus faecalis, Enterotoxigenic Bacteroides fragilis (ETBF), Enteropathogenic Escherichia coli (EPEC), and afaC- or pks-positive E. coli) in paired tumour and normal tissue samples from 55 colorectal cancer patients. We further investigate the relationship between a) the presence and b) the level of colonisation of each bacterial species with site and stage of disease, age, gender, ethnicity and MSI-status. With the exception of S. gallolyticus, we detected all bacteria profiled here in both tumour and normal samples at varying frequencies. ETBF (FDR = 0.001 and 0.002 for normal and tumour samples) and afaC-positive E. coli (FDR = 0.03, normal samples) were significantly enriched in the colon compared to the rectum. ETBF (FDR = 0.04 and 0.002 for normal and tumour samples, respectively) and Fusobacterium spp. (FDR = 0.03 tumour samples) levels were significantly higher in late stage (III/IV) colorectal cancers. Fusobacterium was by far the most common bacteria detected, occurring in 82% and 81% of paired tumour and normal samples. Fusobacterium was also the only bacterium that was significantly higher in tumour compared to normal samples (p = 6e-5). We also identified significant associations between high-level colonisation by Fusobacterium and MSI-H (FDR = 0.05), age (FDR = 0.03) or pks-positive E. coli (FDR = 0.01). Furthermore, we exclusively identified atypical EPEC in our cohort, which has not been previously reported in association with colorectal cancer. By quantifying colorectal cancer-associated bacteria across a single cohort, we uncovered inter- and intra-individual patterns of colonization not previously recognized, as well as important associations with clinicopathological features, especially in the case of Fusobacterium and ETBF.

The rotor thermal bending due to the rotor-to-stator rubbing can lead to one of three types of observed rotor lateral motion: (1) spiral with increasing amplitude, (2) oscillating between rub]no-rub conditions, and (3) asymptotical approach to the rotor limit cycle. Based on the machinery observations, it is assumed in the analytical part of the paper that the speed scale of transient thermal effects is considerably lower than that of rotor vibrations, and that the thermal effect reflects only on the rotor steady-state vibrational response. This response would change due to thermally induced bow of the rotor, which can be considered to slowly vary in timefor the purpose of rotor vibration calculations. Thus uncoupled from the thermal problem, the rotor vibration is analyzed. The major consideration is given to the rotor which experiences intermittent contact with the stator, due to predetermined thermal bow, unbalance force, and radial constant load force. In the case of inelastic impact, it causes an on/off, step-change in the stiffness of the system. Using a specially developed variable transformation for the system with discontinuities, and averaging technique the resonance regimes of motion are obtained. These regimes are used to calculate the heat generated during contact stage, as a function of thermal bow modal parameters, which is used as a boundary condition for the rotor heat transfer problem. The latter is treated as quasi-static, which reduces the problem to an ordinary differential equation for the thermal bow vector. It is investigated from the stability standpoint.

This paper presents an analytical model of a rigid rotor supported in two fluid film bearings with an emphasis on predicting the instability threshold speed. The factors contributing to the stability of the rotor are discussed and presented graphically using root locus plots. The parametric study of the stability starts from the discussion of the rotor/bearing system with “mirror symmetry”. Three basic cases are considered:

Zebrafish are becoming increasingly popular as an organism in which to model human disease and to study the effects of small molecules on complex physiological and pathological processes. Since larvae are no more than a few millimetres in length, and can live in volumes as small as 100 microliters, they are particularly amenable to high-throughput and high content compound screening in 96 well plate format. There is a growing literature providing evidence that many compounds show similar pharmacological effects in zebrafish as they do in mammals, and in particular humans. However, a major question regarding their utility for small molecule screening for neurological conditions is whether a molecule will reach its target site within the central nervous system. Studies have shown that Claudin-5 and ZO-1, tight-junction proteins which are essential for blood-brain barrier (BBB) integrity in mammals, can be detected in some cerebral vessels in zebrafish from 3 days post-fertilisation (d.p.f.) onwards and this timing coincides with the retention of dyes, immunoreactive tracers and fluorescent markers within some but not all cerebral vessels. Whilst these findings demonstrate that features of a BBB are first present at 3 d.p.f., it is not clear how quickly the zebrafish BBB matures or how closely the barrier resembles that of mammals. Here, we have combined anatomical analysis by transmission electron microscopy, functional investigation using fluorescent markers and compound uptake using liquid chromatography/tandem mass spectrometry to demonstrate that maturation of the zebrafish BBB occurs between 3 d.p.f. and 10 d.p.f. and that this barrier shares both structural and functional similarities with that of mammals.

We previously reported the identification of TUSC1 (Tumor Suppressor Candidate 1), as a novel intronless gene isolated from a region of homozygous deletion at D9S126 on chromosome 9p in human lung cancer. In this study, we examine the differential expression of TUSC1 in human lung cancer cell lines by western blot and in a primary human lung cancer tissue microarray by immunohistochemical analysis. We also tested the functional activities and mechanisms of TUSC1 as a tumor suppressor gene through growth suppression in vitro and in vivo. The results showed no expression of TUSC1 in TUSC1 homozygously deleted cells and diminished expression in some tumor cell lines without TUSC1 deletion. Interestingly, the results from a primary human lung cancer tissue microarray suggested that higher expression of TUSC1 was correlated with increased survival times for lung cancer patients. Our data demonstrated that growth curves of tumor cell lines transfected with TUSC1 grew slower in vitro than those transfected with the empty vector. More importantly, xenograph tumors in nude mice grew significantly slower in vivo in cells stably transfected with TUSC1 than those transfected with empty vector. In addition, results from confocal microscopy and immunohistochemical analyses show distribution of TUSC1 in the cytoplasm and nucleus in tumor cell lines and in normal and tumor cells in the lung cancer tissue microarray. Taken together, our results support TUSC1 has tumor suppressor activity as a candidate tumor suppressor gene located on chromosome 9p.

Background. Self-expanding metal stents can alleviate malignant colonic obstruction in incurable patients and avoid palliative stoma surgery. Objective. Evaluate stent effectiveness and safety on palliation of patients with malignant colorectal strictures. Design. Two prospective, one Spanish and one global, multicenter studies. Settings. 39 centers (22 academic, 17 community hospitals) from 13 countries. Patients. A total of 257 patients were enrolled, and 255 patients were treated with a WallFlex uncovered enteral colonic stent. Follow-up was up to 12 months or until death or retreatment. Interventions(s). Self-expanding metal stent placement. Main Outcome Measures. Procedural success, clinical success, and safety. Results. Procedural success was 98.4% (251). Clinical success rates were 87.8% at 30 days, 89.7% at 3 months, 92.8% at 6 months, and 96% at 12 months. Overall perforation rate was 5.1%. Overall migration rate was 5.5%. Overall death rate during follow-up was 48.6% (124), with 67.7% of deaths related to the patient’s colorectal cancer, unrelated in 32.3%. Only 2 deaths were related to the stent or procedure. Limitations. No control group. Conclusions. The primary palliative option for patients with malignant colonic obstruction should be self-expanding metal stent placement due to high rates of technical success and efficacy in symptom palliation and few complications.

The sperm protein associated with nucleus in the X chromosome (SPANX) genes cluster at Xq27 in two subfamilies, SPANX-A/D and SPANX-N. SPANX-A/D is specific for hominoids and is fairly well characterized. The SPANX-N gave rise to SPANX-A/D in the hominoid lineage approximately 7 MYA. Given the proposed role of SPANX genes in spermatogenesis, we have extended studies to SPANX-N gene evolution, variation, regulation of expression, and intra-sperm localization. By immunofluorescence analysis, SPANX-N proteins are localized in post-meiotic spermatids exclusively, like SPANX-A/D. But in contrast to SPANX-A/D, SPANX-N are found in all ejaculated spermatozoa rather than only in a subpopulation, are localized in the acrosome rather than in the nuclear envelope, and are expressed at a low level in several nongametogenic adult tissues as well as many cancers. Presence of a binding site for CTCF and its testis-specific paralogue BORIS in the SPANX promoters suggests, by analogy to MAGE-A1 and NY-ESO-1, that their activation in spermatogenesis is mediated by the programmed replacement of CTCF by BORIS. Based on the relative density of CpG, the more extended expression of SPANX-N compared to SPANX-A/D in nongametogenic tissues is likely attributed to differences in promoter methylation. Our findings suggest that the recent duplication of SPANX genes in hominoids was accompanied by different localization of SPANX-N proteins in post-meiotic sperm and additional expression in several nongonadal tissues. This suggests a corresponding functional diversification of SPANX gene families in hominoids. SPANX proteins thus provide unique targets to investigate their roles in the function of spermatozoa, selected malignancies, and for SPANX-N, in other tissues as well.