Search

This paper presents a review of the most relevant current techniques that deal with hole-filling in 3D models. Contrary to earlier reports, which approach mesh repairing in a sparse and global manner, the objective of this review is twofold. First, a specific and comprehensive review of hole-filling techniques (as a relevant part in the field of mesh repairing) is carried out. We present a brief summary of each technique with attention paid to its algorithmic essence, main contributions and limitations. Second, a solid comparison between 34 methods is established. To do this, we define 19 possible meaningful features and properties that can be found in a generic hole-filling process. Then, we use these features to assess the virtues and deficiencies of the method and to build comparative tables. The purpose of this review is to make a comparative hole-filling state-of-the-art available to researchers, showing pros and cons in a common framework.

Background: Dengue is the most important human viral disease transmitted by arthropod vectors. The availability of random peptide libraries (RPL) displayed on phage has provided a powerful tool for selecting sequences that mimic epitopes from microorganisms that are useful for diagnostic and vaccine development purposes. In this paper, we describe peptides that resemble the antigenic structure of B-cell epitopes of dengue virus identified from a phage-peptide library using human sera containing polyclonal antibodies against dengue virus. Materials and Methods: Eighteen phage clones were isolated from the phage-display peptide library, J404, by affinity selection using human antisera against dengue virus type 3. These clones were tested for reactivity by ELISA with a panel of hyperimmune ascitic fluids (HAFs) containing antibodies either against all four dengue serotypes, West Nile virus (WNV) or Eastern equine encephalitis virus (EEEV) with control ascitic fluid (NAF) used as a negative control. Results: Eight clones were recognized by HAFs against the four dengue serotypes, of which four significantly inhibited binding of anti-dengue antibodies to the virus. Two peptides with similar sequences to regions of NS3 and NS4B non-structural dengue virus proteins were identified. Conclusion: Our results suggest that these peptides could be used for the development of diagnostic tools for the detection of dengue virus infection and for a potential vaccine against this pathogen. [ABSTRACT FROM AUTHOR]

Introduction: Lymph-nodal involvement (N+) represents an adverse prognostic factor after pancreatoduodenectomy (PD) for pancreatic adenocarcinoma (PDAC). Preoperative diagnostic and staging modalities lack sensitivity for identifying N+. This study aimed to investigate preoperative carbohydrate antigen 19.9 (CA 19.9) in predicting the N+ stage in resectable-PDAC (R-PDAC)., Methods: Patients included in a multi-institutional retrospective database of PDs performed for R-PDAC from January 2000 to June 2021 were analysed. A preoperative laboratory value of CA 19.9 greater than 37 U/l was used in univariate and multivariate logistic regression analysis to determine a possible association with N+. Additionally, different cut-offs of CA 19.9 related to the preoperative clinical T (cT) stage was assessed to evaluate the risk of N+., Results: A total of 2034 PDs from thirteen centres were included in the study. CA 19.9 greater than 37 U/l was significantly associated with higher N+ at univariate and multivariate analysis ( P <0.001). CA 19.9 levels greater than 37 U/l were associated with N+ in 75.9%, 81.3%, and 85.7% of patients, respectively, in cT1, cT2, and cT3 tumours and with higher cut-off values for all cT stages., Conclusion: Lymph-nodal involvement is strongly related to preoperative CA 19.9 levels. Specially in patients staged as cT3 the CA 19.9 could represent a valid and easy tool to suspect nodal involvement. Due to these findings, R-PDAC patients with elevated CA 19.9 values should be considered in a more biologically advanced stage., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Identifying transcriptional enhancers and their target genes is essential for understanding gene regulation and the impact of human genetic variation on disease 1-6 . Here we create and evaluate a resource of >13 million enhancer-gene regulatory interactions across 352 cell types and tissues, by integrating predictive models, measurements of chromatin state and 3D contacts, and largescale genetic perturbations generated by the ENCODE Consortium 7 . We first create a systematic benchmarking pipeline to compare predictive models, assembling a dataset of 10,411 elementgene pairs measured in CRISPR perturbation experiments, >30,000 fine-mapped eQTLs, and 569 fine-mapped GWAS variants linked to a likely causal gene. Using this framework, we develop a new predictive model, ENCODE-rE2G, that achieves state-of-the-art performance across multiple prediction tasks, demonstrating a strategy involving iterative perturbations and supervised machine learning to build increasingly accurate predictive models of enhancer regulation. Using the ENCODE-rE2G model, we build an encyclopedia of enhancer-gene regulatory interactions in the human genome, which reveals global properties of enhancer networks, identifies differences in the functions of genes that have more or less complex regulatory landscapes, and improves analyses to link noncoding variants to target genes and cell types for common, complex diseases. By interpreting the model, we find evidence that, beyond enhancer activity and 3D enhancer-promoter contacts, additional features guide enhancerpromoter communication including promoter class and enhancer-enhancer synergy. Altogether, these genome-wide maps of enhancer-gene regulatory interactions, benchmarking software, predictive models, and insights about enhancer function provide a valuable resource for future studies of gene regulation and human genetics., Competing Interests: Conflict of Interest Statement Z.A. is employed by Google DeepMind. J.C.U. is an employee of Illumina, Inc. D.R.K. is employed by Calico Life Sciences LLC. Z.W. co-founded Rgenta Therapeutics, and she serves as a scientific advisor for the company and is a member of its board. W.J.G. is an inventor on IP licensed by 10x Genomics. A.Kundaje is on the scientific advisory board of PatchBio, SerImmune and OpenTargets, was a consultant with Illumina, and owns shares in DeepGenomics, ImmunAI and Freenome. J.M.E. is a consultant and equity holder in Martingale Labs, Inc. and has received materials from 10x Genomics unrelated to this study.

We possess rather little detailed information on the lives of the first inhabitants of Puerto Rico-the so-called "Archaic" or "Pre-Arawak" people-despite more than a century of archeological research. This is particularly true bioarchaeologically, as fewer than twenty burials of the several millennia of the Archaic Age have been recovered, let alone analyzed in any detail. Here, we present the results of archeological, osteological, radiometric, and isotopic analysis of five individuals from the Ortiz site in Cabo Rojo, southwestern Puerto Rico. Study of these previously unpublished remains, which represent a 20-25% increase in the sample size of remains attributed to the period, provides many critical insights into earliest Puerto Rican lifeways, including aspects of mortuary practice, paleodiet, and possibly even social organization. A review of their burial treatment finds a mostly standardized set of mortuary practices, a noteworthy finding given the site's potential millennium-long use as a mortuary space and the possibly distinct place(s) of origin of the individuals interred there. Although osteological analysis was limited by poor preservation, we were able to reconstruct aspects of the demography that indicate the presence of both male and female adults. Stable isotope analysis revealed dietary differences from later Ceramic Age individuals, while dental pathology indicated heavy masticatory wear attributable to diet and/or non-masticatory function. Perhaps most crucially, direct AMS dating of the remains confirms these as the oldest burials yet recovered from the island, providing us both with a glimpse into the lives of some of the island's first inhabitants, and with tantalizing clues to the existence of a different degree of cultural "complexity" than is often ascribed to these earliest peoples. The existence of what radiocarbon dates suggest may be a persistent formal cemetery space at the Ortiz site has potentially significant implications concerning the territoriality, mobility, and social organization of the earliest peoples of southwestern Puerto Rico., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Pestle et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Immune checkpoint blockers (ICBs) have failed in all phase III glioblastoma trials. Here, we found that ICBs induce cerebral edema in some patients and mice with glioblastoma. Through single-cell RNA sequencing, intravital imaging, and CD8 + T cell blocking studies in mice, we demonstrated that this edema results from an inflammatory response following antiprogrammed death 1 (PD1) antibody treatment that disrupts the blood-tumor barrier. Used in lieu of immunosuppressive corticosteroids, the angiotensin receptor blocker losartan prevented this ICB-induced edema and reprogrammed the tumor microenvironment, curing 20% of mice which increased to 40% in combination with standard of care treatment. Using a bihemispheric tumor model, we identified a "hot" tumor immune signature prior to losartan+anti-PD1 therapy that predicted long-term survival. Our findings provide the rationale and associated biomarkers to test losartan with ICBs in glioblastoma patients.

This research examines the spatial structure of a sample of breast cancer (BC) cases and their spatial interaction with contaminated areas in the Monterrey Metropolitan Area (MMA). By applying spatial statistical techniques that treat the space as a continuum, degrees of spatial concentration were determined for the different study groups, highlighting their concentration pattern. The results indicate that 65 percent of the BC sample had exposure to more than 56 points of PM 10 . Likewise, spatial clusters of BC cases of up to 39 cases were identified within a radius of 3.5 km, interacting spatially with environmental contamination sources, particularly with refineries, food processing plants, cement, and metals. This study can serve as a platform for other clinical research by identifying geographic clusters that can help focus health policy efforts., Competing Interests: The authors declare no conflict of interest., (© 2021 The Authors.)

Targeting of the most aggressive tumor cell subpopulations is key for effective management of most solid malignancies. However, the metastable nature of tumor heterogeneity, which allows cells to transition between strong and weak tumorigenic phenotypes, and the lack of reliable markers of tumor-promoting properties hamper identification of the most relevant cells. To overcome these obstacles, we designed a functional microRNA (miR)-based live-cell reporter assay to identify highly tumorigenic cells in xenotransplants of primary Ewing sarcoma (EwS) 3D cultures. Leveraging the inverse relationship between cell pluripotency and miR-145 expression, we successfully separated highly tumorigenic, metastasis-prone (miR-145 low ) cells from poorly tumorigenic, nonmetastatic (miR-145 high ) counterparts. Gene expression and functional studies of the two cell populations identified the EPHB2 receptor as a prognostic biomarker in patients with EwS and a major promoter of metastasis. Our study provides a simple and powerful means to identify and isolate tumor cells that display aggressive behavior., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

T cells are critical effectors of cancer immunotherapies, but little is known about their gene expression programs in diffuse gliomas. Here, we leverage single-cell RNA sequencing (RNA-seq) to chart the gene expression and clonal landscape of tumor-infiltrating T cells across 31 patients with isocitrate dehydrogenase (IDH) wild-type glioblastoma and IDH mutant glioma. We identify potential effectors of anti-tumor immunity in subsets of T cells that co-express cytotoxic programs and several natural killer (NK) cell genes. Analysis of clonally expanded tumor-infiltrating T cells further identifies the NK gene KLRB1 (encoding CD161) as a candidate inhibitory receptor. Accordingly, genetic inactivation of KLRB1 or antibody-mediated CD161 blockade enhances T cell-mediated killing of glioma cells in vitro and their anti-tumor function in vivo. KLRB1 and its associated transcriptional program are also expressed by substantial T cell populations in other human cancers. Our work provides an atlas of T cells in gliomas and highlights CD161 and other NK cell receptors as immunotherapy targets., Competing Interests: Declaration of interests N.D.M., O.A., I.T., A.R., M.L.S., and K.W.W. are co-inventors of a patent application on the CLEC2D-CD161 pathway for the treatment of cancer. K.W.W., M.L.S., and A.R. are co-founders of Immunitas Therapeutics. K.W.W., M.L.S., and I.T. are advisory board members of Immunitas Therapeutics. K.W.W. serves on the scientific advisory board of TCR2 Therapeutics, T-Scan Therapeutics, SQZ Biotech, and Nextechinvest and received sponsored research funding from Bristol-Myers Squibb and Novartis. A.R. is a founder and equity holder of Celsius Therapeutics, an equity holder in Immunitas Therapeutics, and until August 31, 2020, was an SAB member of Syros Pharmaceuticals, Neogene Therapeutics, Asimov, and Thermo Fisher Scientific. From August 1, 2020, A.R. is an employee of Genentech. N.D.M. serves as a scientific advisor to Immunitas Therapeutics. A.M. is cofounder, member of the Boards of Directors, and member of Scientific Advisory Boards of Spotlight Therapeutics and Arsenal Biosciences. A.M. has served as an advisor to Juno Therapeutics, was a member of the scientific advisory board at PACT Pharma, and an advisor to Trizell. A.M. has received an honorarium from Merck and a consulting fee from AlphaSights and is an investor in and informal advisor to Offline Ventures. A.M. owns stock in Arsenal Biosciences, Spotlight Therapeutics, and PACT Pharma. The Marson lab has received research support from Juno Therapeutics, Epinomics, Sanofi, GlaxoSmithKline, Gilead, and Anthem. E.A.C. is currently an advisor to Advantagene Inc., Alcyone Biosciences, Insightec, Inc., Sigilon Therepeutics, and DNAtrix Inc. and has equity interest in DNAtrix; A.M. has advised Oncorus, Merck, Tocagen, Ziopharm, Stemgen, NanoTx., Ziopharm Oncology, Cerebral Therapeutics, Genenta, Merck, Janssen, Karcinolysis, and Shanaghai Biotech and has received research support from Advantagene, NewLink Genetics, and Amgen. A.M. is a named inventor on patents related to oncolytic HSV1. D.A.R. has received research support from Acerta Phamaceuticals, Agenus, Celldex, EMD Serono, Incyte, Inovio, Midatech, Omniox, and Tragara, and he has served as paid consultant for Abbvie, Advantagene, Agenus, Amgen, Bayer, Bristol-Myers Squibb, Celldex, DelMar, EMD Serono, Genentech/Roche, Inovio, Merck, Merck KGaA, Monteris, Novocure, Oncorus, Oxigene, Regeneron, Stemline, and Taiho Oncology, Inc. P.K.B., outside the scope of this work, has consulted for Angiochem, Genentech-Roche, Lilly, Tesaro, ElevateBio, Pfizer (Array), SK Life Sciences, and Dantari and is supported by the Breast Cancer Research Foundation, Damon Runyon Cancer Research Foundation, Ben and Catherine Ivy Foundation, and the National Cancer Institute (5R01CA244975-02, 5R21CA220253-02, and 5R01CA227156-03), BMS, Lilly, and honoraria from Merck, Genentech-Roche, and Lilly. D.P.C. has consulted for Lilly and Boston Pharmaceuticals and has received honoraria and travel reimbursement from Merck. O.R.-R. is an employee of Genentech since October 2020. O.R.-R. is a co-inventor on patent applications filed by the Broad Institute for inventions relating to work in single-cell genomics, such as in PCT/US2018/060860 and US provisional application 62/745,259. E.A.C. is currently an advisor to Advantagene Inc., Alcyone Biosciences, Insightec Inc., DNAtrix, Immunomic Therapeutics, Sangamo Therapeutics, and Seneca Therapeutics, has equity interest in DNAtrix, Immunomic Therapeutics, and Seneca Therapeutics, and has also advised Oncorus, Merck, Tocagen, Ziopharm, Stemgen, NanoTx., Ziopharm Oncology, Cerebral Therapeutics, Genenta. Merck, Janssen, Karcinolysis, and Shanghai Biotech. E.A.C. has received research support from NIH, US Department of Defense, American Brain Tumor Association, National Brain Tumor Society, Alliance for Cancer Gene Therapy, Neurosurgical Research Education Foundation, Advantagene, NewLink Genetics, and Amgen and also is a named inventor on patents related to oncolytic HSV1 and noncoding RNAs. X.S.L. is a cofounder, board member, and consultant of GV20 Oncotherapy and its subsidiaries, SAB of 3DMedCare, a consultant for Genentech, a stockholder of Bristol Myers Squibb (BMY), Thermo Fisher Scientific (TMO), Walgreens Boots Alliance (WBA), Abbott Laboratories (ABT), AbbVie Inc. (ABBV), and Johnson & Johnson (JNJ), and receives research funding from Takeda and Sanofi., (Copyright © 2021 Elsevier Inc. All rights reserved.)

We present our experience in the implementation of an antibiotic stewardship quality improvement initiative directed toward infants born at ≥35 weeks using as a primary tool the Kaiser Permanente early onset sepsis calculator (KP-EOS-C) at the Baylor Scott & White Medical Center - Frisco. After the approval and support of the medical staff and administration, we proceeded to launch an extensive educational program for all women's services nursing staff on how to utilize this calculator to communicate results to the pediatricians on staff. After implementation, we saw a 54% reduction in the number of infants undergoing sepsis workup evaluations and a 51% reduction in the number of infants receiving antibiotics ( P < 0.001). We conclude that the implementation of this type of initiative may be feasible and worthwhile in other similar community hospitals, provided there is buy-in by physicians and administration as well as an extensive educational program to the hospital medical and nursing staff., (Copyright © 2019 Baylor University Medical Center.)

Diverse genetic, epigenetic, and developmental programs drive glioblastoma, an incurable and poorly understood tumor, but their precise characterization remains challenging. Here, we use an integrative approach spanning single-cell RNA-sequencing of 28 tumors, bulk genetic and expression analysis of 401 specimens from the The Cancer Genome Atlas (TCGA), functional approaches, and single-cell lineage tracing to derive a unified model of cellular states and genetic diversity in glioblastoma. We find that malignant cells in glioblastoma exist in four main cellular states that recapitulate distinct neural cell types, are influenced by the tumor microenvironment, and exhibit plasticity. The relative frequency of cells in each state varies between glioblastoma samples and is influenced by copy number amplifications of the CDK4, EGFR, and PDGFRA loci and by mutations in the NF1 locus, which each favor a defined state. Our work provides a blueprint for glioblastoma, integrating the malignant cell programs, their plasticity, and their modulation by genetic drivers., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Atypical antipsychotic drugs have been associated with the development of obesity and diabetes. In particular, olanzapine can induce peripheral insulin resistance and compensatory hyperinsulinemia independent of weight gain or psychiatric disease. To determine if this compensatory increase in insulin is mediated by parasympathetic muscarinic stimulation, we randomized 15 healthy subjects 2:1 to receive double-blind olanzapine or placebo for 9 days under diet- and activity-controlled inpatient conditions. Before and after 7 days of study drug administration, subjects underwent frequently sampled intravenous glucose tolerance tests with either saline or atropine infused on subsequent days to assess insulin secretion and hepatic insulin extraction in the absence or presence of muscarinic blockade. We found that olanzapine led to an increase in the acute insulin response to glucose, which was not seen with placebo, and was attenuated in the olanzapine group by atropine. Deconvolution of C-peptide data confirmed an increase in insulin secretion with olanzapine, which was blocked by atropine, with a modest reduction in hepatic insulin extraction with olanzapine. These results support the contribution of muscarinic augmentation of insulin secretion to olanzapine-induced hyperinsulinemia, and provide a mechanism for the compensatory hyperinsulinemia that normally serves to prevent deterioration of glucose tolerance under conditions of metabolic challenge.

The human genome folds to create thousands of intervals, called "contact domains," that exhibit enhanced contact frequency within themselves. "Loop domains" form because of tethering between two loci-almost always bound by CTCF and cohesin-lying on the same chromosome. "Compartment domains" form when genomic intervals with similar histone marks co-segregate. Here, we explore the effects of degrading cohesin. All loop domains are eliminated, but neither compartment domains nor histone marks are affected. Loss of loop domains does not lead to widespread ectopic gene activation but does affect a significant minority of active genes. In particular, cohesin loss causes superenhancers to co-localize, forming hundreds of links within and across chromosomes and affecting the regulation of nearby genes. We then restore cohesin and monitor the re-formation of each loop. Although re-formation rates vary greatly, many megabase-sized loops recovered in under an hour, consistent with a model where loop extrusion is rapid., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Previous Epstein-Barr virus (EBV) prophylactic vaccines based on the major surface glycoprotein gp350/220 as an immunogen have failed to block viral infection in humans, suggesting a need to target other viral envelope glycoproteins. In this study, we reasoned that incorporating gH/gL or gB, critical glycoproteins for viral fusion and entry, on the surface of a virus-like particle (VLP) would be more immunogenic than gp350/220 for generating effective neutralizing antibodies to prevent viral infection of both epithelial and B cell lines. To boost the humoral response and trigger cell-mediated immunity, EBV nuclear antigen 1 (EBNA1) and latent membrane protein 2 (LMP2), intracellular latency proteins expressed in all EBV-infected cells, were also included as critical components of the polyvalent EBV VLP. gH/gL-EBNA1 and gB-LMP2 VLPs were efficiently produced in Chinese hamster ovary cells, an FDA-approved vehicle for mass-production of biologics. Immunization with gH/gL-EBNA1 and gB-LMP2 VLPs without adjuvant generated both high neutralizing antibody titers in vitro and EBV-specific T-cell responses in BALB/c mice. These data demonstrate that will be invaluable not only in preventing EBV infection, but importantly, in preventing and treating the 200,000 cases of EBV-associated cancers that occur globally every year.

Background and Objectives: Protein-energy and micronutrient malnutrition are global public health problems which, when not prevented and severe, require medical management by clinicians with nutrition expertise, preferably as a collectively skilled team, especially when disease-related. This study aimed to investigate barriers and facilitators of clinical nutrition services (CNS), especially the use of oral, enteral (EN) and parenteral (PN) nutrition in institutional and home settings., Methods and Study Design: An international survey was performed between January and December 2014 in twenty-six countries from all continents. Electronic questionnaires were distributed to 28 representatives of clinical nutrition (PEN) societies, 27 of whom responded. The questionnaire comprised questions regarding a country's economy, reimbursement for CNS, education about and the use of EN and PN., Results: The prevalence of malnutrition was not related to gross domestic product (GDP) at purchasing power parity (PPP) per capita (p=0.186). EN and PN were used in all countries surveyed (100%), but to different extents. Reimbursement of neither EN nor PN use depended on GDP, but was associated with increased use of EN and PN in hospitals (p=0.035), although not evident for home or chronic care facilities. The size of GDP did not affect the use of EN (p=0.256), but it mattered for PN (p=0.019)., Conclusions: A worldwide survey by nutrition support societies did not find a link between national economic performance and the implementation of medical nutrition services. Reimbursement for CNS, available through health insurance systems, is a factor in effective nutrition management.

DNA vaccination holds the potential to treat or prevent nearly any immunogenic disease, including cancer. To date, these vaccines have demonstrated limited immunogenicity in vivo due to the absence of a suitable delivery system which can protect DNA from degradation and improve transfection efficiencies in vivo. Recently, microneedles have been described as a novel physical delivery technology to enhance DNA vaccine immunogenicity. Of these devices, dissolvable microneedles promise a safe, pain-free delivery system which may simultaneously improve DNA stability within a solid matrix and increase DNA delivery compared to solid arrays. However, to date little work has directly compared the suitability of different dissolvable matrices for formulation of DNA-loaded microneedles. Therefore, the current study examined the ability of 4 polymers to formulate mechanically robust, functional DNA loaded dissolvable microneedles. Additionally, complexation of DNA to a cationic delivery peptide, RALA, prior to incorporation into the dissolvable matrix was explored as a means to improve transfection efficacies following release from the polymer matrix. Our data demonstrates that DNA is degraded following incorporation into PVP, but not PVA matrices. The complexation of DNA to RALA prior to incorporation into polymers resulted in higher recovery from dissolvable matrices, and increased transfection efficiencies in vitro. Additionally, RALA/DNA nanoparticles released from dissolvable PVA matrices demonstrated up to 10-fold higher transfection efficiencies than the corresponding complexes released from PVP matrices, indicating that PVA is a superior polymer for this microneedle application.

Mammalian genomes are pervasively transcribed to produce thousands of long non-coding RNAs (lncRNAs). A few of these lncRNAs have been shown to recruit regulatory complexes through RNA-protein interactions to influence the expression of nearby genes, and it has been suggested that many other lncRNAs can also act as local regulators. Such local functions could explain the observation that lncRNA expression is often correlated with the expression of nearby genes. However, these correlations have been challenging to dissect and could alternatively result from processes that are not mediated by the lncRNA transcripts themselves. For example, some gene promoters have been proposed to have dual functions as enhancers, and the process of transcription itself may contribute to gene regulation by recruiting activating factors or remodelling nucleosomes. Here we use genetic manipulation in mouse cell lines to dissect 12 genomic loci that produce lncRNAs and find that 5 of these loci influence the expression of a neighbouring gene in cis. Notably, none of these effects requires the specific lncRNA transcripts themselves and instead involves general processes associated with their production, including enhancer-like activity of gene promoters, the process of transcription, and the splicing of the transcript. Furthermore, such effects are not limited to lncRNA loci: we find that four out of six protein-coding loci also influence the expression of a neighbour. These results demonstrate that cross-talk among neighbouring genes is a prevalent phenomenon that can involve multiple mechanisms and cis-regulatory signals, including a role for RNA splice sites. These mechanisms may explain the function and evolution of some genomic loci that produce lncRNAs and broadly contribute to the regulation of both coding and non-coding genes.

We describe, for the first time the use of hydrogel-forming microneedle (MN) arrays for minimally-invasive extraction and quantification of drug substances and glucose from skin in vitro and in vivo. MN prepared from aqueous blends of hydrolysed poly(methyl-vinylether-co-maleic anhydride) (11.1% w/w) and poly(ethyleneglycol) 10,000 daltons (5.6% w/w) and crosslinked by esterification swelled upon skin insertion by uptake of fluid. Post-removal, theophylline and caffeine were extracted from MN and determined using HPLC, with glucose quantified using a proprietary kit. In vitro studies using excised neonatal porcine skin bathed on the underside by physiologically-relevant analyte concentrations showed rapid (5 min) analyte uptake. For example, mean concentrations of 0.16 μg/mL and 0.85 μg/mL, respectively, were detected for the lowest (5 μg/mL) and highest (35 μg/mL) Franz cell concentrations of theophylline after 5 min insertion. A mean concentration of 0.10 μg/mL was obtained by extraction of MN inserted for 5 min into skin bathed with 5 μg/mL caffeine, while the mean concentration obtained by extraction of MN inserted into skin bathed with 15 μg/mL caffeine was 0.33 μg/mL. The mean detected glucose concentration after 5 min insertion into skin bathed with 4 mmol/L was 19.46 nmol/L. The highest theophylline concentration detected following extraction from a hydrogel-forming MN inserted for 1 h into the skin of a rat dosed orally with 10 mg/kg was of 0.363 μg/mL, whilst a maximum concentration of 0.063 μg/mL was detected following extraction from a MN inserted for 1 h into the skin of a rat dosed with 5 mg/kg theophylline. In human volunteers, the highest mean concentration of caffeine detected using MN was 91.31 μg/mL over the period from 1 to 2 h post-consumption of 100 mg Proplus® tablets. The highest mean blood glucose level was 7.89 nmol/L detected 1 h following ingestion of 75 g of glucose, while the highest mean glucose concentration extracted from MN was 4.29 nmol/L, detected after 3 hours skin insertion in human volunteers. Whilst not directly correlated, concentrations extracted from MN were clearly indicative of trends in blood in both rats and human volunteers. This work strongly illustrates the potential of hydrogel-forming MN in minimally-invasive patient monitoring and diagnosis. Further studies are now ongoing to reduce clinical insertion times and develop mathematical algorithms enabling determination of blood levels directly from MN measurements.

Upon their initial discovery, hydrothermal vents and methane seeps were considered to be related but distinct ecosystems, with different distributions, geomorphology, temperatures, geochemical properties and mostly different species. However, subsequently discovered vents and seep systems have blurred this distinction. Here, we report on a composite, hydrothermal seep ecosystem at a subducting seamount on the convergent Costa Rica margin that represents an intermediate between vent and seep ecosystems. Diffuse flow of shimmering, warm fluids with high methane concentrations supports a mixture of microbes, animal species, assemblages and trophic pathways with vent and seep affinities. Their coexistence reinforces the continuity of reducing environments and exemplifies a setting conducive to interactive evolution of vent and seep biota.

The reactivity of xenon with terrestrial oxides was investigated by in situ synchrotron x-ray diffraction. At high temperature (T > 500 kelvin), some silicon was reduced, and the pressure stability of quartz was expanded, attesting to the substitution of some xenon for silicon. When the quartz was quenched, xenon diffused out and only a few weight percent remained trapped in samples. These results show that xenon can be covalently bonded to oxygen in quartz in the lower continental crust, providing an answer to the missing xenon problem; synthesis paths of rare gas compounds are also opened.

The aim of this study was to determine whether iron deficiency anemia (IDA) in young South African mothers alters mother-infant interactions and the infant's development. The study was a prospective, randomized, controlled intervention trial with 3 groups of mothers: nonanemic controls and anemic mothers administered either placebo (25 mg ascorbic acid and 10 microg folate) or daily iron treatment (125 mg FeSO(4) plus ascorbate and folate). Mothers of full-term, normal birth weight infants (n = 81) were followed from 10 wk to 9 mo postpartum. Maternal iron status, socioeconomic level, mother-infant interaction [Parent/Caregiver Involvement Scale (PCIS scale)], and infant development (Griffiths scale) were assessed. At baseline, anemic mothers tended (P < 0.10) to be less responsive to, and more controlling of, their infants. Infants of anemic mothers were developmentally delayed at 10 wk in hand-eye movement and overall quotient. Despite normalization of maternal iron status with supplementation in some mothers, the developmental delays were not diminished at 9 mo. At 9 mo, anemic mothers were significantly more "negative" towards their babies, engaged less in goal setting, and were less "responsive" than control mothers. In contrast, the behavior of anemic mothers given iron treatment toward their children was similar to that of the control mothers on all 11 scales of the PCIS. In conclusion, IDA altered mother-child interactions at both 10 wk and 9 mo postpartum. Additionally, infants whose mothers were anemic in the early postpartum scored worse on developmental tests at 10 wk and 9 mo of age.

The aim of this study was to determine whether iron deficiency anemia (IDA) in mothers alters their maternal cognitive and behavioral performance, the mother-infant interaction, and the infant's development. This article focuses on the relation between IDA and cognition as well as behavioral affect in the young mothers. This prospective, randomized, controlled, intervention trial was conducted in South Africa among 3 groups of mothers: nonanemic controls and anemic mothers receiving either placebo (10 microg folate and 25 mg vitamin C) or daily iron (125 mg FeS0(4), 10 microg folate, 25 mg vitamin C). Mothers of full-term normal birth weight babies were followed from 10 wk to 9 mo postpartum (n = 81). Maternal hematologic and iron status, socioeconomic, cognitive, and emotional status, mother-infant interaction, and the development of the infants were assessed at 10 wk and 9 mo postpartum. Behavioral and cognitive variables at baseline did not differ between iron-deficient anemic mothers and nonanemic mothers. However, iron treatment resulted in a 25% improvement (P < 0.05) in previously iron-deficient mothers' depression and stress scales as well as in the Raven's Progressive Matrices test. Anemic mothers administered placebo did not improve in behavioral measures. Multivariate analysis showed a strong association between iron status variables (hemoglobin, mean corpuscular volume, and transferrin saturation) and cognitive variables (Digit Symbol) as well as behavioral variables (anxiety, stress, depression). This study demonstrates that there is a strong relation between iron status and depression, stress, and cognitive functioning in poor African mothers during the postpartum period. There are likely ramifications of this poorer "functioning" on mother-child interactions and infant development, but the constraints around this relation will have to be defined in larger studies.

Human brucellosis, a multisystem disease which may mimic other conditions, has a low incidence in childhood and the diagnosis may easily be missed. Over a 7-month period 9 children with brucellosis presented to the Department of Paediatrics and Child Health, Tygerberg Hospital. Six of the children had consumed unpasteurized milk. The main presenting symptoms were fever, fatigue, headache, myalgia and haematuria. Clinical signs included lymphadenopathy (3), nasopharyngitis (2), features of lower respiratory tract infection (2), splenomegaly (2) and pyrexia (1). The diagnosis was made on the basis of a positive serological titre (> 1:160) for Brucella abortus. The prozone phenomenon was encountered in 6 cases; however, the Coombs test confirmed the diagnosis in these cases. Children under 7 years were treated with co-trimoxazole and rifampicin and those over 7 years with tetracycline and rifampicin, for at least 6 weeks. No relapses were detected on follow-up.