Machine learning approach to muon spectroscopy analysis.

In recent years, artificial intelligence techniques have proved to be very successful when applied to problems in physical sciences. Here we apply an unsupervised machine learning (ML) algorithm called principal component analysis (PCA) as a tool to analyse the data from muon spectroscopy experiments. Specifically, we apply the ML technique to detect phase transitions in various materials. The measured quantity in muon spectroscopy is an asymmetry function, which may hold information about the distribution of the intrinsic magnetic field in combination with the dynamics of the sample. Sharp changes of shape of asymmetry functions-measured at different temperatures-might indicate a phase transition. Existing methods of processing the muon spectroscopy data are based on regression analysis, but choosing the right fitting function requires knowledge about the underlying physics of the probed material. Conversely, PCA focuses on small differences in the asymmetry curves and works without any prior assumptions about the studied samples. We discovered that the PCA method works well in detecting phase transitions in muon spectroscopy experiments and can serve as an alternative to current analysis, especially if the physics of the studied material are not entirely known. Additionally, we found out that our ML technique seems to work best with large numbers of measurements, regardless of whether the algorithm takes data only for a single material or whether the analysis is performed simultaneously for many materials with different physical properties.

How do office workers respond to media coverage of sitting?

BACKGROUND: Sitting time is associated with adverse physical and mental health outcomes, and premature mortality. Office workers sit for prolonged periods, so are at particular risk. Scientific advances in public health threats are predominantly communicated to the public through media reports. AIMS: This study aimed to examine office workers' impromptu responses to media coverage of scientific evidence related to the health risks of sedentary behaviour. METHODS: Semi-structured interviews were run with 26 office workers (mean age 35 years), recruited from four organizations in southern England. Within the interview, each participant provided a 'think-aloud' narrative as they read three real-world news reports relating to sedentary behaviour. Thematic analysis was conducted on verbatim transcripts. RESULTS: Three themes were extracted from the data: gauging the personal relevance of the news reports; questioning their trustworthiness and challenging the feasibility of proposed sitting-reduction strategies. Participants voiced scepticism about the applicability of the reports to their personal circumstances, and the validity of the reports and the scientific evidence underpinning them. CONCLUSIONS: Researchers, press officers and journalists should emphasise the ways in which participants in research studies represent the broader population of office workers, and offer greater transparency in reporting study methods, when reporting scientific advances in sedentary behaviour.

Universal newborn screening: A roadmap for action.

Newborn screening (NBS) prevents morbidity and mortality by screening babies for selected disorders in the first days of life so that early diagnosis and treatment can be initiated. Congenital disorders impact an estimated 8 million or 6% of annual births worldwide, and of the top five that contribute 25% to the global burden of these disorders, three can be identified and managed by NBS. There are determined pockets of activity in Latin America, Sub-Saharan Africa, and the Asia Pacific region, where partnerships among government, non-governmental organizations, academia, the private sector and civil society are developing novel NBS programs that are both saving lives and preventing disability in those who survive.

The magnetic and electronic properties of oxyselenides-influence of transition metal ions and lanthanides.

Magnetic oxyselenides have been a topic of research for several decades, firstly in the context of photoconductivity and thermoelectricity owing to their intrinsic semiconducting properties and ability to tune the energy gap through metal ion substitution. More recently, interest in the oxyselenides has experienced a resurgence owing to the possible relation to strongly correlated phenomena given the fact that many oxyselenides share a similar structure to unconventional superconducting pnictides and chalcogenides. The two dimensional nature of many oxyselenide systems also draws an analogy to cuprate physics where a strong interplay between unconventional electronic phases and localised magnetism has been studied for several decades. It is therefore timely to review the physics of the oxyselenides in the context of the broader field of strongly correlated magnetism and electronic phenomena. Here we review the current status and progress in this area of research with the focus on the influence of lanthanides and transition metal ions on the intertwined magnetic and electronic properties of oxyselenides. The emphasis of the review is on the magnetic properties and comparisons are made with iron based pnictide and chalcogenide systems.

Botox treatment for migraine and chronic daily headache in adolescents.

Children and adolescents experience headaches as do adults and usually present with migraine and chronic daily or tension-type headaches. As some adolescents are unable to achieve headache relief after various treatment strategies, we currently provide botulinum toxin type A (Botox) injections as a clinical treatment (off-label use) in selected cases. Botulinum toxin type A by injection has been found to be effective in the treatment of headache disorders in adults. We treated 12 adolescents (aged 14 to 18 years) with Botox injections for migraine and chronic daily headache. Six patients (all female adolescents) were in long-term treatment and received Botox in the standard "migraine" and "follow-the-pain" patterns every 3 months. Effectiveness was evaluated using pain scales and a standardized quality-of-life survey at baseline and prior to each treatment session. Duration of treatment was 3-29 months. Each patient had 9-63 (average = 42) injections per treatment. All 6 long-term patients reported improvement in headache symptoms, with decreases on pain scales and an average of 33%-75% improvement in quality of life. Two long-term patients had complete relief of headaches between injection series. Four patients had only one series of injections with good results. Two patients had no improvement and refused additional injections. Side effects were mild ptosis (n = 1), blurred vision (n = 1), hematoma at neck injection site with tingling in one arm lasting 24 hours (n = 1), and burning sensations at all injection sites which lasted 1 week (n = 1). Our group findings warrant a controlled trial evaluation of Botox because it may be an effective treatment option for certain adolescents with intractable migraine and chronic daily headaches.

Completely self-contained cell culture system: from storage to use.

In vitro cell culture systems provide researchers the appropriate tools for effectively studying cell growth and differentiation, understanding cellular response to specific environmental stimuli, and elucidating the function of heterologous biological molecules produced from expression systems. All in vitro cell culture systems require a specific culture media formulated to the nutritional and metabolic requirements of the particular cell type to be cultured. However, the complexity of these systems varies depending on the model organism origin of the cells being cultured (e.g., bacteria, plants, yeast or animal). Unlike bacteria and yeast, mammalian cell cultures require sophisticated auxiliary technologies (e.g., controlled gas mixtures and pressure flow systems, specialized facilities and equipment) and careful handling by trained personnel. These complex requirements pose a limitation to transferring cells to and from remote field locations for investigations. Furthermore, this limitation is a technical hurdle in the development of technologies involving use of live cells (e.g., cytosensors). We identified a novel and unrealized feature in the conventional cell culture system that may be exploited to adapt simple existing technologies to form a portable apparatus for storing and growing cells. The approach we describe is a completely self-contained cell culture system that not only will bring down the cost of culturing cells but also will expand cell culture applications in medicine, research, environmental health, and safety.

Zebrafish dax1 is required for development of the interrenal organ, the adrenal cortex equivalent.

Mutations in the human nuclear receptor, DAX1, cause X-linked adrenal hypoplasia congenita (AHC). We report the isolation and characterization of a DAX1 homolog, dax1, in zebrafish. The dax1 cDNA encodes a protein of 264 amino acids, including the conserved carboxy-terminal ligand binding-like motif; but the amino-terminal region lacks the unusual repeats of the DNA binding-like domain in mammals. Genomic sequence analysis indicates that the dax1 gene structure is conserved also. Whole-mount in situ hybridization revealed the onset of dax1 expression in the developing hypothalamus at approximately 26 h post fertilization (hpf). Later, at about 28 hpf, a novel expression domain for dax1 appeared in the trunk. This bilateral dax1-expressing structure was located immediately above the yolk sac, between the otic vesicle and the pronephros. Interestingly, weak and transient expression of dax1 was observed in the interrenal glands (adrenal cortical equivalents) at approximately 31 hpf. This gene was also expressed in the liver after 3 dpf in the zebrafish larvae. Disruption of dax1 function by morpholino oligonucleotides (MO) down-regulated expression of steroidogenic genes, cyp11a and star, and led to severe phenotypes similar to ff1b (SF1) MO-injected embryos. Injection of dax1 MO did not affect ff1b expression, whereas ff1b MO abolished dax1 expression in the interrenal organ. Based on these results, we propose that dax1 is the mammalian DAX1 ortholog, functions downstream of ff1b in the regulatory cascades, and is required for normal development and function of the zebrafish interrenal organ.

Mouth cell collection device for newborn mice.

For efficient and accurate genotyping of transgenic and knockout mice, the ability to reduce pain and suffering and to obtain DNA early in life are critical. We have developed a novel method to sample buccal cells from neonatal mice to obtain DNA. Our mouse mouth cell collection process includes an oral speculum and collection device which enables rapid extraction of enough DNA for up to 50 PCRs from each buccal sampling. This cell collection device fills a clear need for buccal sampling from neonatal mice, greatly facilitating research in mouse models of human disease. Eliminating the pain, distress, and death caused by invasive and mutilating procedures lessens the potential for confounding variables between control and experimental animals. In conclusion, our mouse mouth cell collection process can be applied to very small animals for which there exists no current device.

DAX1 origin, function, and novel role.

The orphan nuclear receptor NR0B1 encodes the DAX1 protein, which stands for the dosage sensitive sex-reversal (DSS), adrenal hypoplasia congenita (AHC) critical region on the X-chromosome, gene 1. DAX1 was initially identified as part of a contiguous gene syndrome and is known to function in the proper formation of the adult adrenal gland. It has been hypothesized that DAX1 is responsible for the establishment and maintenance of the steroidogenic axis of development. Recent insight from the murine ortholog Dax1 along with reports of an alternatively spliced variant in humans suggests that Dax1 has additional functional roles beyond those previously understood. Here, we review DAX1/Dax1 known functional roles and the recently hypothesized function in the development of the embryo and in the maintenance of embryonic stem cell pluripotency.

Gene therapy for murine glycerol kinase deficiency: importance of murine ortholog.

A glycerol kinase (Gyk) knock-out (KO) mouse model permits improved understanding of glycerol kinase (GK) deficiency (GKD) pathogenesis, however, early death of affected mice limits its utility. The purpose of this work was to delay death of affected males to investigate thoroughly their phenotypes. An adenoviral vector carrying the human (Adeno-XGK) or mouse (Adeno-XGyk) GK gene was injected into KO mice within 24 h of birth. Adeno-XGK did not change KO mouse survival time despite liver GK activity greater than 100% of wild type. However, Adeno-XGyk improved KO mouse survival time greater than two-fold. These investigations demonstrate that gene replacement therapy for Gyk KO mice is more efficacious using murine Gyk than human GK. These studies expand our understanding of GKD pathogenesis in the murine model, and show that while murine GKD is more severe than in humans, GKD mice have similar metabolic disturbances to affected humans with hypoglycemia and acidemia.

Nr0b1 and its network partners are expressed early in murine embryos prior to steroidogenic axis organogenesis.

Ahch is an orphan nuclear receptor encoded by Nr0b1 on the murine X chromosome and is the ortholog of human DAX1. Nr0b1/NR0B1 expression at appropriate dosages is required for normal steroidogenic axis development: mutation of the human ortholog, NR0B1, results in adrenal hypoplasia congenita and hypogonadotropic hypogonadism; and duplication or transgenic overexpression in humans or mice, respectively, results in XY phenotypic females, a phenotype known as dosage sensitive sex-reversal. Complete loss of Nr0b1 by targeted deletion has been hypothesized to be lethal in embryonic stem (ES) cells and preliminary evidence suggested that ES cells might express Nr0b1. These investigations examined Nr0b1 expression and its network partners in both cultured ES cells and preimplantation embryos. We cultured ES cells in the absence or presence of differentiation agents and analyzed expression of Nr0b1 and associated network partners by northern blot hybridization and reverse transcriptase-polymerase chain reaction. Nrob1 was highly expressed by totipotent ES cells with reduced expression following induction toward individual germ layer fates. Nr5a1/Sf1, Wt1 and other genes that encode proteins known to interact with Nr0b1 were also expressed. Immunohistochemical analysis of preimplantation embryos for Ahch and key partners confirmed in vivo expression of network components. These findings are consistent with the existence of a potentially functional network of transcription factors, including Ahch, very early in embryonic development. These results validate ES cells as a developmentally dynamic model for mechanistic investigations into this regulatory network early in embryogenesis preceding organogenesis.

Use of a telephone nursing line in a pediatric neurology clinic: one approach to the shortage of subspecialists.

OBJECTIVE: There are not enough pediatric neurologists to meet the many needs of pediatric neurology patients. The Hospital for Sick Children has responded by expanding the nursing role in the pediatric neurology outpatient clinic. The objective of this study was to examine the use of a telephone nursing line in this hospital-based pediatric neurology clinic. METHODS: A cross-sectional study was performed on all telephone call records collected during a 2-week study period. Each initial incoming call concerning a patient was counted as an index call. Associations between clinic type or diagnosis and length of telephone calls were assessed using the chi(2) test. RESULTS: A total of 208 index calls were received, generating a total of 597 incoming and outgoing calls. The most common clinic types were Epilepsy clinic (35.6%) and General Neurology clinic (32.7%), and the most common patient diagnoses were epilepsy (63.5%) and developmental delay (45.2%). Most patients were between the ages of 1 and <7 years (33.9%) and 12 and <18 years (32.8%) and male (55.2%). Most calls were made by mothers (57.2%) to ask about medical administrative issues (28.4%) and/or symptoms (27.9%). Physicians were notified for 47.1% of calls; nurses were twice as likely to notify physicians for calls concerning new symptoms (relative risk: 2.1; 95% confidence interval: 1.6-2.7). Most calls required between 1 and 5 minutes (49.0%). Long telephone calls (>10 minutes) were strongly associated with a diagnosis of epilepsy. CONCLUSIONS: There is a high demand for the neurology nursing line in our clinic. Most telephone calls and most long telephone calls concerned patients with epilepsy. Nurses managed more than half of all telephone calls without physician assistance. Use of a nursing line can aid in the provision of care to complicated subspecialty patients. Additional strategies are needed to optimize delivery of care to high-need medical populations.

Human ARX gene: genomic characterization and expression.

Arx is a homeobox-containing gene with a high degree of sequence similarity between mouse and zebrafish. Arx is expressed in the forebrain and floor plate of the developing central nervous systems of these vertebrates and in the presumptive cortex of fetal mice. Our goal was to identify genes in Xp22.1-p21.3 involved in human neuronal development. Our in silico search for candidate genes noted that annotation of a human Xp22 PAC (RPCI1-258N20) sequence (GenBank Accession No. AC002504) identified putative exons consistent with an Arx homologue in Xp22. Northern blot analysis showed that a 3.3kb human ARX transcript was expressed at high levels in fetal brain. A 5.9kb transcript was expressed in adult heart, skeletal muscle, and liver with very faint expression in other adult tissues, including brain. In situ hybridization of ARX in human fetal brain sections at various developmental stages showed the highest expression in neuronal precursors in the germinal matrix of the ganglionic eminence and in the ventricular zone of the telencephalon. Expression was also observed in the hippocampus, cingulate, subventricular zone, cortical plate, caudate nucleus, and putamen. The expression pattern suggests that ARX is involved in the differentiation and maintenance of specific neuronal cell types in the human central nervous system. We also mapped the murine Arx gene to the mouse genome using a mouse/hamster radiation hybrid panel and showed that Arx and ARX are orthologues. Therefore, investigations in model vertebrates may provide insight into the role of ARX in development. The recent identification of ARX mutations in patients with various forms of mental retardation make such studies in model organisms even more compelling.

Genetic network identification by high density, multiplexed reversed transcriptional (HD-MRT) analysis in steroidogenic axis model cell lines.

Transcriptional network analysis in steroidogenic axis cell lines requires an understanding of cellular network composition and complexity. Previous studies have shown that absence of transcriptional network components in a cell line compromises that cell line's functional capacity for transcriptional regulation. Our goal was to analyze qualitatively steroidogenic axis-derived cell lines' expression of a putative transcriptional network involved in human and mouse development. To pursue this analysis we used Northern blots and a high density-multiplexed reverse transcription-polymerase chain reaction (HD-MRT-PCR) approach. Our results revealed that, while some members of this putative network were universally expressed, only a minority of the non-constitutive targeted transcripts were present in any single line. Based on our data and previously published results for contextual expression of these transcription factors, a model was constructed possessing the topology suggestive of a scale-free network: certain network members were highly connected nodes and would represent critical sites of vulnerability. The importance of these highly connected nodes for network function is supported by the severe phenotypes exhibited by human patients and animal models when these genes are mutated. We conclude that knowledge of network composition in specific cell lines is essential for their use as models to investigate functional interactions within selected subnetworks.

Mutations in NR0B1 (DAX1) and NR5A1 (SF1) responsible for adrenal hypoplasia congenita.

Adrenal hypoplasia congenita (AHC) causes primary adrenal insufficiency due to the failure of development of the adrenal cortex. Clinical and pedigree data indicate that the condition is genetically heterogeneous. The predominant adrenal hypoplasia congenita locus, however, is the NR0B1 gene, at Xp21, encoding the protein DAX1. In this article, we present a compendium of published NR0B1 mutations and polymorphisms, and discuss them in the contexts of known biology and clinical applicability. The recent descriptions of patients with primary adrenal insufficiency due to mutations of NR5A1, which encodes SF1, are also discussed.

Nine novel mutations in NR0B1 (DAX1) causing adrenal hypoplasia congenita.

X-linked adrenal hypoplasia congenita (AHC) is caused by mutations in the NR0B1 gene. This gene encodes an orphan member of the nuclear receptor superfamily, DAX1. Ongoing efforts in our laboratory have identified nine novel NR0B1 mutations in X-linked AHC patients (Y81X, 343delG, 457delT, 629delG, L295P, 926-927delTG, 1130delA, 1141-1155del15, and E428X). Two additional families segregate previously identified NR0B1 mutations (501delA and R425T). Sequence analysis of the mitochondrial D-loop indicates that the 501delA family is unrelated through matrilineal descent to our previously analyzed 501delA family.

Single-tube gene-specific expression analysis by high primer density multiplex reverse transcription.

Molecular genetics is rapidly moving from simple identification of a gene of interest to characterization of gene products as components in complex networks. Critical tools for gene product analysis require a rapid method for evaluation of contextual expression. Here, we describe a robust, high primer density, single-tube, multiplex reverse transcription (HD-MRT) technique. This approach is capable of analyzing for the presence of numerous transcripts when polymerase chain reaction (PCR) is subsequently employed for individual gene-specific sequence amplification (HD-MRT-PCR). This assay substantially increases the total number of different cDNAs for amplification beyond previously published techniques. Our approach simultaneously eliminates RNA quality control issues for samples run in parallel while improving efficiency in the use of time and materials. This assay is designed for broad applicability and accessibility, employs modifications of commercially available components, and allows more than 25 independently selected gene-specific primers to be used simultaneously. Our protocol allows multiplexed primers to behave similarly to uniplex RT reactions, while avoiding potential interference between gene-specific and/or nonspecific primers during annealing and reverse transcription. Expression of putatively networked homologous transcripts was analyzed in multiple cell lines and tissues from mouse and human to validate the technique.