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Summary Statistical hypotheses are translations of scientific hypotheses into statements about one or more distributions, often concerning their centre. Tests that assess statistical hypotheses of centre implicitly assume a specific centre, e.g., the mean or median. Yet, scientific hypotheses do not always specify a particular centre. This ambiguity leaves the possibility for a gap between scientific theory and statistical practice that can lead to rejection of a true null. In the face of replicability crises in many scientific disciplines, significant results of this kind are concerning. Rather than testing a single centre, this paper proposes testing a family of plausible centres, such as that induced by the Huber loss function. Each centre in the family generates a testing problem, and the resulting family of hypotheses constitutes a familial hypothesis. A Bayesian nonparametric procedure is devised to test familial hypotheses, enabled by a novel pathwise optimization routine to fit the Huber family. The favourable properties of the new test are demonstrated theoretically and experimentally. Two examples from psychology serve as real-world case studies. 

Hybrid fs/ps coherent anti-Stokes Raman scattering (CARS) is employed to investigate the vibrational temperature evolution of N2 in lean methane flames exposed to pulsed microwave irradiation. Vibrational temperature during and post microwave illumination by a 2 μs, 30 kW peak power, 3.05 GHz pulse is monitored in flames diluted with N2, N2 and CO2 , and N2 and Ar. Electric field strengths inside the microwave cavity are monitored directly using electric field probes. Temperature increases up to 140 K were observed in flames with additional Ar and CO2 dilution, whereas temperature increases by 80 K were observed in mixtures diluted with only N2 . The microwave energy deposition to excited states begins to thermalize over scales of 100 μs, however, equilibrium is not reached before excited combustion products convect out of the probe volume on the order of several 1 ms. Understanding the impact of varying bath gases on microwave interaction, magnitude of temperature rise and thermalization timescales is critical for the development and validation of new kinetic models for applications exhibiting significant degrees of thermal non-equilibrium, such as high-speed reentry flows and plasma-assisted combustion. 

Hox genes are key developmental patterning genes that impact segmental identity and skeletal patterning. Hox11 genes are known to impact wrist and ankle development and are expressed around the developing pisiform and calcaneus. These paralogous bones in the wrist and ankle are the only carpal and tarsal to form a growth plate in mammals, although humans have lost this growth plate and the associated primary ossification center in the pisiform. Loss-of-function mutations to Hoxa11 and Hoxd11 result in pisiform truncation and appear to also cause at least some disorganization of the growth plate cartilage; however, little is known about the nature of this disorganization or if ossification timing is impacted by Hox11 genes. The present study investigates the role of Hoxa11 and Hoxd11 in pisiform growth plate organization and ossification timing. We conducted histological analysis of the pisiform growth plate in juvenile mice with Hoxa11 and Hoxd11 loss-of-function mutations and compared them to ossification patterns observed in age- and genotype-matched whole-mount specimens that were cleared and stained with Alizarin red and Alcian blue to visualize bone and cartilage, respectively. Histological analysis reveals a dosage-dependent impact of Hox11 mutations on pisiform ossification to both the primary and secondary ossification center. As the number of Hox11 mutation alleles increase, less bone is present in the early primary ossification center compared to age-matched specimens. In specimens with three loss-of-function alleles, no trabeculae or growth plate organization are visible at P9, when both are well established in wild type specimens. Cleared and stained specimens indicate a possible pseudo epiphysis forming with Hoxd11 mutation, while Hoxa11 knockout specimens have not formed any visible epiphysis or calcification by P9. These results indicate that ossification timing and patterns, along with growth plate organization, are affected by Hox11 mutations during early pisiform ossification. Furthermore, Hoxa11 and Hoxd11 alter the pisiform epiphysis differently, suggesting that each plays a specific role in formation of the ossification front and epiphysis ossification either by influencing timing, ossification progression, or both. Further work is needed to understand the mechanisms by which Hox genes impact ossification patterns and timing, as well as the differential roles of Hoxa11 and Hoxd11 in growth plate organization and epiphysis formation. 

Hox genes are key developmental patterning genes that impact segmental identity and skeletal patterning. While Hox11 genes are known to be expressed around the developing calcaneus bone of the ankle, previous studies on mice with Hox11 mutations have indicated that calcaneus morphology is not affected until both Hoxa11 and Hoxd11are knocked out, at which point the calcaneus and talus fail to form.The pisiform bone, a wrist bone that is paralogous to the calcaneus, exhibits substantial morphological and growth plate alterations with Hox11 mutations. We have previously shown that some length differences are present in the adult calcanei of mice with Hoxa11 and Hoxd11 loss-of-function mutations. The present study investigates whether or not the calcaneus growth plate is altered by Hoxa11 and Hoxd11 loss-of-function mutation. We conducted histological analysis of the calcaneus growth plate in juvenile mice with Hoxa11 and Hoxd11 loss-of-function mutations and compared them to ossification patterns observed in whole-mount specimens that were cleared and stained with alizarin red and alcian blue to visualize bone and cartilage, respectively. Histological analysis reveals that early calcaneus growth plates preserve the hypertrophic and proliferative growth plate zones. This is in contrast to the pisiform and likely a result of Hoxc gene expression in the hind limb but not the forelimb. The shape of the epiphyseal cartilage, however, differs greatly in mice with a combined three loss-of-function alleles between Hoxa11 and Hoxd11. In these mice, the calcaneus epiphyseal cartilage is conical shaped with an elongated region of reserve zone chondrocytes. The ossification front and calcaneal tendon insertion are also altered compared to wild type specimens. The first evidence of calcaneal epiphysis ossification appears at P9 in some Hox11 mutant mice, while it typically appears at P11 in wild type specimens. By P17, the epiphysis appears to be larger in specimens with both Hoxa11 and Hoxd11 mutations compared to wild type. These results indicate that the calcaneus growth plate is more resilient to Hox11 mutations than the pisiform, but that the calcaneus exhibits morphological changes and evidence of altered ossification timing with fewer loss-of-function alleles than identified by previous studies. 

Abstract Neural differentiation of mesenchymal stem cells is a controversial phenomenon, as it would require transdifferentiation across the mesoderm-ectoderm barrier. However, several laboratories have observed that MSCs are able to be induced to express neural characteristics. Previously, we demonstrated that the cAMP-elevating agents, forskolin and IBMX, induced neural-like differentiation of MSCs, including expression of neural markers and increased sensitivity to neurotransmitters. However, due to the broad range of effects that forskolin and IBMX can elicit through the intracellular second messenger, cAMP, a better mechanistic understanding is required. Here, we show that neural induction by forskolin and IBMX is dependent on downregulation of expression of the master transcriptional regulator, neuron restrictive silencer factor (NRSF), and its downstream target genes. Since silencing of NRSF is known to initiate neural differentiation, it suggests that forskolin and IBMX result in transdifferentiation of MSCs into a neural lineage. 

The Neuron Restrictive Silencer Factor (NRSF) is the well-known master transcriptional repressor of the neuronal phenotype. Research to date has shown that it is an important player in the growth and development of the nervous system. Its role in the maturation of neural precursor cells to adult neurons has been well characterized in stem cell models. While much has been characterized from a developmental perspective, research is revealing that NRSF plays a role in various neurological diseases, ranging from neurodegenerative, neuropsychiatric, to cancer. Dysregulation of NRSF activity disrupts downstream gene expression that is responsible for neuronal cell homeostasis in several models that contribute to pathologic states. Interestingly, it is now becoming apparent that the dysregulation of NRSF contributes to neurological disease through epigenetic mechanisms. Although NRSF itself is a transcription factor, its major effectors are chromatin modifiers. At the level of epigenetics, changes in NRSF activity have been well characterized in models of neuropathic pain and epilepsy. Better understanding of the epigenetic basis of brain diseases has led to design and use of small molecules that can prevent NRSF from repressing gene expression by neutralizing its interactions with its chromatin remodelers. This review will address the basic function of NRSF and its cofactors, investigate their mechanisms, then explore how their dysfunction can cause disease states. This review will also address research on NRSF as a therapeutic target and delve into new therapeutic strategies that focus on disrupting NRSF’s ability to recruit chromatin remodelers.