Miracle-dz/UniFAR-FTUs huggingface dataset:
Neural pathways mediating cross education of motor function

Cross education is the process whereby training of one limb gives rise to enhancements in the performance of the opposite, untrained limb. Despite interest in this phenomenon having been sustained for more than a century, a comprehensive explanation of the mediating neural mechanisms remains elusive. With new evidence emerging that cross education may have therapeutic utility, the need to provide a principled evidential basis upon which to design interventions becomes ever more pressing. Generally, mechanistic accounts of cross education align with one of two explanatory frameworks. Models of the “cross activation” variety encapsulate the observation that unilateral execution of a movement task gives rise to bilateral increases in corticospinal excitability. The related conjecture is that such distributed activity, when present during unilateral practice, leads to simultaneous adaptations in neural circuits that project to the muscles of the untrained limb, thus facilitating subsequent performance of the task. Alternatively, “bilateral access” models entail that motor engrams formed during unilateral practice, may subsequently be utilized bilaterally—that is, by the neural circuitry that constitutes the control centers for movements of both limbs. At present there is a paucity of direct evidence that allows the corresponding neural processes to be delineated, or their relative contributions in different task contexts to be ascertained. In the current review we seek to synthesize and assimilate the fragmentary information that is available, including consideration of knowledge that has emerged as a result of technological advances in structural and functional brain imaging. An emphasis upon task dependency is maintained throughout, the conviction being that the neural mechanisms that mediate cross education may only be understood in this context.
Time-lapse changes of in vivo injured neuronal substructures in the central nervous system after low energy two-photon nanosurgery

There is currently very little research regarding the dynamics of the subcellular degenerative events that occur in the central nervous system in response to injury. To date, multi-photon excitation has been primarily used for imaging applications; however, it has been recently used to selectively disrupt neural structures in living animals. However, understanding the complicated processes and the essential underlying molecular pathways involved in these dynamic events is necessary for studying the underlying process that promotes neuronal regeneration. In this study, we introduced a novel method allowing in vivo use of low energy (less than 30 mW) two-photon nanosurgery to selectively disrupt individual dendrites, axons, and dendritic spines in the murine brain and spinal cord to accurately monitor the time-lapse changes in the injured neuronal structures. Individual axons, dendrites, and dendritic spines in the brain and spinal cord were successfully ablated and in vivo imaging revealed the time-lapse alterations in these structures in response to the two-photon nanosurgery induced lesion. The energy (less than 30 mW) used in this study was very low and caused no observable additional damage in the neuronal sub-structures that occur frequently, especially in dendritic spines, with current commonly used methods using high energy levels. In addition, our approach includes the option of monitoring the time-varying dynamics to control the degree of lesion. The method presented here may be used to provide new insight into the growth of axons and dendrites in response to acute injury.
Genome Sequence of “Candidatus Microthrix parvicella” Bio17-1, a Long-Chain-Fatty-Acid-Accumulating Filamentous Actinobacterium from a Biological Wastewater Treatment Plant

ABSTRACT “Candidatus Microthrix” bacteria are deeply branching filamentous actinobacteria which occur at the water-air interface of biological wastewater treatment plants, where they are often responsible for foaming and bulking. Here, we report the first draft genome sequence of a strain from this genus: “Candidatus Microthrix parvicella” strain Bio17-1.
Imbalances in the Hsp90 Chaperone Machinery: Implications for Tauopathies

The ATP-dependent 90 kDa heat shock protein, Hsp90, is a major regulator of protein triage, from assisting in nascent protein folding to refolding or degrading aberrant proteins. Tau, a microtubule associated protein, aberrantly accumulates in Alzheimer's disease (AD) and other neurodegenerative diseases, deemed tauopathies. Hsp90 binds to and regulates tau fate in coordination with a diverse group of co-chaperones. Imbalances in chaperone levels and activity, as found in the aging brain, can contribute to disease onset and progression. For example, the levels of the Hsp90 co-chaperone, FK506-binding protein 51 kDa (FKBP51), progressively increase with age. In vitro and in vivo tau models demonstrated that FKBP51 synergizes with Hsp90 to increase neurotoxic tau oligomer production. Inversely, protein phosphatase 5 (PP5), which dephosphorylates tau to restore microtubule-binding function, is repressed with aging and activity is further repressed in AD. Similarly, levels of cyclophilin 40 (CyP40) are reduced in the aged brain and further repressed in AD. Interestingly, CyP40 was shown to breakup tau aggregates in vitro and prevent tau-induced neurotoxicity in vivo. Moreover, the only known stimulator of Hsp90 ATPase activity, Aha1, increases tau aggregation and toxicity. While the levels of Aha1 are not significantly altered with aging, increased levels have been found in AD brains. Overall, these changes in the Hsp90 heterocomplex could drive tau deposition and neurotoxicity. While the relationship of tau and Hsp90 in coordination with these co-chaperones is still under investigation, it is clear that imbalances in these proteins with aging can contribute to disease onset and progression. This review highlights the current understanding of how the Hsp90 family of molecular chaperones regulates tau or other misfolded proteins in neurodegenerative diseases with a particular emphasis on the impact of aging.
Things softly attained are long retained: Dissecting the Impacts of Selection Regimes on Polymorphism Maintenance in Experimental Spatially Heterogeneous Environments

This preprint has been reviewed and recommended by Peer Community In Evolutionary Biology (http://dx.doi.org/10.24072/pci.evolbiol.100020). Predicting and managing contemporary adaption requires a proper understanding of the determinants of genetic variation. Spatial heterogeneity of the environment may stably maintain polymorphism when habitat contribution to the next generation can be considered independent of the degree of adaptation of local populations within habitats (i.e., under soft selection). In contrast, when habitats contribute proportionally to the mean fitness of the populations they host (hard selection), polymorphism is not expected to be maintained by selection. Although mathematically established decades ago, this prediction had never been properly explored. Here we provide an experimental test in which polymorphic populations of Escherichia coli growing in heterogeneous habitats were exposed to hard and soft selection regimes. As predicted by theory, polymorphism was longer preserved under soft selection. Complementary tests established that soft selection slowed down fixation processes and could even protect polymorphism on the long term by providing a systematic advantage to rare genotypes.
nusA amber mutation that causes temperature-sensitive growth of Escherichia coli

The nusA134 mutation was isolated from a sup0 strain as a temperature-sensitive mutant which grew at 32 degrees C but not at 42 degrees C. Immunoblot analysis showed that this mutant produced a 31,000-dalton nusA-encoded protein instead of the full-size 54,500-dalton product. Sequence and genetic analyses of the mutant nusA gene revealed a substitution of T for C at the PstI site (i.e., CTGCAG to CTGTAG), thereby creating a nonsense UAG codon. These results indicate that nusA134 is an amber mutation and that the 31,000-dalton amber fragment is active for Escherichia coli growth at 32 degrees C but not at 42 degrees C. Most lambda bacteriophage variants tested grew normally on the nusA134 mutant both at permissive and at nonpermissive temperatures. However, lambda r32, which carries an IS2 insertion beyond the tR1 terminator, was restricted at 42 degrees C. Defects in the transcriptional antitermination process, but not in transcription termination, were observed. A comparative study of nusA134 protein and a PstI-truncated protein suggests that truncation of the peptide chain at the PstI site by the amber mutation, rather than the loss of the glutamine residue, is primarily responsible for the defect in antitermination. The mode of the involvement of mutant nusA proteins in the N-mediated antitermination reaction is discussed.
β-adrenergic stimulation increases the intra-SR Ca termination threshold for spontaneous Ca waves in cardiac myocytes

β-adrenergic stimulation of cardiac myocytes enhances intracellular calcium cycling, which frequently associates with pro-arrhythmic Ca waves. The threshold level of free calcium in the sarcoplasmic reticulum ([Ca]SR) where waves initiate is increased during β-adrenergic stimulation.1 Here, we measured [Ca]SR directly to monitor the [Ca]SR level at which spontaneous Ca waves terminated (termination threshold) during β-adrenergic stimulation. Compared with control conditions, application of the β-adrenergic receptor agonist isoproterenol (ISO; 1 μM) resulted in an increase in basal [Ca]SR and an increase in the [Ca]SR at which spontaneous Ca waves terminated. When [Ca]SR was experimentally matched, ISO stimulation resulted in a decrease in the depletion amplitude of the waves. Sensitization of ryanodine receptor SR Ca release channels to Ca with a low dose of caffeine in the presence of ISO was able to decrease the termination threshold compared with control conditions. Therefore, the Ca wave termination level may represent an important mode of altering Ca depletion from the SR and reducing the arrhythmogenic potential during β-adrenergic stimulation.
Skeletal and Dental Health of Early Tongans: The Bioarchaeology of the Human Skeletons from the To-At-36 Site, Ha‘ateiho, Tongatapu, Tonga

Abstract Using a variety of skeletal and dental indicators (e.g., stature, linear enamel hypoplasia, cribra orbitalia, infection, trauma, dental pathologies) recorded in 33 adult and 11 subadult skeletons from the To-At-36 site at Ha‘ateiho, Tongatapu, this study examines the health, diet, and lifestyle of precontact Tongans during the Tongan Chiefdom Period (ca. 750–150 BP). Limited comparisons with skeletons from the ‘Atele mound sites (To-At-1 and To-At-2) on Tongatapu and other Pacific Island series are also made. Very few differences in the indicators of health were observed between the adult male and female skeletons from the To-At-36 site and between To-At-36 and the ‘Atele skeletons. Regional comparisons indicate that precontact Tongans and Polynesians were relatively tall and less subject to physiological stress than other Pacific Islanders. Bone infection, most likely attributable to yaws, was more prevalent in early Tongans. Although not significant, the frequency of bone fractures, including spondylolysis, is higher in the Tongan skeletons compared to other precontact Pacific Islanders. Advanced degenerative joint disease in precontact Tongans is comparable to other Pacific Island series. The oral-dental health of early Tongans was generally good. Overall, the frequencies of skeletal and dental indicators of health observed in the precontact Tongan skeletons fall in the medium range and are most similar to those reported for skeletons from the Hane dune site in the Marquesas and the Mariana Islands. Although evidence for physiological stress and bone infection is documented in the subadult skeletons from To-At-36, the prevalence of bone infection is generally higher in other subadult series examined.
Transmural Myocardial Infarction in the Dog Produces Sympathectomy in Noninfarcted Myocardium

Because sympathetic fibers travel in the subepicardium and generally follow the coronary arteries in a basal to apical course, we tested the hypothesis that transmural myocardial infarction that involves this subepicardial region interrupts sympathetic axons traveling through the infarct and produces sympathetic denervation at noninfarcted sites apical to the infarction. A rapidly hardening vinyl latex solution injected into the first diagonal branch of the left anterior descending coronary artery produced the transmural myocardial infarction by embolizing the vasculature. Ten dogs were studied 90 minutes after coronary artery embolization (acute) and 12 dogs were studied 7–21 days after infarction (chronic). The integrity of the sympathetic innervation was tested in an open-chest preparation of the acutely and chronically infarcted dogs by measuring endocardial and epicardial effective refractory period changes during left and right stellate stimulation. Additionally, regional myocardial norepinephrine content and fluorescence were examined in the chronically infarcted dogs. Transmural infarction was verified using nitroblue tetrazolium staining. In the 10 acutely infarcted dogs, left and right stellate stimulation shortened the effective refractory period at all 56 sites examined before infarction and at 30 sites basal or lateral to the infarction after embolization. Twenty-six noninfarcted sites apical to, but not within, the zone of infarction did not respond to left or right stellate stimulation after infarction. In the 12 chronically infarcted dogs, left and right stellate stimulation shortened the effective refractory period at all 20 sites basal to infarction. In noninfarcted sites apical to the infarction, left stellate stimulation did not shorten the eifective refractory period at 23 of 41 sites, while right stellate stimulation was ineffective at 24 of 41 sites. Both left and right stellate stimulation were ineffective at 18 of 41 sites. Twelve of 41 sites apical to the infarct had normal effective refractory period shortening during left and right stellate stimulation. In both groups of dogs, norepinephrine infusion, 0.05, ug/kg/min, i.v. , shortened the refractory period at all sites apical to the infarct that did not shorten refractory period in response to stellate stimulation. In chronically infarcted dogs, myocardial norepinephrine content was reduced at the denervated sites, and histologically reduced norepinephrine fluorescence in noninfarcted, denervated myocardium was found. We conclude that transmural myocardial infarction produces heterogeneous sympathetic denervation in noninfarcted sites apical to the area of necrosis. This denervation is probably the result of interrupting sympathetic nerves coursing from base to apex.
Coordinated reset has sustained aftereffects in Parkinsonian monkeys

Coordinated reset neuromodulation consists of the application of consecutive brief high‐frequency pulse trains through the different contacts of the stimulation electrode. In theoretical studies, by achieving unlearning of abnormal connectivity between neurons, coordinated reset neuromodulation reduces pathological synchronization, a hallmark feature of Parkinson's disease pathophysiology. Here we show that coordinated reset neuromodulation of the subthalamic nucleus has both acute and sustained long‐lasting aftereffects on motor function in parkinsonian nonhuman primates. Long‐lasting aftereffects were not observed with classical deep brain stimulation. These observations encourage further development of coordinated reset neuromodulation for treating motor symptoms in Parkinson disease patients. ANN NEUROL 2012;72:816–820
Resistance Profiling of Hepatitis C Virus Protease Inhibitors using Full-Length NS3

Background The NS3 protease of hepatitis C virus (HCV) is a prime target for anti-HCV drugs but resistance towards inhibitors of the enzyme is likely to emerge because of mutations in the viral genome that modify the structure of the protein. Enzyme inhibition data supporting this is limited to studies with few compounds and analysis performed with truncated NS3. Experimental The potential of HCV acquiring resistance towards NS3 protease inhibitors and the structural features associated with resistance has been explored with a series of inhibitors and by using full-length NS3 protease/helicase variants with amino acid substitutions (A156T, D168V and R155Q) in the protease domain. Results The A156T and D168V substitutions did not influence the kinetic properties of the protease, whereas the R155Q substitution reduced the catalytic efficiency 20 times, as compared with the wild type. Inhibition studies revealed that these substitutions primarily affected the potency of compounds which effectively inhibit the wild-type enzyme, and had little effect on weak or moderate inhibitors. As a consequence, all compounds had similar inhibitory potencies to the substituted enzyme variants. An exception was VX-950, which inhibited the D168V enzyme more efficiently than the wild type. For this inhibitor, the present data correlated better with replicon data than data from assays with truncated enzyme. Conclusions These results have provided a structural basis for designing inhibitors that may be less susceptible to resistance by three known mutations, and suggest that the present variants of full-length NS3 constitute effective models for resistance profiling of NS3 protease inhibitors.
THE THERMO-MECHANICAL EVOLUTION OF THE SUBDUCTION-COLLISION SYSTEMS

The aim of this work was to develop a 2D thermo-mechanical model to analyse in detail the effects of the shear heating and mantle wedge hydration on the thermal state and dynamics of an ocean/continent subduction system. The thermal setting and dynamics that result from models with shear heating and/or mantle hydration are directly compared to a model that does not account for either (Marotta and Spalla, 2007) to analyse their effects on both the strain rate and the viscosity. The new model show the activation of short-wavelength mantle convection related to the hydration and the serpentinisation of the mantle wedge, with the consequent recycling of oceanic and continental subducted material. The effects of the subduction velocities on the size of the hydrated area are also analysed, andpredictions of the pressure-temperature evolutions of crustal markers and the thermal field, which affect different portions of subduction systems, are used to infer the thermal regimes that affect the models. Similarly, the model can help to understand extensively both the distribution and the evolution, in time and space, of metamorphic conditions characterised by contrasting P/T ratios in subduction systems. In a second phase, P-T predicted by the model has been compared with natural P max -T estimates related to the Variscan metamorphism, from both the present domains of the Alps and from the French Central Massif. However, the model did not allow to compare simulated P-T paths with successive metamorphic stages recorded and preserved by the rocks during their metamorphic evolution, because of the lack of exhumation of subducted material up to the shallowest portion of the crust.
Investigating the Potential Role of Genetic and Epigenetic Variation of DNA Methyltransferase Genes in Hyperplastic Polyposis Syndrome

Background Hyperplastic Polyposis Syndrome (HPS) is a condition associated with multiple serrated polyps, and an increased risk of colorectal cancer (CRC). At least half of CRCs arising in HPS show a CpG island methylator phenotype (CIMP), potentially linked to aberrant DNA methyltransferase (DNMT) activity. CIMP is associated with methylation of tumor suppressor genes including regulators of DNA mismatch repair (such as MLH1, MGMT), and negative regulators of Wnt signaling (such as WIF1). In this study, we investigated the potential for interaction of genetic and epigenetic variation in DNMT genes, in the aetiology of HPS. Methods We utilized high resolution melting (HRM) analysis to screen 45 cases with HPS for novel sequence variants in DNMT1, DNMT3A, DNMT3B, and DNMT3L. 21 polyps from 13 patients were screened for BRAF and KRAS mutations, with assessment of promoter methylation in the DNMT1, DNMT3A, DNMT3B, DNMT3L MLH1, MGMT, and WIF1 gene promoters. Results No pathologic germline mutations were observed in any DNA-methyltransferase gene. However, the T allele of rs62106244 (intron 10 of DNMT1 gene) was over-represented in cases with HPS (p<0.01) compared with population controls. The DNMT1, DNMT3A and DNMT3B promoters were unmethylated in all instances. Interestingly, the DNMT3L promoter showed low levels of methylation in polyps and normal colonic mucosa relative to matched disease free cells with methylation level negatively correlated to expression level in normal colonic tissue. DNMT3L promoter hypomethylation was more often found in polyps harbouring KRAS mutations (p = 0.0053). BRAF mutations were common (11 out of 21 polyps), whilst KRAS mutations were identified in 4 of 21 polyps. Conclusions Genetic or epigenetic alterations in DNMT genes do not appear to be associated with HPS, but further investigation of genetic variation at rs62106244 is justified given the high frequency of the minor allele in this case series.
Polymorphisms in Interleukin-6-6331 Influences the Susceptibility of a Chinese Population to Gastric Cancer

We investigated the association of Interleukin (IL)-6-6331 polymorphisms with susceptibility to gastric cancer in 375 patients with gastric cancer and 386 age- and gender-matched healthy controls. After adjustment for the potential confounding effects of gender and age, IL-6-6331TC genotype was associated with a decreased risk of gastric cancer compared with the CC genotype. Further stratification analyses indicated that the protective effect of TC genotype was also observed in poorly differentiated gastric cancer, noncardia gastric cancer, and intestinal-type gastric cancer, respectively. These results suggest that the IL-6-6331 polymorphism is involved in susceptibility to developing gastric cancer.
Discrete Painlevé equations for a class of PVI τ-functions given as U(N) averages

In a recent work, difference equations (Laguerre–Freud equations) for the bi-orthogonal polynomials and related quantities corresponding to the weight on the unit circle were derived. It is shown here that in the case m = 3, these difference equations, when applied to the calculation of the underlying U(N) average, reduce to a coupled system identifiable with that obtained by Adler and van Moerbeke, using the methods of the Toeplitz lattice and Virasoro constraints. Moreover, it is shown that this coupled system can be reduced to yield the discrete fifth Painlevé equation dPV as it occurs in the theory of the sixth Painlevé system. Methods based on affine Weyl group symmetries of Bäcklund transformations have previously yielded the dPV equation, but with different parameters for the same problem. We find an explicit mapping between the two forms. Applications of our results are made to give recurrences for the gap probabilities and moments in the circular unitary ensemble of random matrices, and to the diagonal spin–spin correlation function of the square lattice Ising model.