Miracle-dz/UniFAR-FTUs huggingface dataset:
Evidence for heteromeric gap junction channels formed from rat connexin43 and human connexin37.

Homomeric gap junction channels are composed solely of one connexin type, whereas heterotypic forms contain two homomeric hemichannels but the six identical connexins of each are different from each other. A heteromeric gap junction channel is one that contains different connexins within either or both hemichannels. The existence of heteromeric forms has been suggested, and many cell types are known to coexpress connexins. To determine if coexpressed connexins would form heteromers, we cotransfected rat connexin43 (rCx43) and human connexin37 (hCx37) into a cell line normally devoid of any connexin expression and used dual whole cell patch clamp to compare the observed gap junction channel activity with that seen in cells transfected only with rCx43 or hCx37. We also cocultured cells transfected with hCx37 or rCx43, in which one population was tagged with a fluorescent marker to monitor heterotypic channel activity. The cotransfected cells possessed channel types unlike the homotypic forms of rCx43 or hCx37 or the heterotypic forms. In addition, the noninstantaneous transjunctional conductance-transjunctional voltage ( G j/ V j) relationship for cotransfected cell pairs showed a large range of variability that was unlike that of the homotypic or heterotypic form. The heterotypic cell pairs displayed asymmetric voltage dependence. The results from the heteromeric cell pairs are inconsistent with summed behavior of two independent homotypic populations or mixed populations of homotypic and heterotypic channels types. The G j/ V jdata imply that the connexin-to-connexin interactions are significantly altered in cotransfected cell pairs relative to the homotypic and heterotypic forms. Heteromeric channels are a population of channels whose characteristics could well impact differently from their homotypic counterparts with regard to multicellular coordinated responses.
Harnessing Solute Carrier Transporters for Precision Oncology

Solute Carrier (SLC) transporters are a large superfamily of transmembrane carriers involved in the regulated transport of metabolites, nutrients, ions and drugs across cellular membranes. A subset of these solute carriers play a significant role in the cellular uptake of many cancer therapeutics, ranging from chemotherapeutics such as antimetabolites, topoisomerase inhibitors, platinum-based drugs and taxanes to targeted therapies such as tyrosine kinase inhibitors. SLC transporters are co-expressed in groups and patterns across normal tissues, suggesting they may comprise a coordinated regulatory circuit serving to mediate normal tissue functions. In cancer however, there are dramatic changes in expression patterns of SLC transporters. This frequently serves to feed the increased metabolic demands of the tumor cell for amino acids, nucleotides and other metabolites, but also presents a therapeutic opportunity, as increased transporter expression may serve to increase intracellular concentrations of substrate drugs. In this review, we examine the regulation of drug transporters in cancer and how this impacts therapy response, and discuss novel approaches to targeting therapies to specific cancers via tumor-specific aberrations in transporter expression. We propose that among the oncogenic changes in SLC transporter expression there exist emergent vulnerabilities that can be exploited therapeutically, extending the application of precision medicine from tumor-specific drug targets to tumor-specific determinants of drug uptake.
Sidewall GaAs tunnel junctions fabricated using molecular layer epitaxy

Abstract In this article we review the fundamental properties and applications of sidewall GaAs tunnel junctions. Heavily impurity-doped GaAs epitaxial layers were prepared using molecular layer epitaxy (MLE), in which intermittent injections of precursors in ultrahigh vacuum were applied, and sidewall tunnel junctions were fabricated using a combination of device mesa wet etching of the GaAs MLE layer and low-temperature area-selective regrowth. The fabricated tunnel junctions on the GaAs sidewall with normal mesa orientation showed a record peak current density of 35 000 A cm-2. They can potentially be used as terahertz devices such as a tunnel injection transit time effect diode or an ideal static induction transistor.
Adaptive Robust Precision Motion Control of a High-Speed Industrial Gantry With Cogging Force Compensations

This paper studies the precision motion control of a high-speed/acceleration linear motor driven commercial gantry which is subject to significant nonlinear cogging forces. A discontinuous projection based desired compensation adaptive robust controller (DCARC) is constructed. In particular, based on the special structures of various nonlinear forces, design models consisting of known basis functions with unknown weights are used to approximate those unknown nonlinear forces with approximation errors being explicitly accounted for in the design process. Online parameter adaptation is then utilized to reduce the effect of various parametric uncertainties while certain robust control laws are used to handle effects of various modeling uncertainties. Theoretically, the resulting controller achieves a guaranteed transient performance and final tracking accuracy in the presence of both parametric uncertainties and uncertain nonlinearities. In addition, in the presence of parametric uncertainties, the controller achieves asymptotic output tracking. Comparative experimental results obtained on a high-speed Anorad commercial gantry with a linear encoder resolution of 0.5 μ m and a position measurement resolution of 20 nm by external laser interferometer are presented to verify the excellent tracking performance of the proposed control strategy.
Balanced Polymorphisms and the Evolution of Dominance

We explore the evolution of dominance at polymorphisms maintained either by overdominant selection or by migration‐selection balance. At such balanced polymorphisms, heterozygotes remain at appreciable frequencies over long periods of time, allowing extensive modification of dominance to occur. The strength of selection favoring a modifier of dominance is roughly proportional to the probability that a modifier allele is found in a heterozygote at the locus subject to balancing selection times the heterozygote fitness increase caused by the modifier. Using a two‐locus model, we elucidate the interesting ways in which recombination and migration cause departures from this rough expectation. For example, with overdominance, a genetic association with the rarest allele favors a modifier that increases heterozygote fitness because the modifier occurs more often in heterozygotes. With migration‐selection balance, dominance evolves more readily in patches experiencing the strongest selection. We also find that, while there are more heterozygotes in sink populations (which have higher rates of immigration than emigration), selection for dominance in sink and source populations is nearly equal because sink populations make a lower genetic contribution to future generations. We conclude that the evolution of dominance is likely to occur whenever polymorphism is maintained by either overdominance or migration.
European Policies to Promote Children’s Rights and Combat Child Poverty

The upbringing of children relies heavily on shared responsibilities between parents and society. The Council of Europe Recommendation (2006) 19 on Policy to Support Positive Parenting and the European Commission Recommendation (2013) Investing in Children: Breaking the Cycle of Disadvantage, both aim at supporting parents to care and provide for their children in accordance with the UN Convention on the Rights of the Child. By means of a document analysis this article examines what kind of parental practices and provision to parents the recommendations suggest to safeguard children’s rights in the family. Three findings are highlighted: first, both recommendations reflect a commitment to respecting children’s rights while at the same time acknowledging parents as children’s primary caregivers. Second, both recognize parents’ rights to work, while also recognizing the necessity of adequate income support if work is not available or income too low. Third, adequate resources are defined as a combination of universal policies and services, which guarantee a minimum level for all, and targeted measures reaching out to the most disadvantaged. The recommendations’ emphasis on children and parents as partners and on the families’ economic situations are valuable for future development of family and child policy and support programs.
MUTYH and ORAI1 polymorphisms are associated with susceptibility to osteoarthritis in the Chinese Han population

Background This study analyzed the associations between single nucleotide polymorphisms (SNPs) in the mutY homolog gene (MUTYH) and the calcium release-activated calcium channel gene (ORAI1) with susceptibility to osteoarthritis in the Chinese Han population. Methods A total of 350 patients diagnosed with osteoarthritis from October 2013 to May 2016 were selected as the study group, together with 350 age- and gender-matched healthy controls. MUTYH SNP rs3219463 and ORAI1 SNPs rs712853, rs12313273, rs6486795, rs12320939, and rs7135617 were analyzed by Sanger sequencing. Serum MUTYH levels were measured by enzyme-linked immunosorbent assay. The relationship between SNPs in MUTYH and ORAI1 and osteoarthritis susceptibility was analyzed and compared with the level of serum MUTYH in the osteoarthritis and control groups. Results MUTYH rs3219463 G allele carriers (GG or GA genotypes) and ORAI1 rs7135617 T allele carriers had a higher risk of osteoarthritis than patients with other genotypes. The level of serum MUTYH in the study group was significantly higher than in the control group (22.05 ± 19.14 ng/mL vs. 14.15 ± 13.54 ng/mL). Conclusions MUTYH and ORAI1 SNPs are associated with osteoarthritis susceptibility in the Chinese Han population.
Tissue‐specific bioconcentration and biotransformation of cypermethrin and chlorpyrifos in a native fish (Jenynsia multidentata) exposed to these insecticides singly and in mixtures

The aim of the present study was to evaluate the accumulation of cypermethrin and chlorpyrifos when the fish Jenynsia multidentata was exposed to these pesticides singly and in technical and commercial mixtures. Adult female fish were exposed over 96 h to 0.04 μg/L of cypermethrin; 0.4 μg/L of chlorpyrifos; 0.04 μg/L of cypermethrin + 0.4 μg/L of chlorpyrifos in a technical mixture; and 0.04 μg/L of cypermethrin + 0.4 μg/L of chlorpyrifos in a mixture of commercial products. Fish exposed to cypermethrin accumulated this compound only in muscle, probably because of the low biotransformation capacity of this organ and the induction of cytochrome P4501A1 (CYP1A1) expression in the liver. The accumulation of chlorpyrifos occurred in fish exposed to the insecticide (intestine > liver > gills) even when these fish had higher gluthatione‐S‐transferase (GST) activity in gills and P‐glycoprotein (P‐gp) expression in the liver, compared with the control. Fish exposed to the technical mixture showed cypermethrin accumulation (liver > intestine > gills) with higher levels than those measured in fish after only cypermethrin exposure. Higher expression levels of CYP1A1 in the liver were also observed compared with the Control. Fish exposed to the commercial mixture accumulated both insecticides (cypermethrin: intestine > gills and chlorpyrifos: liver > intestine > gills > muscle). In the organs where accumulation occurred, biotransformation enzymes were inhibited. Consequently, the commercial formulation exposure provoked the highest accumulation of cypermethrin and chlorpyrifos in J. multidentata, possibly associated with the biotransformation system inhibition. Environ Toxicol Chem 2017;36:1764–1774. © 2016 SETAC
Invasive hemodynamics and force-frequency relationships in open- versus closed-chest mice.

We compared hemodynamics, ventricular function, and force-frequency relationships in six open-chest and six closed-chest anesthetized mice (FVB/N strain). Left ventricular (LV) pressure was measured with a 1.8- or 1.4-Fr Millar catheter placed via the right carotid artery and the LV apex in the closed- and open-chest state, respectively. Pacing was performed with electrodes placed either directly on atrial appendages (open chest) or with a 1-Fr bipolar catheter via the jugular vein (closed chest). Closed-chest animals had greater spontaneous heart rate (267 ± 106 vs. 147 ± 27 beats/min), LV systolic (81 ± 14 vs. 48 ± 9 mmHg) and diastolic pressures (11.2 ± 4.8 vs. 5.6 ± 2.4 mmHg), and maximal rise (+dP/d t max: 6,208 ± 2,519 vs. 3,682 ± 671 mmHg/s) and fall in pressure development (-dP/d t max: -6,094 ± 2,386 vs. -3,001 ± 399 mmHg/s). LV systolic pressure (98 ± 18 vs. 52 ± 11 mmHg), +dP/d t max (9,240 ± 2,459 vs. 5,777 ± 2,473 mmHg/s), and -dP/d t max(-8,375 ± 2,551 vs. -3,753 ± 1,170 mmHg/s) were significantly higher when animals were matched at a heart rate of 420 beats/min in closed-chest vs. open-chest animals. Biphasic force-frequency relationships were seen in all animals, but the critical heart rate was greater in the closed- than open-chest animals (432 ± 42 vs. 318 ± 42 beats/min). We conclude that 1) there are significant differences between invasive indexes of systolic and diastolic function between the closed- and open-chest preparations, 2) there is a biphasic force-frequency relationship in the anesthetized mouse, and 3) dP/d t max can be used to assess the cardiovascular phenotype.
Zymogen proteolysis within the pancreatic acinar cell is associated with cellular injury.

The pathological activation of digestive zymogens within the pancreatic acinar cell probably plays a central role in initiating many forms of pancreatitis. To examine the relationship between zymogen activation and acinar cell injury, we investigated the effects of secretagogue treatment on isolated pancreatic acini. Immunofluorescence studies using antibodies to the trypsinogen-activation peptide demonstrated that both CCK (10-7 M) hyperstimulation and bombesin (10-5 M) stimulation of isolated acini resulted in trypsinogen processing to trypsin. These treatments also induced the proteolytic processing of procarboxypeptidase A1 to carboxypeptidase A1(CA1). After CCK hyperstimulation, most CA1remained in the acinar cell. In contrast, the CA1 generated by bombesin was released from the acinar cell. CCK hyperstimulation of acini was associated with cellular injury, whereas bombesin treatment did not induce injury. These studies suggest that 1) proteolytic zymogen processing occurs within the pancreatic acinar cell and 2) both zymogen activation and the retention of enzymes within the acinar cell may be required to induce injury.
Lipolytic suppression following carbohydrate ingestion limits fat oxidation during exercise.

This study determined if the suppression of lipolysis after preexercise carbohydrate ingestion reduces fat oxidation during exercise. Six healthy, active men cycled 60 min at 44 ± 2% peak oxygen consumption, exactly 1 h after ingesting 0.8 g/kg of glucose (Glc) or fructose (Fru) or after an overnight fast (Fast). The mean plasma insulin concentration during the 50 min before exercise was different among Fast, Fru, and Glc (8 ± 1, 17 ± 1, and 38 ± 5 μU/ml, respectively; P< 0.05). After 25 min of exercise, whole body lipolysis was 6.9 ± 0.2, 4.3 ± 0.3, and 3.2 ± 0.5 μmol ⋅ kg-1 ⋅ min-1and fat oxidation was 6.1 ± 0.2, 4.2 ± 0.5, and 3.1 ± 0.3 μmol ⋅ kg-1 ⋅ min-1during Fast, Fru, and Glc, respectively (all P < 0.05). During Fast, fat oxidation was less than lipolysis ( P < 0.05), whereas fat oxidation approximately equaled lipolysis during Fru and Glc. In an additional trial, the same subjects ingested glucose (0.8 g/kg) 1 h before exercise and lipolysis was simultaneously increased by infusing Intralipid and heparin throughout the resting and exercise periods (Glc+Lipid). This elevation of lipolysis during Glc+Lipid increased fat oxidation 30% above Glc (4.0 ± 0.4 vs. 3.1 ± 0.3 μmol ⋅ kg-1 ⋅ min-1; P < 0.05), confirming that lipolysis limited fat oxidation. In summary, small elevations in plasma insulin before exercise suppressed lipolysis during exercise to the point at which it equaled and appeared to limit fat oxidation.
Peripheral nerve injury increases contribution of L-type calcium channels to synaptic transmission in spinal lamina II: Role of α2δ–1 subunits

Background Following peripheral nerve chronic constriction injury, the accumulation of the α2δ–1 auxiliary subunit of voltage-gated Ca2+ channels in primary afferent terminals contributes to the onset of neuropathic pain. Overexpression of α2δ–1 in Xenopus oocytes increases the opening properties of Cav1.2 L-type channels and allows Ca2+ influx at physiological membrane potentials. We therefore posited that L-type channels play a role in neurotransmitter release in the superficial dorsal horn in the chronic constriction injury model of neuropathic pain. Results Whole-cell recording from lamina II neurons from rats, subject to sciatic chronic constriction injury, showed that the L-type Ca2+ channel blocker, nitrendipine (2 µM) reduced the frequency of spontaneous excitatory postsynaptic currents. Nitrendipine had little or no effect on spontaneous excitatory postsynaptic current frequency in neurons from sham-operated animals. To determine whether α2δ–1 is involved in upregulating function of Cav1.2 L-type channels, we tested the effect of the α2δ–1 ligand, gabapentin (100 µM) on currents recorded from HEK293F cells expressing Cav1.2/β4/α2δ–1 channels and found a significant decrease in peak amplitude with no effect on control Cav1.2/β4/α2δ–3 expressing cells. In PC-12 cells, gabapentin also significantly reduced the endogenous dihydropyridine-sensitive calcium current. In lamina II, gabapentin reduced spontaneous excitatory postsynaptic current frequency in neurons from animals subject to chronic constriction injury but not in those from sham-operated animals. Intraperitoneal injection of 5 mg/kg nitrendipine increased paw withdrawal threshold in animals subject to chronic constriction injury. Conclusion We suggest that L-type channels show an increased contribution to synaptic transmission in lamina II dorsal horn following peripheral nerve injury. The effect of gabapentin on Cav1.2 via α2δ–1 may contribute to its anti-allodynic action.
Neurosteroid modulation of arterial baroreflexsensitive neurons in rat rostral ventrolateral medulla.

The major metabolite of progesterone, 3α-OH-dihydroprogesterone (3α-OH-DHP), is the most potent endogenous positive modulator of central nervous system GABAA receptors. Acute intravenous administration of 3α-OH-DHP to virgin female rats potentiates arterial baroreflex sympathoinhibitory responses. The current experiments tested the possibility that circulating 3α-OH-DHP potentiates central GABAergic influences in the rostral ventrolateral medulla (RVLM). The unit activity of spontaneously active, spinally projecting, and arterial pressure-sensitive neurons was recorded in the RVLM of urethan-anesthetized rats. Arterial pressure sensitivity of RVLM neurons was tested before (control) and 10 min after bolus injection (44 μl iv) of 3α-OH-DHP (1.12 μg/kg, n = 19) or vehicle (40% β-cyclodextrin, n = 8). Both threshold pressure and saturation pressure for inhibition of RVLM neurons were decreased after acute administration of a physiological dose of 3α-OH-DHP (1.12 μg/kg iv), which produces plasma concentrations similar to those seen during pregnancy (20-30 ng/ml), suggesting potentiated responsiveness to endogenously released GABA. Following suppression by 3α-OH-DHP, high doses of the inactive stereoisomer 3β-OH-DHP (112-224 μg/kg iv; n = 8) restored unit activity, presumably by displacing 3α-OH-DHP from the neurosteroid binding site on GABAA receptors.
Social preference weights for treatments in Fabry disease in the UK: a discrete choice experiment

Abstract Objective: Fabry disease is a rare inherited lysosomal storage disorder caused by deficiency of α-galactosidase A. Effective enzyme replacement therapies are available that are administered intravenously. However, a new oral treatment is being developed as an alternative option for patients with amenable mutations. This study was designed to understand the value that people place on the different features of treatments for Fabry disease. Research design and methods: A discrete choice experiment (DCE) was designed to assess the importance of different aspects of treatments for Fabry disease. The attributes included overall survival, mode of administration, treatment related reactions, treatment related headaches and risk of antibody formation. Attributes were combined using a published orthogonal array into choice sets. A research panel was used to survey the UK general public. The mixed logit model was used to estimate strength of preference for the attributes and marginal rates of substitution (MRSs). Disutilities were estimated from the DCE data for changes in each attribute. Results: The sample (n = 506) was broadly representative of UK demographics. The logit model revealed that all attributes were significant predictors of choice. Participants were significantly more likely to choose a treatment which meant an increase in their life expectancy by 1 year (odds ratio = 1.574; 95% CI = 1.504–1.647) and significantly less likely to choose self-administered intravenous (IV) treatment compared to an every other day tablet (OR = 0.426 95% CI = 0.384–0.474). Estimated disutilities were −0.0543 (self-administered infusion), treatment related headaches 12 times a year (−0.0361) and infusion reactions six times a year (−0.0202). Conclusions: The survey revealed a significant preference for oral treatment compared with IV even in the context of a treatment that can extend overall survival. MRSs were used as a basis for estimating disutilities associated with changes in attribute levels which could be used to weight QALYs. It is possible that other important treatment attributes are missing from this research which may have provided further insights. It would also be useful to extend this research to include Fabry disease patients so their preferences can be assessed against the societal perspective.
Task-specific sensory coding strategies are matched to detection and discrimination performance

ABSTRACT The acquisition of sensory information is limited by the neural encoding method used, constraining perceptual abilities. The most relevant aspects of stimuli may change as behavioral context changes, making efficient encoding of information more challenging. Sensory systems must balance rapid detection of a stimulus with perception of fine details that enable discrimination between similar stimuli. Here, we show that in a species of weakly electric fish, Apteronotus leptorhynchus, two coding strategies are employed for these separate behavioral tasks. Using communication signals, we demonstrate a strong correlation between neural coding strategies and behavioral performance on a discrimination task. Extracellular recordings of pyramidal cells within the electrosensory lateral line lobe of alert fish show two distinct response patterns, either burst discharges with little variation between different signals of the same category, or a graded, heterogeneous response that contains sufficient information to discriminate between signals with slight variations. When faced with a discrimination-based task, the behavioral performance of the fish closely matches predictions based on coding strategy. Comparisons of these results with neural and behavioral responses observed in other model systems suggest that our study highlights a general principle in the way sensory systems utilize different neural codes. Summary: Two distinct neural coding schemes show how weakly electric fish sensory neurons change response patterns to adapt to context-specific perceptual needs.