Striatal activity topographically reflects cortical activity.

The cortex projects to the dorsal striatum topographically1,2 to regulate behaviour3-5, but spiking activity in the two structures has previously been reported to have markedly different relations to sensorimotor events6-9. Here we show that the relationship between activity in the cortex and striatum is spatiotemporally precise, topographic, causal and invariant to behaviour. We simultaneously recorded activity across large regions of the cortex and across the width of the dorsal striatum in mice that performed a visually guided task. Striatal activity followed a mediolateral gradient in which behavioural correlates progressed from visual cue to response movement to reward licking. The summed activity in each part of the striatum closely and specifically mirrored activity in topographically associated cortical regions, regardless of task engagement. This relationship held for medium spiny neurons and fast-spiking interneurons, whereas the activity of tonically active neurons differed from cortical activity with stereotypical responses to sensory or reward events. Inactivation of the visual cortex abolished striatal responses to visual stimuli, supporting a causal role of cortical inputs in driving the striatum. Striatal visual responses were larger in trained mice than untrained mice, with no corresponding change in overall activity in the visual cortex. Striatal activity therefore reflects a consistent, causal and scalable topographical mapping of cortical activity.

Learning in the Rodent Motor Cortex.

The motor cortex is far from a stable conduit for motor commands and instead undergoes significant changes during learning. An understanding of motor cortex plasticity has been advanced greatly using rodents as experimental animals. Two major focuses of this research have been on the connectivity and activity of the motor cortex. The motor cortex exhibits structural changes in response to learning, and substantial evidence has implicated the local formation and maintenance of new synapses as crucial substrates of motor learning. This synaptic reorganization translates into changes in spiking activity, which appear to result in a modification and refinement of the relationship between motor cortical activity and movement. This review presents the progress that has been made using rodents to establish the motor cortex as an adaptive structure that supports motor learning.

Echocardiographic parameters associated with less reverse left ventricular remodeling after transcatheter aortic valve implant in subjects with prosthesis patient mismatch.

BACKGROUND: Transaortic valve implant (TAVI) is the treatment of choice for severe aortic stenosis (AS). Some patients develop prosthesis patient mismatch (PPM) after TAVI. It is challenging to determine which patients are at risk for clinical deterioration. METHODS: We retrospectively measured echocardiographic parameters of left ventricular (LV) morphology and function, prosthetic aortic valve effective orifice area (iEOA) and hemodynamics in 313 patients before and 1 year after TAVI. Our objective was to compare the change in echocardiographic parameters associated with left ventricular reverse modeling in subjects with and without PPM. Our secondary objective was to evaluate echo parameters associated with PPM and the relationship to patient functional status and survival post-TAVI. RESULTS: We found that 82 (26.2%) of subjects had moderate and 37 (11.8%) had severe PPM post-TAVI. There was less relative improvement in LVEF with PPM (1.9 ± 21.3% vs. 8.2 + 30.1%, p = .045). LV GLS also exhibited less relative improvement in those with PPM (13.4 + 34.1% vs. 30.9 + 73.3%, p = .012). NYHA functional class improved in 84.3% of subjects by one grade or more. Echocardiographic markers of PPM were worse in those without improvement in NYHA class (mean AT/ET was .29 vs. .27, p = .05; DVI was .46 vs. .51, p = .021; and iEOA was .8 cm/m2 vs. .9 cm/m2 , p = .025). There was no association with PPM and survival. CONCLUSIONS: There was no improvement in LVEF and less improvement in LV GLS in those with PPM post-TAVI. Echocardiographic markers of PPM were present in those with lack of improvement in NYHA functional class.

Implementation of probe rheology simulation technique in atomistically detailed molecular dynamics simulations.

The probe rheology simulation technique is a technique for measuring the viscosity of a fluid by measuring the motion of an inserted probe particle. This approach has the benefit of greater potential accuracy at a lower computational cost than other conventional simulation techniques used for the calculation of mechanical properties, such as the Green-Kubo approach and nonequilibrium molecular dynamics simulations, and the potential to allow for sampling local variations of properties. This approach is implemented and demonstrated for atomistically detailed models. The viscosity of four different simple Newtonian liquids is calculated from both the Brownian motion (passive mode) and the forced motion (active mode) of an embedded probe particle. The probe particle is loosely modeled as a nano-sized diamond particle: a rough sphere cut out of an FCC lattice made of carbon atoms. The viscosities obtained from the motion of the probe particle are compared with those obtained from the periodic perturbation method, and good agreement between the two sets of values is observed once the probe-fluid interaction strength (i.e., ε ij in the pair-wise Lennard-Jones interaction) is two times higher than their original values, and the artificial hydrodynamic interactions between the probe particle and its periodic images are accounted for. The success of the proposed model opens new opportunities for applying such a technique in the rheological characterization of local mechanical properties in atomistically detailed molecular dynamics simulations, which can be directly compared with or help guide experiments of similar nature.

Hidden Y Chromosome Material and Congenital Cardiovascular Malformations in a Cohort of Turner Syndrome Patients with 45,X Blood Karyotype.

INTRODUCTION: Bicuspid aortic valve is the most common congenital cardiac malformation (CCM) in adults and is 30-50 times more frequent in Turner syndrome (TS). We hypothesize that both X and Y chromosome dosages contribute to the prevalence of CCM in TS. The recognition of genotype-phenotype correlations may improve risk stratification of patients with 45,X karyotypes who have cryptic Y chromosome mosaicism. METHODS: Utilizing data and samples from the UTHealth Turner Syndrome Research Registry, we correlated Y chromosome DNA identified by multiplex quantitative PCR and SNP microarrays with the presence of congenital heart lesions. RESULTS: We identified Y chromosome DNA in more than 10% of registry participants, including 2 participants who had no detectable Y DNA by karyotype or SNP microarray. CONCLUSIONS: There were no significant correlations between the presence of Y DNA and CCM.

Relationship between left atrial reservoir strain, volumes, and geometry: Insights from simple theoretical model.

BACKGROUND: Left atrial (LA) volume is related to LA reservoir strain (LASR ), but the relationship is not fully resolved. We sought to model the relationship between LA end-diastolic and end-systolic volumes (LAEDV and LAESV) and LASR based on a geometrical approach to exploit the relationship between LASR and volume. METHODS: Modeling the LA as a hemisphere with radius r, LASR was recognized to vary linearly with r and LA volume with r3 . Expanding this cubic relation as a Taylor series resulted in a simple linear equation: LAESV/LAEDV = 1 + 3 × LASR . To validate this, 52 transthoracic echocardiograms were analyzed from 18 patients who underwent transcatheter edge-to-edge repair (TEER) with MitraClip with serial assessment pre-procedure, 1 month post-clip, and 12 months post-TEER. Linear regression was performed to compare the geometric equation to a statistical model created by a line of best fit to relate LAESV/LAEDV to LASR . RESULTS: The statistical and geometric model both resulted in a strong correlation (r = .8, p < .001, respectively). The slope of the line in the statistical model was 3.3, which was statistically indistinguishable from the expected slope of 3 based on the geometric model (Figure 2A). Using the geometric model to compare the measured versus calculated LAESV/LAEDV also resulted in a strong correlation (r = .8, p < .001)(Figure 2B). CONCLUSION: We describe the relationship between LA volume and strain mathematically by considering the geometry of the LA. This model enhances our understanding of the interaction between atrial strain and volume. Further research is necessary to validate this using 3D atrial volumes in a broader cohort of subjects.

Novel use of fused cardiac computed tomography and transesophageal echocardiography for left atrial appendage closure.

The use of the Watchman left atrial appendage occlusion device (Boston Scientific Inc.) is becoming increasingly frequent in patients with atrial fibrillation. Cardiac computed tomography (CT) for device sizing pre-procedure can help facilitate more accurate device selection compared with transesophageal echo (TEE) alone. CT can also help identify minor lobes and trabeculations that may not be apparent on TEE. We report a series of three cases to highlight the utility of a novel application of CT-TEE fusion imaging to provide procedural guidance during Watchman implant and to assess for peri-device leak post-implant.

Temporal trends in right heart strain in patients undergoing pulmonary thromboendarterectomy for chronic thromboembolic pulmonary hypertension.

BACKGROUND: Pulmonary thromboendarterectomy (PTE) is a curative procedure for chronic thromboembolic pulmonary hypertension (CTEPH). Right ventricular free wall strain (RV FWS) and right atrial strain (RAS) are not well studied in a CTEPH population. We sought to determine temporal trends in RAS and RV FWS in patients post-PTE. METHODS: 28 patients undergoing PTE for CTEPH were prospectively enrolled in a surgical database. Comprehensive echocardiographic assessment of the right heart was performed including RV FWS, right atrial volume, and the three components of RAS: reservoir, conduit, and booster strain. RESULTS: Patients undergoing PTE demonstrated improvement in NYHA functional class (P < 0.001). Hemodynamic assessment showed improvement in mean pulmonary artery pressure from 49.7 ± 8.5 mm Hg to 23.9 ± 6.5 mm Hg (P < 0.001) and pulmonary vascular resistance decreased from 7.8 ± 3.2 wu to 2.4 ± 1.3 wu (P < 0.001). Tricuspid annular plane systolic excursion (TAPSE) and lateral S` declined immediately post-op. RV FWS improved from -14.4 ± 4% to -19 ± 3.4% post-op and -21.2 ± 4.7% at long-term follow-up (P < 0.001). Improvement in RV FWS post-op was driven primarily by increases in the apical and mid segments. RA volume declined significantly during the study period. RA reservoir and conduit strain improved after PTE. CONCLUSION: Patients undergoing PTE for CTEPH had significant improvement in right heart hemodynamics immediately post-op. Traditional echo metrics of RV performance including TAPSE and lateral S` did not improve. RV FWS improved, which was driven by changes in the apical and mid segments. This highlights that RV FWS is a viable and useful metric to follow in CTEPH patients post-PTE.

Breeding strategies for improving smallholder dairy cattle productivity in Sub-Saharan Africa.

Breeding strategies for smallholder dairy farming systems in Sub-Saharan Africa (SSA) were simulated and evaluated considering cow traits identified as priorities by farmers in different agro-ecological zones. These traits were related to cow milk yield, fertility, temperament, feed intake and disease resistance. The first breeding strategy was based on continuous importation of genetically superior exotic dairy sire semen to SSA and crossing with local females leading to a gradual upgrade of the indigenous population. The second strategy assumed that semen from elite exotic bulls would be imported to SSA and used on indigenous cows to produce F1 animals. Thereafter, elite animals would be selected from within the F1 and each subsequent generation to establish a new synthetic breed. The third strategy was to improve the indigenous population by genetically selecting the best sires available domestically. Results showed positive genetic progress for all breeding goal traits. After 15 generations of selection, the genetic response of the importation strategy exceeded the corresponding genetic response of the synthetic breed strategy by 20%-60%. The former also exceeded the genetic response of the indigenous breed improvement strategy by 43%-75%. Potentially there is an opportunity for breeders to choose an appropriate breeding strategy that fits a specific need of smallholder dairy farmers.

Selection Shapes Synonymous Stop Codon Use in Mammals.

Phylogenetic models of the evolution of protein-coding sequences can provide insights into the selection pressures that have shaped them. In the application of these models synonymous nucleotide substitutions, which do not alter the encoded amino acid, are often assumed to have limited functional consequences and used as a proxy for the neutral rate of evolution. The ratio of nonsynonymous to synonymous substitution rates is then used to categorize the selective regime that applies to the protein (e.g., purifying selection, neutral evolution, diversifying selection). Here, we extend the Muse and Gaut model of codon evolution to explore the extent of purifying selection acting on substitutions between synonymous stop codons. Using a large collection of coding sequence alignments, we estimate that a high proportion (approximately 57%) of mammalian genes are affected by selection acting on stop codon preference. This proportion varies substantially by codon, with UGA stop codons far more likely to be conserved. Genes with evidence of selection acting on synonymous stop codons have distinctive characteristics, compared to unconserved genes with the same stop codon, including longer [Formula: see text] untranslated regions (UTRs) and shorter mRNA half-life. The coding regions of these genes are also much more likely to be under strong purifying selection pressure. Our results suggest that the preference for UGA stop codons found in many multicellular eukaryotes is selective rather than mutational in origin.

Diverse Trichomonas lineages in Australasian pigeons and doves support a columbid origin for the genus Trichomonas.

Trichomonas is a significant protist genus, and includes T. vaginalis, the most prevalent sexually transmitted non-viral infection of humans, and T. gallinae of rock doves (Columba livia), one of the earliest known avian pathogens. New Trichomonas genotypes, including T. vaginalis-like isolates, have been discovered in American columbid hosts, suggesting geographically widespread cryptic diversity of Trichomonas in pigeons and doves. We sampled 319 birds from 22 columbid species in Australia, Papua New Guinea, New Zealand and southern Africa and uncovered 15 novel lineages of Trichomonas, more than doubling the known diversity of this parasite genus and providing evidence for frequent host-switching that eventually gave rise to T. vaginalis in humans. We show that Trichomonas has a columbid origin and likely underwent Miocene expansion out of Australasia. Our chronological topology for Trichomonas is calibrated on the evolution of a host phenotypic trait associated with ecological entrapment of the most basal extant lineage of Trichomonas in Ptilinopus fruit-doves.

Phase behavior of AB/CD diblock copolymer blends via coarse-grained simulation.

The phase diagram of equimolar blends of AB and CD diblock copolymers has been studied using dissipative particle dynamics. All unlike blocks interacted with the same χ, except for the B-C interaction, for which χBC < 0 in order to prevent macrophase separation. The BC interaction was able to prevent macrophase separation except for low volume fractions of B and C (φBC⪅ 0.1) and relatively equal fractions of A and D. For high φBC (φBC⪆ 0.92), a disordered state was obtained. For all microphase separated states the shapes/morphologies were described by the ratios of the eigenvalues of the radius of gyration tensor and their sphericity. These were used to classify the domains as forming sphere, cylinders, lamellae, or branched/gyroidal structures. For φBC < 0.5 the BC domains acted as an interfacial region which compatibilized the A and D domains, while for φBC > 0.5 the BC domain filled in the space between A and D domains. Several interesting structures were formed including a novel connected/branched spheres morphology, hierarchical lamellae, concentric spheres/cylinders, and a combination of cylinders/lamellae. Comparisons are made with the linear diblock and linear triblock phase diagrams.

Reversal of Aortic Enlargement Induced by Increased Biomechanical Forces Requires AT1R Inhibition in Conjunction With AT2R Activation.

Objective- Pharmacological inhibition of the AT1R (angiotensin II type 1 receptor) with losartan can attenuate ascending aortic remodeling induced by transverse aortic constriction (TAC). In this study, we investigated the role of the AT2R (angiotensin II type 2 receptor) and MasR (Mas receptor) in TAC-induced ascending aortic dilation and remodeling. Approach and Results- Wild-type C57BL/6J mice were subjected to sham or TAC surgeries in the presence and absence of various drugs. Aortic diameters were assessed by echocardiography, central blood pressure was measured in the ascending aorta 2 weeks post-operation, and histology and gene expression analyses completed. An angiotensin-converting enzyme inhibitor, captopril, decreased systolic blood pressure to the same level as losartan but did not attenuate aortic dilation, adventitial inflammation, medial collagen deposition, elastin breakage, or Mmp9 (matrix metalloproteinase-9) expression when compared with TAC mice. In contrast, co-administration of captopril with an AT2R agonist, compound 21, attenuated aortic dilation, medial collagen content, elastin breaks, and Mmp9 expression, whereas co-administration of captopril with a MasR agonist (AVE0991) did not reverse aortic dilation and led to aberrant aortic remodeling. An AT2R antagonist, PD123319, reversed the protective effects of losartan in TAC mice. Treatment with compound 21 alone showed no effect on TAC-induced aortic enlargement, blood pressure, elastin breakage, or Mmp9 expression. Conclusions- Our data indicate that when AT1R signaling is blocked, AT2R activation is a key modulator to prevent aortic dilation that occurs with TAC. These data suggest that angiotensin-converting enzyme inhibitor may not be as effective as losartan for slowing aneurysm growth because losartan requires intact AT2R signaling to prevent aortic enlargement.

Emergence of reproducible spatiotemporal activity during motor learning.

The motor cortex is capable of reliably driving complex movements yet exhibits considerable plasticity during motor learning. These observations suggest that the fundamental relationship between motor cortex activity and movement may not be fixed but is instead shaped by learning; however, to what extent and how motor learning shapes this relationship are not fully understood. Here we addressed this issue by using in vivo two-photon calcium imaging to monitor the activity of the same population of hundreds of layer 2/3 neurons while mice learned a forelimb lever-press task over two weeks. Excitatory and inhibitory neurons were identified by transgenic labelling. Inhibitory neuron activity was relatively stable and balanced local excitatory neuron activity on a movement-by-movement basis, whereas excitatory neuron activity showed higher dynamism during the initial phase of learning. The dynamics of excitatory neurons during the initial phase involved the expansion of the movement-related population which explored various activity patterns even during similar movements. This was followed by a refinement into a smaller population exhibiting reproducible spatiotemporal sequences of activity. This pattern of activity associated with the learned movement was unique to expert animals and not observed during similar movements made during the naive phase, and the relationship between neuronal activity and individual movements became more consistent with learning. These changes in population activity coincided with a transient increase in dendritic spine turnover in these neurons. Our results indicate that a novel and reproducible activity-movement relationship develops as a result of motor learning, and we speculate that synaptic plasticity within the motor cortex underlies the emergence of reproducible spatiotemporal activity patterns for learned movements. These results underscore the profound influence of learning on the way that the cortex produces movements.

Three-dimensional echocardiography for the assessment of the tricuspid valve.

Tricuspid valve pathology is increasingly recognized as an important contributor to patient morbidity. Accordingly, interest in transcatheter interventions for tricuspid valve disease has continued to grow. Echocardiographic imaging of the tricuspid valve has therefore become an integral component of patient assessment and the essential imaging modality for interventional procedures. The need for improved tricuspid valve imaging has highlighted the variability in tricuspid valve anatomy and the difficulties of using two-dimensional (2D) echocardiography alone to determine the location and type of tricuspid valve disease. Here, three-dimensional (3D) imaging using tools such as biplane imaging, multiplanar reconstruction and live 3D acquisition allow a more accurate and efficient evaluation of the tricuspid valve. The 3D imaging of the tricuspid valve is often focused on transesophageal echocardiography, but the more anterior location of the tricuspid valve also lends itself to assessment with transthoracic echocardiography. In this review, we will examine how 3D imaging can complement and enhance the information obtained from 2D echocardiography, and present novel applications for the quantitation of valvular disease and its utility in intraprocedural imaging.

Multimodality imaging to guide transcatheter treatment of severe degenerative tricuspid regurgitation with tricuspid valve-in-ring implantation and paravalvular leak closure.

Tricuspid valve (TV) degeneration after surgical repair with an annuloplasty ring is problematic as redo operation carries high mortality. This can be addressed with transcatheter therapies to implant a valve within in prior ring (tricuspid valve-in-ring). When an incomplete ring is present, paravalvular leak is commonly encountered after tricuspid valve-in-ring (TViR) implant; however, this can be addressed with paravalvular leak closure devices. Multimodality imaging including cardiac computed tomography and three-dimensional (3D) transesophageal echocardiography (TEE) are important for successful TViR implant. We report a case of tricuspid regurgitation after tricuspid repair with an incomplete annuloplasty ring and subsequent paravalvular leak closure.

Loss of Smooth Muscle α-Actin Leads to NF-κB-Dependent Increased Sensitivity to Angiotensin II in Smooth Muscle Cells and Aortic Enlargement.

RATIONALE: Mutations in ACTA2, encoding the smooth muscle isoform of α-actin, cause thoracic aortic aneurysms, acute aortic dissections, and occlusive vascular diseases. OBJECTIVE: We sought to identify the mechanism by which loss of smooth muscle α-actin causes aortic disease. METHODS AND RESULTS: Acta2-/- mice have an increased number of elastic lamellae in the ascending aorta and progressive aortic root dilation as assessed by echocardiography that can be attenuated by treatment with losartan, an angiotensin II (AngII) type 1 receptor blocker. AngII levels are not increased in Acta2-/- aortas or kidneys. Aortic tissue and explanted smooth muscle cells from Acta2-/- aortas show increased production of reactive oxygen species and increased basal nuclear factor κB signaling, leading to an increase in the expression of the AngII receptor type I a and activation of signaling at 100-fold lower levels of AngII in the mutant compared with wild-type cells. Furthermore, disruption of smooth muscle α-actin filaments in wild-type smooth muscle cells by various mechanisms activates nuclear factor κB signaling and increases expression of AngII receptor type I a. CONCLUSIONS: These findings reveal that disruption of smooth muscle α-actin filaments in smooth muscle cells increases reactive oxygen species levels, activates nuclear factor κB signaling, and increases AngII receptor type I a expression, thus potentiating AngII signaling in vascular smooth muscle cells without an increase in the exogenous levels of AngII.

Assessing circovirus gene flow in multiple spill-over events.

The establishment of viral pathogens in new host environments following spillover events probably requires adaptive changes within both the new host and pathogen. After many generations, signals for ancient cross-species transmission may become lost and a strictly host-adapted phylogeny may mimic true co-divergence while the virus may retain an inherent ability to jump host species. The mechanistic basis for such processes remains poorly understood. To study the dynamics of virus-host co-divergence and the arbitrary chances of spillover in various reservoir hosts with equal ecological opportunity, we examined structural constraints of capsid protein in extant populations of Beak and feather disease virus (BFDV) during known spillover events. By assessing reservoir-based genotype stratification, we identified co-divergence defying signatures in the evolution BFDV which highlighted primordial processes of cryptic host adaptation and competing forces of host co-divergence and cross-species transmission. We demonstrate that, despite extensive surface plasticity gathered over a longer span of evolution, structural constraints of the capsid protein allow opportunistic host switching in host-adapted populations. This study provides new insights into how small populations of endangered psittacine species may face multidirectional forces of infection from reservoirs with apparently co-diverging genotypes.