Miracle-dz/UniFAR-FTUs huggingface dataset:
ORR_A_342738 247..254

1Department of Orthopaedic Surgery, University Malaya Medical Centre, Kuala Lumpur, Malaysia; 2National Orthopaedic Center of Excellence for Research & Learning (NOCERAL), University of Malaya, Kuala Lumpur, Malaysia Abstract: We report the case of an eleven-year-old girl with untreated bilateral clubfoot. She had a total of nine long leg castings changed weekly, Achilles tendon Z-lengthening and posterior ankle release followed by another six weeks of long leg cast immobilization postoperatively. We encouraged using night-time foot abduction brace for twelve months. Independent walking was achieved six months post-treatment. No recurrence was noted at eighteen months following treatment. The modified Ponseti weekly casting method was successful up to adolescent age; however, more cast changes, longer stretching before each cast application and posterior ankle release will be needed to achieve functional correction.
Monetary Policy Effects on Energy Sector Bubbles

We investigate the effects of monetary policy shocks, including unconventional policy measures, on the bubbles of the energy sector, for the case of the United States. We estimate a time-varying Bayesian VAR model that allows for quantifying the impact of monetary policy shocks on asset prices and bubbles. The energy sector is measured through the S&P Energy Index, while bubbles are measured through the difference between asset prices and the corresponding dividends for the energy sector. We find significant differences in the impact of monetary policy shocks for the aggregate economy and for the energy sector. The findings seem sensitive to the interest rate use, i.e., whether one uses the shadow interest rate or the long-term interest rate.
Beyond the Average Case: The Mean Focus Fallacy of Standard Linear Regression and the Use of Quantile Regression for the Social Sciences

This article outlines the limitations and fallacies of the routine use of standard linear regression.The method confines the analysis to the effect of the explanatory variable(s) on the mean of the dependent variable, and precludes the exploration of the various other ways in which the dependent variable responds to changes on the explanatory variable(s). The implications for the discovery and development of theories in the social sciences are discussed. Using the empirical example of the relationship between income and happiness, the article shows how quantile regression can help avoiding these fallacies and allow the researcher to address a broader range of research questions.
A Tunable SiGe BiCMOS Gain-Equalizer For X-Band Phased-Array RADAR Applications

This brief presents a compact-size tunable gain-equalizer for X-band phased-array RADAR applications in a 0.25- $ \mu \text{m}$ SiGe BiCMOS technology. An isolated nMOS-based variable resistance was used for the first time to tune the slope of the gain-equalizer. For nMOS, an isolated body created by a deep n-well was utilized to reduce insertion loss due to the substrate conductivity. Furthermore, the power-handling capability of the tunable gain-equalizer was improved thanks to the resistive body-floating technique. The designed tunable gain-equalizer operates in the frequency range from 8 to 12.5 GHz with a measured positive slope of 1 dB/GHz and 1 dB tunable slope. The effective chip area excluding the pads is 0.21 mm2, and the total area including pads is 0.31 mm2. To authors best knowledge, this brief is the first tunable gain-equalizer in SiGe technology presented for X-band phased-array RADAR applications.
Elastic finite difference modelling with stability and dispersion corrections

SUMMARY This paper presents a general method to limit the dispersion and instability inherent within finite-difference elastic modelling in two dimensions. The method is based on an extension of the Von Neumann stability analysis. For a fixed frequency an analytic relationship is derived between the continuous derivatives in the elastic wave equation and their second-order finitedifference approximations. Typically, the continuous derivative is equal to a finite-difference result divided by a correction factor that is a squared sinc function dependant on frequency and grid size. When the continuous derivatives are replaced by these expressions, an exact formulation of the elastic wave equation results that involves finite differences and correction factors. These correction factors are all frequency dependent. The frequency dependence can be converted to wavenumber dependence using P and S wave velocities. This allows the correction factors to be applied as spatial filters. Numerical tests show that these correction factors compensate for a wide range of dispersion and instability.
Average treatment effect estimates robust to the “limited overlap” problem: robustate

We introduce a new command, robustate, that executes the inverseprobability weighting estimation and inference for the average treatment effect with robustness against limited overlap (that is, weak satisfaction of the common support condition). This command produces estimates, standard errors, p-values, and confidence intervals for the average treatment effect. The utility of the command is demonstrated with both simulated and real data of right heart catheterization. These illustrations show that the proposed estimator implemented by the robustate command indeed exhibits more robustness against limited overlap than the traditional inverse-probability weighting estimator. The main method of the command is proposed in Sasaki and Ura (2022, Econometric Theory 38: 66–112).
Palidis: fast discovery of novel insertion sequences

The diversity of microbial insertion sequences, crucial mobile genetic elements in generating diversity in microbial genomes, needs to be better represented in current microbial databases. Identification of these sequences in microbiome communities presents some significant problems that have led to their underrepresentation. Here, we present a bioinformatics pipeline called Palidis that recognises insertion sequences in metagenomic sequence data rapidly by identifying inverted terminal repeat regions from mixed microbial community genomes. Applying Palidis to 264 human metagenomes identifies 879 unique insertion sequences, with 519 being novel and not previously characterised. Querying this catalogue against a large database of isolate genomes reveals evidence of horizontal gene transfer events across bacterial classes. We will continue to apply this tool more widely, building the Insertion Sequence Catalogue, a valuable resource for researchers wishing to query their microbial genomes for insertion sequences. Data Summary Palidis is available here: github.com/blue-moon22/palidis The Insertion Sequence Catalogue is available to download here: https://github.com/blue-moon22/ISC The raw reads from the Human Microbiome Project can be retrieved using the download links provided in Supplementary Data 1 The analysis for this paper is available here: github.com/blue-moon22/palidis_paper_analysis The output of Palidis that was run on these reads is available in Supplementary Data 2 Impact Statement Insertion sequences are a class of transposable element that play an important role in the dissemination of antimicrobial resistance genes. However, it is challenging to completely characterise the transmission dynamics of insertion sequences and their precise contribution to the spread of antimicrobial resistance. The main reasons for this are that it is impossible to identify all insertion sequences based on limited reference databases and that de novo computational methods are ill-equipped to make fast or accurate predictions based on incomplete genomic assemblies. Palidis generates a larger, more comprehensive catalogue of insertion sequences based on a fast algorithm harnessing genomic diversity in mixed microbial communities. This catalogue will enable genomic epidemiologists and researchers to annotate genomes for insertion sequences more extensively and advance knowledge of how insertion sequences contribute to bacterial evolution in general and antimicrobial resistance spread across microbial lineages in particular. This will be useful for genomic surveillance, and for development of microbiome engineering strategies targeting inactivation or removal of important transposable elements carrying antimicrobial resistance genes.
Quantitative prediction and measurement of Piezo's membrane footprint

Piezo proteins are mechanosensitive ion channels that can locally curve the membrane into a dome shape (Y. R. Guo, R. MacKinnon, 2017). The curved shape of the Piezo dome is expected to deform the surrounding lipid bilayer membrane into a membrane footprint, which may serve to amplify Piezo’s sensitivity to applied forces (C. A. Haselwandter, R. MacKinnon, 2018). If Piezo proteins are embedded in lipid bilayer vesicles, the membrane shape deformations induced by the Piezo dome depend on the vesicle size. We employ here membrane elasticity theory to predict, with no free parameters, the shape of such Piezo vesicles outside the Piezo dome, and show that the predicted vesicle shapes agree quantitatively with the corresponding measured vesicle shapes obtained through cryo-electron tomography, for a range of vesicle sizes (Helfrich W. 1973). On this basis, we explore the coupling between Piezo and membrane shape, and demonstrate that the features of the Piezo dome affecting Piezo’s membrane footprint follow approximately a spherical cap geometry. Our work puts into place the foundation for deducing key elastic properties of the Piezo dome from membrane shape measurements and provides a general framework for quantifying how proteins deform bilayer membranes. Classification Biophysicss
Exon-intron architecture determines mRNA stability by dictating m6A deposition

N6-methyladenosine (m6A), a widespread destabilizing mark on mRNA, is non-uniformly distributed across the transcriptome, yet the basis for its selective deposition is unknown. Here, we uncover that m6A deposition is not selective. Instead, m6A distribution is exclusion-based: m6A-consensus harboring sites are methylated by default, unless they are within a window of up to ∼200 nt from an exon-intron junction. A simple model, relying exclusively on presence of m6A motifs and exon-intron architecture allows high accuracy recapitulation of experimentally-measured m6A profiles and of all m6A hallmarks. We further establish that m6A serves as the long-sought mechanism underlying the strong association between exon-intron architecture and mRNA stability. Our findings establish a mechanism by which the memory of nuclear RNA splicing is covalently etched on an mRNA, in the form of m6A, and determines its cytoplasmic stability, with broad implications on the regulation, function, and evolution of both m6A and mRNA stability.
Increasing Muscle Hypertrophy with a Natural Product Designed to Inhibit SIRT1

Muscle mass and strength are predictors of longevity. We have previously identified a series of molecular brakes that slow muscle growth in response to stress. One potential stress that we hypothesized would limit muscle growth is caloric stress through the activation of SIRT1. We therefore identified natural product inhibitors of SIRT1 and tested their effects on load-induced increases in muscle fiber cross-sectional area (fCSA) using an incomplete factorial design. Supplying varying amounts of three natural products for the full two-week period of overload resulted in increases in fCSA that varied from −2 to 113%. Using these data, we produced a model that predicted the optimal combination and concentration of each natural product and validated this model in a separate cohort of animals. Following two weeks of overload, fCSA in the optimal group increased 62%, whereas in the placebo fCSA increased only 3%. The greater increase in fCSA was not the result of an increase in ribosomal mass. In fact, the optimal group showed significantly less of the 5⍰ external transcribed spacer, a marker of 47S ribosomal RNA synthesis, and a trend for decreased total RNA. In spite of the lower ribosome mass, the increase in protein synthesis was similar, suggesting that the natural product cocktail may be increasing ribosomal efficiency rather than capacity. These data suggest that inhibition of SIRT1, together with exercise, may be useful in increasing muscle fCSA.
Colorectal Cancer Metastases in the Liver Establish Immunosuppressive Spatial Networking between Tumor-Associated SPP1+ Macrophages and Fibroblasts

Purpose The liver is the most frequent metastatic site for colorectal cancer (CRC). Its microenvironment is modified to provide a niche that allows CRC cell growth. This study focused on characterizing the cellular changes in the metastatic CRC (mCRC) liver tumor microenvironment (TME). Experimental Design We analyzed a series of microsatellite stable (MSS) mCRCs to the liver, paired normal liver tissue and peripheral blood mononuclear cells using single cell RNA-seq (scRNA-seq). We validated our findings using multiplexed spatial imaging and bulk gene expression with cell deconvolution. Results We identified TME-specific SPP1-expressing macrophages with altered metabolism features, foam cell characteristics and increased activity for extracellular matrix (ECM) organization. SPP1+ macrophages and fibroblasts expressed complementary ligand receptor pairs with the potential to mutually influence their gene expression programs. TME lacked dysfunctional CD8 T cells and contained regulatory T cells, indicative of immunosuppression. Spatial imaging validated these cell states in the TME. Moreover, TME macrophages and fibroblasts had close spatial proximity, a requirement for intercellular communication and networking. In an independent cohort of mCRCs in the liver, we confirmed the presence of SPP1+ macrophages and fibroblasts using gene expression data. An increased proportion of TME fibroblasts was associated with worst prognosis in these patients. Conclusions We demonstrated that mCRC in the liver is characterized by transcriptional alterations of macrophages in the TME. Intercellular networking between macrophages and fibroblasts supports CRC growth in the immunosuppressed metastatic niche in the liver. These features can be used to target these immune checkpoint resistant MSS tumors. TRANSLATIONAL RELEVANCE The liver is the commonest site for metastatic colorectal cancer (mCRC). Alterations in the tumor microenvironment (TME) allow metastatic cells to seed the distant liver site and grow. Leveraging single-cell RNA sequencing, we discovered a distinct SPP1+ macrophage cell state with pro-fibrogenic gene expression and altered metabolism. These SPP1+ macrophages communicated with fibroblasts, mutually influencing each other’s gene expression program. Using spatial imaging, we confirmed proximal colocalization between macrophages and fibroblasts in the mCRC TME, which is required for intercellular communication. These states and intercellular communication promoted immunosuppression in the TME, with a lack of dysfunctional anti-tumor CD8 T cells and prevalence of regulatory T cells. Increased fibroblasts were associated with worst prognosis in an independent patient cohort. Our results identified novel TME features that result in reshaping of the metastatic niche that allows progression of mCRC. These features can be potential targets for mCRC treatment, which is microsatellite stable and resistant to immune checkpoint blockade.
Multimodal Brain Signal Complexity Predicts Human Intelligence

Abstract Spontaneous brain activity builds the foundation for human cognitive processing during external demands. Neuroimaging studies based on functional magnetic resonance imaging (fMRI) identified specific characteristics of spontaneous (intrinsic) brain dynamics to be associated with individual differences in general cognitive ability, i.e., intelligence. However, fMRI research is inherently limited by low temporal resolution, thus, preventing conclusions about neural fluctuations within the range of milliseconds. Here, we used resting-state electroencephalographical (EEG) recordings from 144 healthy adults to test whether individual differences in intelligence (Raven’s Advanced Progressive Matrices scores) can be predicted from the complexity of temporally highly resolved intrinsic brain signals. We compared different operationalizations of brain signal complexity (multiscale entropy, Shannon entropy, Fuzzy entropy, and specific characteristics of microstates) regarding their relation to intelligence. The results indicate that associations between brain signal complexity measures and intelligence are of small effect sizes (r ∼ 0.20) and vary across different spatial and temporal scales. Specifically, higher intelligence scores were associated with lower complexity in local aspects of neural processing, and less activity in task-negative brain regions belonging to the default-mode network. Finally, we combined multiple measures of brain signal complexity to show that individual intelligence scores can be significantly predicted with a multimodal model within the sample (10-fold cross-validation) as well as in an independent sample (external replication, N = 57). In sum, our results highlight the temporal and spatial dependency of associations between intelligence and intrinsic brain dynamics, proposing multimodal approaches as promising means for future neuroscientific research on complex human traits.
Sub-operon promoter arrangement of disA facilitates c-di-AMP homeostasis and selective stress responses in M. smegmatis

Bacterial second messenger signaling often plays an important role in cellular physiology. In this study, we have attempted to understand how c-di-AMP synthesis and degradation are transcriptionally regulated in M. smegmatis. We have discovered that, although c-di-AMP synthesis gene disA exists in a multi-gene operon; a sub-operon promoter arrangement plays a key role under various stress conditions, keeping its dual function property intact. Further, we learned that c-di-AMP plays a role in the autoregulation of the disA promoter to limit intracellular c-di-AMP concentration. We also identified an alternate start codon within the disA gene which can lead to the synthesis of truncated DisA protein at times using an independent stress-inducible promoter. All in all, this study was helpful to understand how c-di-AMP synthesis is regulated under normal and stress conditions linked to its physiological relevance in M. smegmatis.
Connecting sequence features within the disordered C-terminal linker of Bacillus subtilis FtsZ to functions and bacterial cell division

Intrinsically disordered regions (IDRs) can function as autoregulators of folded enzymes to which they are tethered. One example is the bacterial cell division protein, FtsZ. This includes a folded core and a C-terminal tail (CTT) that encompasses a poorly conserved, disordered C-terminal linker (CTL) and a well-conserved 17-residue C-terminal peptide (CT17). Sites for GTPase activity of FtsZs are formed at the interface between GTP binding sites and T7 loops on cores of adjacent subunits within dimers. Here, we explore the basis of autoregulatory functions of the CTT in Bacillus subtilis FtsZ (Bs-FtsZ). Molecular simulations show that the CT17 of Bs- FtsZ makes statistically significant CTL-mediated contacts with the T7 loop. Statistical Coupling Analysis of more than 103 sequences from FtsZ orthologs reveals clear covariation of the T7 loop and the CT17 with most of the core domain whereas the CTL is under independent selection. Despite this, we discover the conservation of non-random sequence patterns within CTLs across orthologs. To test how the non-random patterns of CTLs mediate CTT-core interactions and modulate FtsZ functionalities, we designed Bs-FtsZ variants by altering the patterning of oppositely charged residues within the CTL. Such alterations disrupt the core-CTT interactions, lead to anomalous assembly and inefficient GTP hydrolysis in vitro and protein degradation, aberrant assembly, and disruption of cell division in vivo. Our findings suggest that viable CTLs in FtsZs are likely to be IDRs that encompass non-random, functionally relevant sequence patterns that also preserve three-way covariation of the CT17, the T7 loop, and core domain. Significance Statement Z-ring formation by the protein FtsZ controls cell division in rod-shaped bacteria. The C-terminus of FtsZ encompasses a disordered C-terminal linker (CTL) and a conserved CT17 motif. Both modules are essential for Z-ring formation and proper localization of FtsZ in cells. Previous studies suggested that generic intrinsically disordered regions (IDRs) might be suitable functional replacements for naturally occurring CTLs. Contrary to this suggestion, we find that the sequence-encoded conformational properties of CTLs help mediate autoregulatory interactions between covarying regions within FtsZ. Functional properties of the CTL are encoded via evolutionarily conserved, non-random sequence patterns. Disruption of these patterns impair molecular functions and cellular phenotypes. Our findings have broad implications for discovering functionally consequential sequence features within IDRs of other proteins.
The disconnect2 mutation disrupts the tjp1b gene that is required for electrical synapse formation

To investigate electrical synapse formation in vivo we used forward genetics to disrupt genes affecting Mauthner cell electrical synapses in larval zebrafish. We identify the disconnect2 (dis2) mutation for its failure to localize neural gap junction channels at electrical synapses. We mapped this mutation to chromosome 25 and identified a splice-altering mutation in the tjp1b gene. We demonstrated that the dis2 mutation disrupts tjp1b function using complementation analysis with CRISPR generated mutants. We conclude that the dis2 mutation disrupts the tjp1b gene that is required for electrical synapse formation. Description Neural networks are circuits of neurons wired together during development that provide an animal with specialized behavioral outputs. Dedicated adhesions called neuronal synapses create sites of communication between neurons and can be categorized as either electrical or chemical. This work identifies a new mutation in tjp1b that is shown to be required for electrical synapse formation.