Miracle-dz/UniFAR-FTUs huggingface dataset:
Warning Signs From the Crypt: Aberrant Protein Glycosylation Marks Opportunities for Early Colorectal Cancer Detection

Colorectal cancer (CRC) remains a leading cause of cancer-related deaths despite being the most preventable and treatable forms of cancer when caught early through screening. There is an unmet need for novel screening approaches with improved accuracy, less invasiveness, and reduced costs. In recent years, evidence has accumulated around particular biological events that happen during the adenoma-to-carcinoma transition, especially focusing on precancerous immune responses in the colonic crypt. Protein glycosylation plays a central role in driving those responses, and recently, numerous reports have been published on how aberrant protein glycosylation both in colonic tissue and on circulating glycoproteins reflects these precancerous developments. The complex field of glycosylation, which exceeds complexity of proteins by several orders of magnitude, can now be studied primarily because of the availability of new high-throughput technologies such as mass spectrometry and artificial intelligence-powered data processing. This has now opened new avenues for studying novel biomarkers for CRC screening. This review summarizes the early events taking place from the normal colon mucosa toward adenoma and adenocarcinoma formation and associated critical protein glycosylation phenomena, both on the tissue level and in the circulation. These insights will help establish an understanding in the interpretation of novel CRC detection modalities that involve high-throughput glycomics.
Evolution of large Aβ16–22 aggregates at atomic details and potential of mean force associated to peptide unbinding and fragmentation events

Atomic characterization of large nonfibrillar aggregates of amyloid polypeptides cannot be determined by experimental means. Starting from β‐rich aggregates of Y and elongated topologies predicted by coarse‐grained simulations and consisting of more than 100 Aβ16–22 peptides, we performed atomistic molecular dynamics (MD), replica exchange with solute scaling (REST2), and umbrella sampling simulations using the CHARMM36m force field in explicit solvent. Here, we explored the dynamics within 3 μs, the free energy landscape, and the potential of mean force associated with either the unbinding of one single peptide in different configurations within the aggregate or fragmentation events of a large number of peptides. Within the time scale of MD and REST2, we find that the aggregates experience slow global conformational plasticity, and remain essentially random coil though we observe slow beta‐strand structuring with a dominance of antiparallel beta‐sheets over parallel beta‐sheets. Enhanced REST2 simulation is able to capture fragmentation events, and the free energy of fragmentation of a large block of peptides is found to be similar to the free energy associated with fibril depolymerization by one chain for longer Aβ sequences.
Evaluating the effect of non-invasive force feedback on prosthetic grasp force modulation in participants with and without limb loss

Grasping an object is one of the most common and complex actions performed by humans. The human brain can adapt and update the grasp dynamics through information received from sensory feedback. Prosthetic hands can assist with the mechanical performance of grasping, however currently commercially available prostheses do not address the disruption of the sensory feedback loop. Providing feedback about a prosthetic hand’s grasp force magnitude is a top priority for those with limb loss. This study tested a wearable haptic system, i.e., the Clenching Upper-Limb Force Feedback device (CUFF), which was integrated with a novel robotic hand (The SoftHand Pro). The SoftHand Pro was controlled with myoelectrics of the forearm muscles. Five participants with limb loss and nineteen able-bodied participants completed a constrained grasping task (with and without feedback) which required modulation of the grasp to reach a target force. This task was performed while depriving participants of incidental sensory sources (vision and hearing were significantly limited with glasses and headphones). The data were analyzed with Functional Principal Component Analysis (fPCA). CUFF feedback improved grasp precision for participants with limb loss who typically use body-powered prostheses as well as a sub-set of able-bodied participants. Further testing, that is more functional and allows participants to use all sensory sources, is needed to determine if CUFF feedback can accelerate mastery of myoelectric control or would benefit specific patient sub-groups.
Uniparental disomy of multiple chromosomes in two cases with a complex phenotype

Uniparental disomy (UPD) is the inheritance of both chromosomal homologs from one parent. Depending on the chromosome involved and the parental origin, UPD may result in phenotypic abnormalities due to aberrant methylation patterns or unmasking recessive conditions in isodisomic regions. UPD primarily originates from somatic rescue of a single meiotically‐derived aneuploidy, most commonly a trisomy. Double UPD is exceedingly rare and triple UPD has not been previously described. Here, we report two unrelated clinical cases with UPD of multiple chromosomes; an 8‐month‐old male with maternal isodisomy of chromosome 7 and paternal isodisomy of chromosome 9, and a 4‐week‐old female with mixed paternal UPD for chromosomes 4, 10, and 14. These cases also demonstrate that although extremely rare, the detection of AOH on two or more chromosomes may warrant additional clinical and laboratory investigation such as methylation and STR marker analysis, especially when involving chromosomes known to be associated with imprinting disorders.
Metabolomics in acromegaly: a systematic review

The therapeutic response heterogeneity in acromegaly persists, despite the medical–surgical advances of recent years. Thus, personalized medicine implementation, which focuses on each patient, is justified. Metabolomics would decipher the molecular mechanisms underlying the therapeutic response heterogeneity. Identification of altered metabolic pathways would open new horizons in the therapeutic management of acromegaly. This research aimed to evaluate the metabolomic profile in acromegaly and metabolomics’ contributions to understanding disease pathogenesis. A systematic review was carried out by querying four electronic databases and evaluating patients with acromegaly through metabolomic techniques. In all, 21 studies containing 362 patients were eligible. Choline, the ubiquitous metabolite identified in growth hormone (GH)-secreting pituitary adenomas (Pas) by in vivo magnetic resonance spectroscopy (MRS), negatively correlated with somatostatin receptors type 2 expression and positively correlated with magnetic resonance imaging T2 signal and Ki-67 index. Moreover, elevated choline and choline/creatine ratio differentiated between sparsely and densely granulated GH-secreting PAs. MRS detected low hepatic lipid content in active acromegaly, which increased after disease control. The panel of metabolites of acromegaly deciphered by mass spectrometry (MS)-based techniques mainly included amino acids (especially branched-chain amino acids and taurine), glyceric acid, and lipids. The most altered pathways in acromegaly were the metabolism of glucose (particularly the downregulation of the pentose phosphate pathway), linoleic acid, sphingolipids, glycerophospholipids, arginine/proline, and taurine/hypotaurine. Matrix-assisted laser desorption/ionization coupled with MS imaging confirmed the functional nature of GH-secreting PAs and accurately discriminated PAs from healthy pituitary tissue.
A Kiss of Deep Homology: Partial Convergence in the Genomic Basis of Hypertrophied Lips in Cichlid Fish and Human Cleft Lip

Abstract The genomic loci generating both adaptive and maladaptive variation could be surprisingly predictable in deeply homologous vertebrate structures like the lips. Variation in highly conserved vertebrate traits such as the jaws and teeth in organisms as evolutionarily disparate as teleost fishes and mammals is known to be structured by the same genes. Likewise, hypertrophied lips that have evolved repeatedly in Neotropical and African cichlid fish lineages could share unexpectedly similar genetic bases themselves and even provide surprising insight into the loci underlying human craniofacial anomalies. To isolate the genomic regions underlying adaptive divergence in hypertrophied lips, we first employed genome-wide associations (GWAs) in several species of African cichlids from Lake Malawi. Then, we tested if these GWA regions were shared through hybridization with another Lake Malawi cichlid lineage that has evolved hypertrophied lips seemingly in parallel. Overall, introgression among hypertrophied lip lineages appeared limited. Among our Malawi GWA regions, one contained the gene kcnj2 that has been implicated in the convergently evolved hypertrophied lips in Central American Midas cichlids that diverged from the Malawi radiation over 50 million years ago. The Malawi hypertrophied lip GWA regions also contained several additional genes that cause human lip–associated birth defects. Cichlid fishes are becoming prominent examples of replicated genomic architecture underlying trait convergence and are increasingly providing insight into human craniofacial anomalies such as a cleft lip.
A General Path–Integral Monte Carlo Method for Exact Simulations of Chemical Reaction Networks

Chemical Reaction Networks (CRNs) are stochastic many-body systems used to model real-world chemical systems through a differential Master Equation (ME); analytical solutions to these equations are only known for the simplest systems. In this paper, we construct a path-integral inspirited framework for studying CRNs. Under this scheme, the time-evolution of a reaction network can be encoded in a Hamiltonian-like operator. This operator yields a probability distribution which can be sampled, using Monte Carlo Methods, to generate exact numerical simulations of a reaction network. We recover the grand probability function used in the Gillespie Algorithm as an approximation to our probability distribution, which motivates the addition of a leapfrog correction step. To assess the utility of our method in forecasting real-world phenomena, and to contrast it with the Gillespie Algorithm, we simulated a COVID-19 epidemiological model using parameters from the United States for the Original Strain and the Alpha, Delta and Omicron Variants. By comparing the results of these simulations with official data, we found that our model closely agrees with the measured population dynamics, and given the generality of this framework it can also be applied to study the spread dynamics of other contagious diseases.
INTRAVENOUS N-ACETYLCYSTEINE TO PREVENT CISPLATIN-INDUCED HEARING LOSS IN CHILDREN: A NONRANDOMIZED CONTROLLED PHASE 1 TRIAL.

PURPOSE Cisplatin-induced hearing loss (CIHL) is common and permanent. As compared to earlier otoprotectants, we hypothesized N-acetylcysteine (NAC) offers potential for stronger otoprotection through stimulation of glutathione production. This study tested the optimal dose, safety, and efficacy of NAC to prevent CIHL. PATIENTS AND METHODS In this nonrandomized, controlled Phase 1a/1b trial, children and adolescents newly diagnosed with non-metastatic, cisplatin-treated tumors received NAC intravenously four hours post-cisplatin. The trial performed dose-escalation across three dose levels to establish a safe dose that exceeded the targeted peak serum NAC concentration of 1.5 mM (as identified from preclinical models). Patients with metastatic disease or otherwise ineligible were enrolled in an observation-only/control arm. To evaluate efficacy, serial age-appropriate audiology assessments were performed. Integrated biology examined genes involved in glutathione metabolism and post-NAC glutathione concentrations. RESULTS Of 52 patients enrolled, 24 received NAC and 28 were in the control arm. The maximum tolerated dose was not reached; analysis of peak [NAC] identified 450 mg/kg as the recommended Phase 2 dose (RP2D). Infusion-related reactions were common. No severe adverse events occurred. Compared to the control arm, NAC decreased likelihood of CIHL at end of cisplatin therapy (odds ratio [OR] 0.13, 95% confidence interval [CI] 0.021-0.847, p=0.033) and recommendations for hearing intervention at end of study (OR 0.082, 95%CI 0.011-0.60, p=0.014). NAC increased glutathione; GSTP1 influenced risk for CIHL and NAC otoprotection. CONCLUSION NAC was safe at the RP2D with strong evidence for efficacy to prevent CIHL, warranting further development as a next-generation otoprotectant. TRIAL NUMBER NCT02094625.
Phenotypic and Genotypic Adaptation of Escherichia coli to Thermal Stress is Contingent on Genetic Background

Abstract Evolution can be contingent on history, but we do not yet have a clear understanding of the processes and dynamics that govern contingency. Here, we performed the second phase of a two-phase evolution experiment to investigate features of contingency. The first phase of the experiment was based on Escherichia coli clones that had evolved at the stressful temperature of 42.2 °C. The Phase 1 lines generally evolved through two adaptive pathways: mutations of rpoB, which encodes the beta subunit of RNA polymerase, or through rho, a transcriptional terminator. We hypothesized that epistatic interactions within the two pathways constrained their future adaptative potential, thus affecting patterns of historical contingency. Using ten different E. coli Founders representing both adaptive pathways, we performed a second phase of evolution at 19.0 °C to investigate how prior genetic divergence or adaptive pathway (rpoB vs. rho) affects evolutionary outcomes. We found that phenotype, as measured by relative fitness, was contingent on founder genotypes and pathways. This finding extended to genotypes, because E. coli from different Phase 1 histories evolved by adaptive mutations in distinct sets of genes. Our results suggest that evolution depends critically on genetic history, likely due to idiosyncratic epistatic interactions within and between evolutionary modules.
Domain-General and Domain-Specific Electrophysiological Markers of Cognitive Distance Coding for What, Where, and When Memory Retrieval

The what, where, and when components of episodic memory can be differentiated based on their distinctive domain-specific underlying neural correlates. However, recent studies have proposed that a common neural mechanism of conceptual mapping may be involved in the coding of cognitive distance across all domains. In this study, we provide evidence that both domain-specific and domain-general processes occur simultaneously during memory retrieval by identifying distinctive and common neural representations for mapping what (i.e., semantic distance), where (i.e., spatial distance), and when (i.e., temporal distance) using scalp EEG from 47 healthy participants (age 21-30, 26 male and 21 female). First, we found that all three components commonly showed a positive correlation between cognitive distance and slow theta power (2.5-5 Hz) in parietal channels. Meanwhile, fast theta power (5-8.5 Hz) specifically represented spatial and temporal distance in occipital and parietal channels, respectively. Additionally, we identified a unique correlate of temporal distance coding in frontal/parietal slow theta power during the early phase of retrieval. All of the above neural markers of cognitive mapping, both domain-general and specific, were associated with individual differences in what, where, and when memory accuracy. SIGNIFICANCE STATEMENT The Cognitive Map Theory was originally founded to explain how we remember and organize the immense amount of spatial information that we face when we navigate. However, memory research has recently trended in the direction of emphasizing the generalizability of cognitive mapping mechanisms to information in any domain, represented as distances in an abstract conceptual space. In a single study, we show that both common and unique neural coding of semantic distance (i.e., what), spatial distance (i.e., where), and temporal distance (i.e., when) simultaneously support episodic memory retrieval. Our results suggest that our ability to accurately distinguish between memories is achieved through an integration of domain-specific and domain-general neurocognitive mechanisms that work in parallel.
Lectures on 2-D gravity and 2-D string theory

emphasis is on 2d target space (c=1 coupled to gravity). Contents: 0. Introduction, Overview, and Purpose 1. Loops and States in Conformal Field Theory 2. 2D Euclidean Quantum Gravity I: Path Integral Approach 3. Brief Review of the Liouville Theory 4. 2D Euclidean Quantum Gravity II: Canonical Approach 5. 2D Critical String Theory 6. Discretized surfaces, matrix models, and the continuum limit 7. Matrix Model Technology I: Method of Orthogonal Polynomials 8. Matrix Model Technology II: Loops on the Lattice 9. Matrix Model Technology III: Free Fermions from the Lattice 10. Loops and States in Matrix Model Quantum Gravity 11. Loops and States in the $c=1$ Matrix Model 12. Fermi Sea Dynamics and Collective Field Theory 13. String scattering in two spacetime dimensions 14. Vertex Operator Calculations and Continuum Methods 15. Achievements, Disappointments, Future Prospects if you read only one set of lecture notes this year, don't read these.
Intelligent Adaptive Motion Controller Design for Mecanum Wheeled Omnidirectional Robots with Parameter Variations

This paper develops an intelligent adaptive motion controller using fuzzy wavelet networks (FWN) for Mecanum wheeled omnidirectional robots (MWOR) with parameter variations. Such a controller is synthesized by backstepping and FWN which are used to on-line approximate some uncertain nonlinear term of the controller, thereby accomplishing out better motion performance. Simulation results show the effectiveness and merit of the proposed control method.
Nanoblot: an R-package for visualization of RNA isoforms from long-read RNA-sequencing data

RT-PCR and northern blots have long been used to study RNA isoforms usage for single genes. Recent advancements in long-read sequencing have yielded unprecedented information about the usage and abundance of these RNA isoforms. However, visualization of long-read sequencing data remains challenging due to the high information density. To alleviate these issues, we have developed NanoBlot, an open-source R-package that generates northern blot and RT-PCR-like images from long-read sequencing data. NanoBlot requires aligned, positionally sorted and indexed BAM files. Plotting is based around ggplot2 and is easily customizable. Advantages of NanoBlot include a robust system for designing probes to visualize isoforms including excluding reads based on the presence or absence of a specified region, an elegant solution to representing isoforms with continuous variations in length, and the ability to overlay multiple genes in the same plot using different colors. We present examples of nanoblots compared to actual northern blot data. In addition to traditional gel-like images, the NanoBlot package can also output other visualizations such as violin plots and 3′-RACE-like plots focused on 3′-end isoforms visualization. The use of the NanoBlot package should provide a simple answer to some of the challenges of visualizing long-read RNA-sequencing data.
A hybrid preconditioner to solve nonsymmetric linear system of equations

In this paper, modified left and right-looking versions of SAINV-Ns (Sta- bilized Approximate Inverse for Nonsymmetric matrices) preconditioner have been presented. Structural modification of prototype versions has been done in such a way that it is possible to make both versions of this preconditioner more robust by using inverse-based dropping technique. Only the information of matrix A is used to gener- ate this preconditioner. To decrease preconditioning time of the right-looking version, matrix A is stored in Compressed Sparse Column format. To construct this version, row traversal of matrix A is also needed. To avoid storing matrix A in Compressed Sparse Row format, the linked list trick has been used. By using some nonsym- metric matrices, modified left and right-looking versions of this preconditioner have been compared. The multilevel nested dissection reordering has also been used as the preprocessing.
In vitro gametogenesis from embryonic stem cells in livestock species: recent advances, opportunities, and challenges to overcome

Abstract Pluripotent stem cells (PSC) can be stabilized in vitro from pre-implantation stage embryos (embryonic stem cells, ESC) or by reprogramming adult somatic cells (induced pluripotent stem cells, iPSC). The last decade has seen significant advances in the livestock PSC field, particularly the development of robust methods for long-term culture of PSC from several livestock species. Along with this, considerable progress has been made in understanding the states of cellular pluripotency and what they mean for cell differentiation capacity, and significant efforts are ongoing to dissect the critical signaling pathways required for the maintenance of PSC in different species and distinct states of pluripotency. Among the cell types that can be generated from PSC, the germline holds special importance as they are the genetic link between generations; and devising methods to enable in vitro gametogenesis (IVG) and produce viable gametes could revolutionize animal agriculture, wildlife conservation, and human assisted reproduction alike. Within the last decade, many pivotal studies about IVG were published using rodent models, filling some critical knowledge gaps in the field. Most importantly, the entire female reproductive cycle was reproduced in vitro from mouse ESC. Although complete male gametogenesis in vitro has not yet been reported, significant advances were made showing the capacity of germline stem cell-like cells to generate healthy offspring. In this review, we provide an overview of PSC and advances in the establishment of livestock PSC; we present the breakthroughs made in rodents regarding IVG and the current progress towards livestock IVG, including the importance of a detailed understanding of fetal germline development. Finally, we discuss some key advances that will be critical to enable this technology at scale. Given the potential impact of IVG for animal agriculture, major efforts will likely continue to be employed by research institutions and industry towards the development of methods to achieve efficient generation of gametes in vitro.