Miracle-dz/UniFAR-FTUs huggingface dataset:
Allele-specific digital PCR enhances precision and sensitivity in the detection and quantification of copy number alterations in heterogeneous DNA samples: an in silico and in vitro validation study

The analysis of genetic variation is of crucial importance in cancer care. Measuring copy number alterations, however, remains challenging in heterogenous DNA samples, such as (liquid) biopsies. Using digital PCR, these alterations are classically studied by comparing the abundances of the target of interest to a stable genomic reference. Alternatively, copy numbers may be quantified based on the allelic (im)balance of a heterozygous common single-nucleotide polymorphism (SNP). In this study, the accuracy, practicability, precision and sensitivity of both approaches are evaluated in silico using a newly introduced R library 'digitalPCRsimulations', and in vitro by analysing control samples and uveal melanoma specimens in duplex and multiplex experimental setups. Our analyses show that both methodologies are equally effective, as long as a stable reference is identified (classic approach) and the allelic imbalance is caused by the loss or gain/amplification of only one of both alleles (SNP-based approach). Though, heterogeneous copy number alterations can be measured with more precision and sensitivity using the SNP-based approach. In DNA from formalin-fixed and paraffin-embedded samples, the latter approach can also overcome technical artefacts causing inconsistencies between DNA amplicons. In conclusion, the limits of detecting copy number alterations in heterogeneous DNA can be improved using the SNP-based approach. Consequently, an increasing number of clinical samples may be successfully analysed, providing novel potential for the identification, prognostication and management of cancer.
Explaining the Favorite-Longshot Bias : Is it Risk-Love or Misperceptions ? ∗

The favorite-longshot bias presents a challenge for theories of decision making under uncertainty. This longstanding empirical regularity is that betting odds provide biased estimates of the probability of a horse winning—longshots are overbet, while favorites are underbet. Neoclassical explanations focus on rational gamblers who overbet longshots due to risk-love. The competing behavioral explanations emphasize the role of misperceptions of probabilities. We provide novel empirical tests that can discriminate between these competing theories by focusing on the pricing of compound bets. We test whether the models that explain gamblers’ choices in one part of their choice set (betting to win) can also rationalize decisions over a wider choice set, including compound bets in the exacta, quinella or trifecta pools. Using a new, large-scale dataset ideally suited to implement these tests we find evidence in favor of the view that misperceptions of probability drive the favorite-longshot bias, as suggested by Prospect Theory. Along the way we provide more robust evidence on the favorite-longshot bias, falsifying the conventional wisdom that the bias is large enough to yield profit opportunities (it isn’t) and that it becomes more severe in the last race (it doesn’t). ∗We thank David Siegel of Equibase for supplying the data, and Scott Hereld, Ravi Pillai and Stephanie Wang for their valuable assistance in managing the data. Jon Bendor, Betsey Stevenson, Matthew White and William Ziemba provided useful feedback. Snowberg gratefully acknowledges the SIEPR Dissertation Fellowship through a grant to the Stanford Institute for Economic Policy Research. Wolfers gratefully acknowledges a Hirtle, Callaghan & Co. Arthur D. Miltenberger Research Fellowship, and the support of the Zull/Lurie Real Estate Center, the Mack Center for Technological Innovation, and Microsoft Research.
Summertime and wintertime atmospheric processes of secondary aerosol in Beijing

Abstract. Secondary aerosol constitutes a large fraction of fine particles in urban air of China. However, its formation mechanisms and atmospheric processes remain largely uncertain despite considerable study in recent years. To elucidate the seasonal variations in fine-particle composition and secondary aerosol formation, an Aerodyne quadrupole aerosol chemical speciation monitor (Q-ACSM), combined with other online instruments, was used to characterize the sub-micrometer particulate matter (diameter < 1 µm, PM1) in Beijing during summer and winter 2015. Our results suggest that photochemical oxidation was the major pathway for sulfate formation during summer, whereas aqueous-phase reaction became an important process for sulfate formation during winter. High concentrations of nitrate (17 % of the PM1 mass) were found during winter, explained by enhanced gas-to-particle partitioning at low temperature, while high nitrate concentrations (19 %) were also observed under the conditions of high relative humidity (RH) during summer, likely due to the hydrophilic property of NH4NO3 and hydrolysis of N2O5. As for organic aerosol (OA) sources, secondary OA (SOA) dominated the OA mass (74 %) during summer, while the SOA contribution decreased to 39 % during winter due to enhanced primary emissions in the heating season. In terms of the SOA formation, photochemical oxidation perhaps played an important role for summertime oxygenated OA (OOA) formation and less-oxidized wintertime OOA (LO-OOA) formation. The wintertime more-oxidized OOA (MO-OOA) showed a good correlation with aerosol liquid water content (ALWC), indicating a more important contribution of aqueous-phase processing over photochemical production to MO-OOA. Meanwhile, the dependence of LO-OOA and the mass ratio of LO-OOA to MO-OOA on atmospheric oxidative tracer (i.e., Ox) both degraded when RH was greater than 60 %, suggesting that RH or aerosol liquid water may also affect LO-OOA formation.
Frictional Strength of the Creeping Segment of the San Andreas Fault

Frictional Strength of the Creeping Segment of the San Andreas Fault. (December 2010) Clayton Gage Coble, B.S., Sam Houston State University Co-Chairs of Advisory Committee: Dr. Frederick M. Chester Dr. Judith S. Chester The San Andreas Fault (SAF) near Parkfield, CA moves by a combination of aseismic creep and micro-earthquake slip. Measurements of in situ stress orientation, stress magnitude, and heat flow are incompatible with an average shear stress on the SAF greater than approximately 20 MPa. To investigate the micro-mechanical processes responsible for the low strength and creeping behavior, gouge samples from the 3 kmdeep scientific borehole near Parkfield (the San Andreas Fault Observatory at Depth, SAFOD) are sheared in a triaxial rock deformation apparatus at conditions simulating those in situ, specifically a temperature of 100°C, effective normal stress of 100 MPa, pore fluid pressure of 25 MPa, and a Na-Ca-K pore fluid chemistry. The 2 mm-thick gouge layers are sheared to 4.25 mm at shear rates of 6.0, 0.6, 0.06, and 0.006 μm/s. The mechanical data are corrected for apparatus effects and the strength of the jacketing material that isolates the sample from the confining fluid. Experiments indicate that gouge is extremely weak with a coefficient of friction of 0.14, and displays velocity and temperature strengthening behavior. The frictional behavior is consistent with the inferred in situ stress and aseismic creep observed at SAFOD. The low frictional
NMN Works in HFD-Induced T2DM by Interesting Effects in Adipose Tissue, and Not by Mitochondrial Biogenesis

Nicotinamide mononucleotide (NMN) has emerged as a promising therapeutic intervention for age-related disorders, including Type 2 Diabetes. In this study, we investigated the effects of NMN treatment on glucose uptake and its underlying mechanisms in various tissue and cell lines. Through a comprehensive proteomic analysis, we uncovered a series of distinct organ-specific effects that contribute to the observed improvements in glucose metabolism. Notably, we observed the upregulation of thermogenic UCP1, promoting enhanced glucose utilization in muscle tissue. Additionally, liver and muscle cells displayed a unique response, characterized by spliceosome down-regulation and concurrent upregulation of chaperones, proteasomes, and ribosomes, leading to a mildly impaired and energy-inefficient protein synthesis machinery. Adipose tissue exhibited increased protein synthesis and degradation, fatty acid degradation, Lysosome and mTOR cell proliferation signalling up-regulation, while showing a surprising repressive effect on mitochondrial biogenesis. Furthermore, our findings revealed a remarkable metabolic rewiring in the brain, involving increased production of ketone bodies, down-regulation of mitochondrial OXPHOS components and the TCA cycle, and the induction of known fasting-associated effects. Collectively, our data elucidate the multifaceted nature of NMN action, highlighting its organ-specific effects and their role in modulating glucose metabolism. These findings deepen our understanding of NMN’s therapeutic potential and pave the way for novel strategies in managing metabolic disorders.
Modeling the dynamics of actin and myosin during bleb stabilization

The actin cortex is very dynamic during migration of eukaryotes. In cells that use blebs as leading-edge protrusions, the cortex reforms beneath the cell membrane (bleb cortex) and completely disassembles at the site of bleb initiation. Remnants of the actin cortex at the site of bleb nucleation are referred to as the actin scar. We refer to the combined process of cortex reformation along with the degradation of the actin scar during bleb-based cell migration as bleb stabilization. The molecular factors that regulate the dynamic reorganization of the cortex are not fully understood. Myosin motor protein activity has been shown to be necessary for blebbing, with its major role associated with pressure generation to drive bleb expansion. Here, we examine the role of myosin in regulating cortex dynamics during bleb stabilization. Analysis of microscopy data from protein localization experiments in Dictyostelium discoideum cells reveals a rapid formation of the bleb’s cortex with a delay in myosin accumulation. In the degrading actin scar, myosin is observed to accumulate before active degradation of the cortex begins. Through a combination of mathematical modeling and data fitting, we identify that myosin helps regulate the equilibrium concentration of actin in the bleb cortex during its reformation by increasing its dissasembly rate. Our modeling and analysis also suggests that cortex degradation is driven primarily by an exponential decrease in actin assembly rate rather than increased myosin activity. We attribute the decrease in actin assembly to the separation of the cell membrane from the cortex after bleb nucleation.
Effect of Human Infant Gut Microbiota on Mouse Behavior, Dendritic Complexity, and Myelination

The mammalian gut microbiome influences numerous developmental processes. In human infants it has been linked with cognition, social skills, hormonal responses to stress, and brain connectivity. Yet, these associations are not necessarily causal. The present study tested whether two microbial stool communities, common in human infants, affected behavior, myelination, dendritic morphology, and spine density when used to colonize mouse models. Humanized animals were more like specific-pathogen free mice than germ-free mice for most phenotypes, although in males, both humanized groups were less social. Both humanized groups had thinner myelin sheaths in the hippocampus, than did germ-free animals. Humanized animals were similar to each other except for dendritic morphology and spine density where one group had greater dendritic length in the prefrontal cortex, greater dendritic volume in the nucleus accumbens, and greater spine density in both regions, compared to the other. Results add to a body of literature suggesting the gut microbiome impacts brain development. Teaser Fecal transplants from human infants with highly abundant Bifidobacterium, an important inhabitant of the intestinal tract of breastfed newborns, may promote brain connectivity in mice.
CST–Polymeraseα-primase solves a second telomere end-replication problem

Telomerase adds G-rich telomeric repeats to the 3ʹ ends of telomeres1, counteracting telomere shortening caused by loss of telomeric 3ʹ overhangs during leading-strand DNA synthesis (“the end-replication problem”2). We report a second end-replication problem that originates from the incomplete duplication of the C-rich telomeric repeat strand by lagging-strand synthesis. This problem is solved by CST–Polymeraseα(Polα)-primase fill-in synthesis. In vitro, priming for lagging-strand DNA replication does not occur on the 3’ overhang and lagging-strand synthesis stops in an ∼150-nt zone more than 26 nt from the end of the template. Consistent with the in vitro data, lagging-end telomeres of cells lacking CST–Polα-primase lost ∼50-60 nt of CCCTAA repeats per population doubling (PD). The C-strands of leading-end telomeres shortened by ∼100 nt/PD, reflecting the generation of 3’ overhangs through resection. The measured overall C-strand shortening in absence of CST–Polα-primase fill-in is consistent with the combined effects of incomplete lagging-strand synthesis and 5ʹ resection at the leading-ends. We conclude that canonical DNA replication creates two telomere end-replication problems that require telomerase to maintain the G-strand and CST–Polα-primase to maintain the C-strand.
Late Quaternary slip-rate along the central Bangong-Chaxikang segment of the Karakorum fault, western Tibet

Insight into the spatial and temporal changes of slip-rate is essential to understand the kinematic role of large strike-slip faults in continental collision zones. Geodetic and geologic rates from present to several million years ago along the Karakorum fault range from 0 to 11 mm/yr. Here, we determine the first late Quaternary slip-rate at the southern end of the linear Bangong-Chaxikang segment of the Karakorum fault, using cumulative offsets (20–200 m) of fans and terraces at three sites, as well as 74 new 10 Be surface-exposure ages to constrain the age of these offset geomorphic markers. The rate is >3 mm/yr at sites Gun and Chaxikang, and it is >1.7–2.2 mm/yr at the Gar fan site. Together with rates obtained along the southernmost Menshi-Kailas segment, the Karakorum fault slip-rate seems to increase southeastward from south of Bangong Lake to Kailas (from >3 to >8 mm/yr). These Karakorum fault slip-rate data (>3–8 mm/yr), together with the total length of the fault (>1000 km) and its initiation age (>13–23 Ma), confirm that the Karakorum fault is the major fault accommodating dextral strike-slip motion NE of the western Himalayas. The dextral Karakorum fault in the south and the conjugate left-lateral Longmu Co–Altyn Tagh fault system in the north are thus the major strike-slip faults of western Tibet, which contribute to eastward extrusion of Tibet.
A Compact Design of Ultra-Wideband Microstrip-Slot Six-Port Network for Wireless Communication Applications

There is a lot of interest in the research and development related to ultra-wideband (UWB) systems because of the increasing demands on applications with low power, low cost, and low interference. Thus, to cope with these demands, various kinds of research are required for the development of a wireless communication transceiver front-end, which includes a six-port network as an alternative to a mixer-based design. Hence, this article presents a compact design for the UWB six-port network that uses two 3-dB couplers, an in-phase power divider, and a 90° power divider. The proposed network is developed using the microstrip-slot technique, which guarantees satisfactory operation across the UWB frequency range with compact dimensions. The design is performed via the use of CST Microwave Studio and realized using Rogers TMM4 with a conductor coating of 35 μm, a thickness of 0.508 mm, and a dielectric constant of 4.5. The developed prototype of the proposed design is verified by measurement using a vector network analyzer (VNA). Performance analysis concerns transmission and reflection coefficients, phase characteristics, and q-points. The presented UWB performance of the proposed six-port network is expected can be implemented for quadrature phase shift keying (QPSK) and quadrature amplitude modulation (QAM) modulator and demodulator applications in various wireless communication transceivers such as fifth generation (5G), and wireless fidelity (Wi-Fi).
Ocular dominance-dependent binocular combination of monocular neuronal responses in macaque V1

Primates rely on two eyes to see depth, while keeping a stable vision when one eye is closed. Although psychophysical and modeling studies have investigated how monocular signals are combined to form binocular vision, the corresponding neuronal mechanisms, especially in V1 where most neurons become binocular but with different eye preferences, are not well understood. Here we used two-photon calcium imaging to compare monocular and binocular responses of thousands of V1 superficial-layer neurons in three awake macaques. Under monocular stimulation, neurons preferring the stimulated eye responded substantially stronger than those preferring both eyes. However, under binocular stimulation, the responses of neurons preferring either eye were suppressed, and those preferring both eyes were enhanced, so that neuronal responses became similar regardless of eye preferences. A neuronally realistic model of binocular combination, which includes ocular dominance-dependent divisive interocular inhibition, and binocular summation, is proposed to account for these observations.
A glycolytic metabolite restores DNA repair activity of polynucleotide kinase 3’-phosphatase in polyglutamine (PolyQ) diseases

We previously reported that the loss of activity of an essential DNA repair enzyme, polynucleotide kinase 3’-phosphatase (PNKP), resulted in accumulation of double strand breaks (DSB) in patient’s brain genome in Huntington’s disease (HD) and Spinocerebellar ataxia type 3 (SCA3). Here we document that PNKP interacts with the nuclear isoform of phosphofructokinase fructose-2,6-bisphosphatase 3 (PFKFB3), which converts fructose-6-phosphate (F6P) into fructose-2,6-bisphosphate (F2,6BP), a potent allosteric modulator of glycolysis. Depletion of PFKFB3 markedly abrogates PNKP activity, thereby affecting PNKP mediated transcription-coupled non-homologous end joining (TC-NHEJ). Both PFKFB3 and F2,6BP levels are significantly lower in the nuclear extracts of HD and SCA3 patients’ brains. Exogenous F2,6BP restored PNKP activity in the brain nuclear extracts of those samples. Moreover, delivery of F2,6BP into HD mouse striata-derived neuronal cells restored PNKP activity, transcribed genome integrity and cellular viability. We thus postulate that F2,6BP serves in vivo as a cofactor for proper functionality of PNKP and thereby of brain health. Our results thus provide a compelling rationale for exploring therapeutic use of F2,6BP and related compounds for treating polyQ diseases.
Selection leads to false inferences of introgression using popular methods

Detecting introgression between closely related populations or species is a fundamental objective in evolutionary biology. Existing methods for detecting migration and inferring migration rates from population genetic data often assume a neutral model of evolution. Growing evidence of the pervasive impact of selection on large portions of the genome across diverse taxa suggests that this assumption is unrealistic in most empirical systems. Further, ignoring selection has previously been shown to negatively impact demographic inferences (e.g., of population size histories). However, the impacts of biologically realistic selection on inferences of migration remain poorly explored. Here, we simulate data under models of background selection, selective sweeps, and adaptive introgression. We show that ignoring selection leads to false inferences of migration in three popularly used methods (fastsimcoal, ∂a∂i, and BPP). Selection results in the rejection of isolation-only models in favor of isolation-with-migration models and leads to elevated estimates of migration rates across methods. Our results suggest that such methods may be unreliable in many empirical systems, such that new methods that are robust to selection will need to be developed. Article Summary Detecting migration between closely related populations is a central objective in many evolutionary biology studies. However, popular methods for detecting migration assume a simplified model of evolution. Here, we evaluate the impacts of biologically realistic natural selection, recombination, and mutation on three methods for detecting migration. We find that biological complexity leads to false inferences of migration, suggesting that results should be interpreted with caution and that new methods are needed to make robust inferences of migration across empirical systems.
Insights into assembly of constitutive filament-forming proteins of novel fold through domain dissection and EGFP insertion-based screen: A case study of Spiroplasma Fibril

Spiroplasma is a cell-wall less, helical bacterium possessing a cytoskeletal ribbon consisting Fibril and 5 MreB paralogs. In absence of any information regarding the filament interface of Fibril, a cytoskeleton protein of novel fold, multiple short constructs of Fibril were designed to identify minimal domains required for polymerization. Purification trials of these short constructs resulted in insoluble protein products. In a parallel approach, we incorporated EGFP at the loop regions aimed to hinder polymerization and obtain non-polymerising constructs. We were able to identify probable interfilament/intrafilament interface residues based on the fluorescence screen. We show that EGFP insertions at many of the positions are tolerated as Fibril filaments were readily observed for these constructs in transmission electron microscopy. Both the approaches suggest that Fibril requires N and C-terminal domains for its polymerization. Earlier studies have shown that FibrilWT interacts with MreB5. Our Fibril-EGFP constructs and MreB5 showed interaction similar to the wild-type. Co-sedimentation assay and visualization of Fibril-EGFP proteins proves that the fluorescent constructs are folded and functional and possess structural and biochemical properties similar to the wild type protein.