Miracle-dz/UniFAR-FTUs huggingface dataset:
CDK19 and CDK8 Mediator kinases drive androgen-independent in vivo growth of castration-resistant prostate cancer

Castration-resistant prostate cancer (CRPC) remains incurable due to its high plasticity. We found that Mediator kinases CDK8 and CDK19, pleiotropic regulators of transcriptional reprogramming, are differentially affected by androgen, which downregulates CDK8 and upregulates CDK19. Accordingly, expression of CDK8 decreases while CDK19 increases during prostate carcinogenesis, but both CDK19 and CDK8 are upregulated in metastatic CRPC. Genetic inactivation of CDK8 and CDK19 suppresses CRPC tumor growth in castrated male mice and renders CRPC responsive to androgen deprivation. Restoration of active CDK19 or CDK8 kinases reverses this phenotype, indicating that CRPC becomes dependent on Mediator kinase activity for in vivo growth under the conditions of androgen deprivation. Selective CDK8/19 inhibitors suppress androgen-independent growth of cell line-based and patient-derived CRPC xenografts, whereas prolonged inhibitor treatment induces tumor regression and even leads to cures. Mediator kinase activity was found to affect tumor and stromal gene expression preferentially in castrated mice, orchestrating castration-induced transcriptional reprogramming. These results warrant the exploration of Mediator kinase inhibitors for CRPC therapy.
Computational inference of eIF4F complex function and structure in human cancers

The canonical eukaryotic initiation factor 4F (eIF4F) complex, composed of eIF4G1, eIF4A1, and the cap-binding protein eIF4E, plays a crucial role in cap-dependent translation initiation in eukaryotic cells (1). However, cap-independent initiation can occur through internal ribosomal entry sites (IRESs), involving only eIF4G1 and eIF4A1 present, which is considered to be a complementary process to cap-dependent initiation in tumors under stress conditions (2). The selection and molecular mechanism of specific translation initiation in human cancers remains poorly understood. Thus, we analyzed gene copy number variations (CNVs) in TCGA tumor samples and found frequent amplification of genes involved in translation initiation. Copy number gains in EIF4G1 and EIF3E frequently co-occur across human cancers. Additionally, EIF4G1 expression strongly correlates with genes from cancer cell survival pathways including cell cycle and lipogenesis, in tumors with EIF4G1 amplification or duplication. Furthermore, we revealed that eIF4G1 and eIF4A1 protein levels strongly co-regulate with ribosomal subunits, eIF2, and eIF3 complexes, while eIF4E co-regulates with 4E-BP1, ubiquitination, and ESCRT proteins. Using Alphafold predictions, we modeled the eIF4F structure with and without eIF4G1-eIF4E binding. The modeling for cap-dependent initiation suggests that eIF4G1 interacts with eIF4E through its N-terminal eIF4E-binding domain, bringing eIF4E near the eIF4A1 mRNA binding cavity and closing the cavity with both eIF4G1 HEAT-2 domain and eIF4E. In the cap-independent mechanism, α-helix5 of eIF4G1 HEAT-2 domain instead directly interacts with the eIF4A1 N-terminal domain to close the mRNA binding cavity without eIF4E involvement, resulting in a stronger interaction between eIF4G1 and eIF4A1. Significance Statement Translation initiation is primarily governed by eIF4F, employing a “cap-dependent” mechanism, but eIF4F dysregulation may lead to a “cap-independent” mechanism in stressed cancer cells. We found frequent amplification of translation initiation genes, and co-occurring copy number gains of EIF4G1 and EIF3E genes in human cancers. EIF4G1 amplification or duplication may be positively selected for its beneficial impact on the overexpression of cancer survival genes. The co-regulation of eIF4G1 and eIF4A1, distinctly from eIF4E, reveals eIF4F dysregulation favoring cap-independent initiation. Alphafold predicts changes in the eIF4F complex assembly to accommodate both initiation mechanisms. These findings have significant implications for evaluating cancer cell vulnerability to eIF4F inhibition and developing treatments that target cancer cells with dependency on the translation initiation mechanism.
Spontaneous and double-strand break repair-associated quasipalindrome and frameshift mutagenesis in budding yeast: role of mismatch repair

Although gene conversion (GC) in Saccharomyces cerevisiae is the most error-free way to repair double-strand breaks (DSBs), the mutation rate during homologous recombination is 1000 times greater than during replication. Many mutations involve dissociating a partially-copied strand from its repair template and re-aligning with the same or another template, leading to -1 frameshifts in homonucleotide runs, quasipalindrome (QP)-associated mutations and microhomology-mediated interchromosomal template switches. We studied GC induced by HO endonuclease cleavage at MATα, repaired by an HMR::Kl-URA3 donor. We inserted into HMR::Kl-URA3 an 18-bp inverted repeat where one arm had a 4-bp insertion. Most GCs yield mat::Kl-ura3::QP+4 (Ura-) outcomes, but template-switching produces Ura+ colonies, losing the 4-bp insertion. If the QP arm without the insertion is first encountered by repair DNA polymerase and is then (mis)used as a template, the palindrome is perfected. When the QP+4 arm is encountered first, Ura+ derivatives only occur after second-end capture and second-strand synthesis. QP+4 mutations are suppressed by mismatch repair (MMR) proteins Msh2, Msh3, and Mlh1, but not Msh6. Deleting Rdh54 significantly reduces QP mutations only when events creating Ura+ occur in the context of a D-loop but not during second-strand synthesis. A similar bias is found with a proofreading-defective DNA polymerase mutation (pol3-01). DSB-induced mutations differed in several genetic requirements from spontaneous events. We also created a +1 frameshift in the donor, expanding a run of 4 Cs to 5 Cs. Again, Ura3+ recombinants markedly increased by disabling MMR, suggesting that MMR acts during GC but favors the unbroken, template strand.
Microbial eukaryotic predation pressure and biomass at deep-sea hydrothermal vents

Deep-sea hydrothermal vent geochemistry shapes the foundation of the microbial food web by fueling chemolithoautotrophic microbial activity. Microbial eukaryotes (or protists) play a critical role in hydrothermal vent food webs as consumers, hosts of symbiotic bacteria, and as a nutritional source to higher trophic levels. We measured cell abundances and predation pressures of vent-associated microbial eukaryotes in low temperature diffuse hydrothermal fluids at the Von Damm and Piccard vent fields along the Mid-Cayman Rise in the Western Caribbean Sea. We present findings from experiments performed under in situ pressure that show higher cell abundances and grazing rates compared to those done at 1 atmosphere (shipboard ambient pressure); this trend was attributed to the impact of depressurization on cell integrity. A relationship between protistan grazing rate, prey cell abundance, and temperature of end member hydrothermal vent fluid was observed at both vent fields, regardless of experimental approach. The quantification of protistan biomass and grazing pressure shows that hydrothermally-fueled microbial food webs play a significant role in the broader deep-sea carbon budget by contributing to local carbon export and supply of nutrient resources to the deep ocean.
The mTOR pathway genes mTOR, Rheb, Depdc5, Pten, and Tsc1 have convergent and divergent impacts on cortical neuron development and function

Brain somatic mutations in various components of the mTOR complex 1 (mTORC1) pathway have emerged as major causes of focal malformations of cortical development and intractable epilepsy. While these distinct gene mutations converge on excessive mTORC1 signaling and lead to common clinical manifestations, it remains unclear whether they cause similar cellular and synaptic disruptions underlying cortical network hyperexcitability. Here, we show that in utero activation of the mTORC1 activators, Rheb or mTOR, or biallelic inactivation of the mTORC1 repressors, Depdc5, Tsc1, or Pten in mouse medial prefrontal cortex leads to shared alterations in pyramidal neuron morphology, positioning, and membrane excitability but different changes in excitatory synaptic transmission. Our findings suggest that, despite converging on mTORC1 signaling, mutations in different mTORC1 pathway genes differentially impact cortical excitatory synaptic activity, which may confer gene-specific mechanisms of hyperexcitability and responses to therapeutic intervention.
Positive Selection Drives cis-regulatory Evolution Across the Threespine Stickleback Y Chromosome

Allele-specific gene expression evolves rapidly on heteromorphic sex chromosomes. Over time, the accumulation of mutations on the Y chromosome leads to widespread loss of gametolog expression, relative to the X chromosome. It remains unclear if expression evolution on degrading Y chromosomes is primarily driven by mutations that accumulate through processes of selective interference, or if positive selection can also favor the downregulation of coding regions on the Y chromosome that contain deleterious mutations. Identifying the relative rates of cis-regulatory sequence evolution across Y chromosomes has been challenging due to the limited number of reference assemblies. The threespine stickleback (Gasterosteus aculeatus) Y chromosome is an excellent model to identify how regulatory mutations accumulate on Y chromosomes due to its intermediate state of divergence from the X chromosome. A large number of Y-linked gametologs still exist across three differently aged evolutionary strata to test these hypotheses. We found that putative enhancer regions on the Y chromosome exhibited elevated substitution rates and decreased polymorphism when compared to non-functional sites, like intergenic regions and synonymous sites. This suggests that many cis-regulatory regions are under positive selection on the Y chromosome. This divergence was correlated with X-biased gametolog expression, indicating the loss of expression from the Y chromosome may be favored by selection. Our findings provide evidence that Y-linked cis-regulatory regions exhibit signs of positive selection quickly after the suppression of recombination and allow comparisons with recent theoretical models that suggest the rapid divergence of regulatory regions may be favored to mask deleterious mutations on the Y chromosome.
Agent-based modeling of nuclear chromosome ensemble identifies determinants of homolog pairing during meiosis

During meiosis, pairing of homologous chromosomes (homologs) ensures the formation of haploid gametes from diploid precursor cells, a prerequisite for sexual reproduction. Pairing during meiotic prophase I facilitates crossover recombination and homolog segregation during the ensuing reductional cell division. Mechanisms that ensure stable homolog alignment in the presence of an excess of non-homologous chromosomes have remained elusive, but rapid chromosome movements during prophase I appear to play a role in the process. Apart from homolog attraction, provided by early intermediates of homologous recombination, dissociation of non-homologous associations also appears to contribute to homolog pairing, as suggested by the detection of stable non-homologous chromosome associations in pairing-defective mutants. Here, we have developed an agent-based model for homolog pairing derived from the dynamics of a naturally occurring chromosome ensemble. The model simulates unidirectional chromosome movements, as well as collision dynamics determined by attractive and repulsive forces arising from close-range physical interactions. In addition to homolog attraction, chromosome number and size as well as movement velocity and repulsive forces are identified as key factors in the kinetics and efficiency of homologous pairing. Dissociation of interactions between non-homologous chromosomes may contribute to pairing by crowding homologs into a limited nuclear area thus creating preconditions for close-range homolog attraction. Predictions from the model are readily compared to experimental data from budding yeast, parameters can be adjusted to other cellular systems and predictions from the model can be tested via experimental manipulation of the relevant chromosomal features. Author summary Pairing of homologous chromosomes (homologs) is a key feature of multiple cellular processes including gene expression control, chromosome break repair, and chromosome segregation. Homolog pairing during meiosis is shared among all sexually reproducing eukaryotes. Mechanistic determinants of homology-specific chromosome alignment are presently unknown. We have developed an agent-based model where contributions of the entire chromosome set to the pairing process is taken into account, comprising both homologous and non-homologous chromosomal encounters. Incorporating natural chromosome lengths, the model accurately recapitulates efficiency and kinetics of homolog pairing observed for wild-type and mutant meiosis in budding yeast, and can be adapted to nuclear dimensions and chromosome sets of other organisms.
The Mobility of Homeless People and Their Use of Public Transit in Long Beach, California

The mobility of the homeless is often constrained by certain social and geographic factors, including the concentration of homeless in neighborhoods with high levels of poverty and in public spaces in downtown areas that can be used for sleeping and networking. Geographically, these spaces may be identified as “spaces of containment,” sites in which marginalized populations, such as the homeless, are maintained through the production of social and spatial barriers to their mobility. Despite the assumption that homeless individuals are relatively immobile because of their circumstances, mobility is crucial to the ability of homeless people to move between stigmatized and nonstigmatized places, such as places of employment. Public transportation services offer a critical outlet for homeless individuals with limited resources who must use public transit to access services, shelter, affordable housing, education, and employment. This research examines the mobility patterns and public transit use by homeless people in Long Beach, CA, and evaluates the extent to which the mobility provided by public transit constrains or enables their ability to navigate between stigmatized and non-stigmatized places. The goal is to provide insights for addressing the needs of the City of Long Beach’s homeless population.
`Where are you Really from?': Representation, Identity and Power in the Fieldwork Experiences of a South Asian Diasporic

Feminist accounts of fieldwork have often been concerned with issues of representation, both of the researched and the researcher, exposing some of the complications that arise when the researcher must make critical decisions about representing herself to her research participants. These accounts demonstrate that a fieldworker's identity does in fact impact upon the research process and product, challenging notions of researcher objectivity and neutrality. I contribute to feminist debates by complicating the process of representation and the power and problem of naming; identity and its impact upon the research process; and the field as a place of complex power structures, which can produce questions that seem all too familiar. One of the questions raised in relation to representation, identity and the field is one that I have been asked virtually all my life, but which has different meanings in different contexts. My research participants often asked, `where are you really from? ' This question in the context of the feminist literature on methodology has enabled me to analyse some of the difficulties and problems I faced in doing fieldwork and to develop a different conceptualization of the research process and research participants. Finally, it has also demonstrated some of the difficulties that our current and limited language of race, ethnicity and nationality pose for first generation South Asian researchers.
Effect of different mulches and herbicides on potato and associated weeds.

An experiment was conducted in 2008 at the University of Agriculture, Peshawar in RCB design. The treatments included in the experiment were Roundup 480 SL @ 0.47, Sencor 70WP @ 0.75 kg a.i. ha -1 , plastic mulches (both black and white), organic mulches (wheat straw @ 5 t ha -1 and saw dust @ 6 t ha -1 ), a hand weeding and a no weeding treatment. Highest fresh weed biomass of 130.9 g m -2 was found in weedy check which was statistically at par with saw dust treatment (114.3), while the lowest fresh biomass of weeds was found in hand weeding (10.2 g m -2 ) followed by glyphosate (13.23 g m -2 ) and metribuzin (22.17 g m -2 ). Similarly, dry biomass of weeds was the highest in weedy check plots (30.63 g m -2 ) and the lowest dry biomass was found in hand weeding, glyphosate and metribuzin (2.42, 3.05 and 5.35 g m -2 , respectively). The largest tuber diameter was recorded in hand weeded plots (5.14 cm) followed by glyphosate treated plots (4.99 cm). The yield was the highest in hand weeding and glyphosate treatments (13750 and 13580 kg ha -1 , respectively). The herbicide treated plots were better in economic return as compared to the mulches and hand weeding practices; however among the herbicides the most remunerative treatments were metribuzin and glyphosate.
CryptOpt: Verified Compilation with Randomized Program Search for Cryptographic Primitives (full version)

Most software domains rely on compilers to translate high-level code to multiple different machine languages, with performance not too much worse than what developers would have the patience to write directly in assembly language. However, cryptography has been an exception, where many performance-critical routines have been written directly in assembly (sometimes through metaprogramming layers). Some past work has shown how to do formal verification of that assembly, and other work has shown how to generate C code automatically along with formal proof, but with consequent performance penalties vs. the best-known assembly. We present CryptOpt, the first compilation pipeline that specializes high-level cryptographic functional programs into assembly code significantly faster than what GCC or Clang produce, with mechanized proof (in Coq) whose final theorem statement mentions little beyond the input functional program and the operational semantics of x86-64 assembly. On the optimization side, we apply randomized search through the space of assembly programs, with repeated automatic benchmarking on target CPUs. On the formal-verification side, we connect to the Fiat Cryptography framework (which translates functional programs into C-like IR code) and extend it with a new formally verified program-equivalence checker, incorporating a modest subset of known features of SMT solvers and symbolic-execution engines. The overall prototype is quite practical, e.g. producing new fastest-known implementations of finite-field arithmetic for both Curve25519 (part of the TLS standard) and the Bitcoin elliptic curve secp256k1 for the Intel $12^{th}$ and $13^{th}$ generations.
Transactions of the Royal Society of Tropical Medicine and Hygiene

This study was conducted among 609 adults on stavudine-based antiretroviral treatment (ART) for at least one year at health center level in Kigali, Rwanda to (a) determine the proportion who manifest weight loss after one year of ART (b) examine the association between such weight loss and a number of variables, namely: lipoatrophy, virological failure, adherence and on-treatment CD4 count and (c) assess the validity and predictive values of weight loss to identify patients with lipoatrophy. Weight loss after the first year of ART was seen in 62% of all patients (median weight loss 3.1 kg/year). In multivariate analysis, weight loss was significantly associated with treatment-limiting lipoatrophy (adjusted effect/kg/year –2.0 kg, 95% confidence interval –0.6;-3.4 kg; P < 0.01). No significant association was found with virological failure or adherence. Higher on-treatment CD4 cell counts were protective against weight loss. Weight loss that was persistent, progressive and/or chronic was predictive of lipoatrophy, with a sensitivity and specificity of 72% and 77%, and positive and negative predictive values of 30% and 95%. In low-income countries, measuring weight is a routine clinical procedure that could be used to filter out individuals with lipoatrophy on stavudine-based ART, after alternative causes of weight loss have been ruled out.
Diffusion Models for Medical Image Analysis: A Comprehensive Survey

provide a systematic taxonomy of diffusion models in the medical domain and propose a multi-perspective categorization based on their application, imaging modality, organ of interest, and algorithms. To this end, we cover extensive applications of diffusion models in the medical domain, including segmentation, anomaly detection, image-to-image translation, 2/3D generation, reconstruction, denoising, and other medically-related challenges. Furthermore, we emphasize the practical use case of some selected approaches, and then we discuss the limitations of the diffusion models in the medical domain and propose several directions to fulﬁll the demands of this ﬁeld. Finally, we gather the overviewed studies with their available open-source implementations at our GitHub 1 . We aim to update the relevant latest papers within it regularly.
Upper-level troughs and tropical plumes at low latitudes: Identification, climatology and their impact on global moisture transport

Intrusions of upper-level extratropical troughs into low latitudes are prominent examples of extratropical-tropical interactions. Along the eastern edge of these troughs tropical moisture is transported poleward into the subtropics, where it may occasionally lead to extreme precipitation events. Furthermore, these situations are often accompanied by enhanced convection and the formation of elongated cloud bands, which develop along the eastern flank of the trough and extend from the Tropics poleand eastward into the subtropics or even midlatitudes. Such bands of midand upper-level clouds are commonly referred to as Tropical Plumes (TP). In the present work, these extratropical-tropical interactions are investigated on the basis of two novel climatologies of low-latitude troughs and of tropical plumes. In the first part of this thesis the focus is on the identification, climatology and evolution of upper-level troughs at low latitudes and their impact on moisture transport is evaluated. For the identification of such events a new algorithm has been developed that analyses, in contrast to prior studies, vertical averages of potential vorticity (VAPV) in the 400 to 100 hPa layer. This leads to a detection of intense troughs with a coherent signal throughout the upper troposphere. Regions with VAPV values of ≥ |2 PVU| between 17◦ North and South are defined as intrusion event. This algorithm is applied to ERA-40 reanalysis data for the 22-year period from 1980 to 2001. The resulting climatology indicates frequency maxima during boreal winter in both hemispheres over the Pacific and Atlantic Oceans, in regions where upper westerly winds are predominant over the equator (“westerly ducts”). In boreal summer the intrusion activity is generally reduced with the exception of the central North Pacific. Interannual variations of intrusion frequency in boreal winter show a clear association with the El Niño-Southern Oscillation (ENSO) in the Northern Hemisphere in such a way that over the North Pacific (North Atlantic) significantly more (less) intrusion events are detected during the cold phase of ENSO.