Miracle-dz/UniFAR-FTUs huggingface dataset:
Colorectal cancer residual disease at maximal response to EGFR blockade displays a druggable Paneth cell–like phenotype

Drug tolerance in EGFR-inhibited mCRC involves secretory pseudodifferentiation and rewiring of oncogenic dependencies. Tumor cells hunker down to escape Targeted therapy inhibiting pathways involved in tumor growth is becoming increasingly common. This includes inhibitors of the epidermal growth factor receptor, which are used for a variety of tumor types including colorectal cancer. Unfortunately, the treatment’s effects are often incomplete such that residual cancer cells stay behind and contribute to relapse. Lupo et al. examined these residual cancer cells, which proliferate relatively slowly, and identified their similarities to a subtype of normal intestinal cells. The authors examined the signaling pathways active in these cells and identified potential interventions that worked in multiple patient-derived xenografts, suggesting that they may translate to patients. Blockade of epidermal growth factor receptor (EGFR) causes tumor regression in some patients with metastatic colorectal cancer (mCRC). However, residual disease reservoirs typically remain even after maximal response to therapy, leading to relapse. Using patient-derived xenografts (PDXs), we observed that mCRC cells surviving EGFR inhibition exhibited gene expression patterns similar to those of a quiescent subpopulation of normal intestinal secretory precursors with Paneth cell characteristics. Compared with untreated tumors, these pseudodifferentiated tumor remnants had reduced expression of genes encoding EGFR-activating ligands, enhanced activity of human epidermal growth factor receptor 2 (HER2) and HER3, and persistent signaling along the phosphatidylinositol 3-kinase (PI3K) pathway. Clinically, properties of residual disease cells from the PDX models were detected in lingering tumors of responsive patients and in tumors of individuals who had experienced early recurrence. Mechanistically, residual tumor reprogramming after EGFR neutralization was mediated by inactivation of Yes-associated protein (YAP), a master regulator of intestinal epithelium recovery from injury. In preclinical trials, Pan-HER antibodies minimized residual disease, blunted PI3K signaling, and induced long-term tumor control after treatment discontinuation. We found that tolerance to EGFR inhibition is characterized by inactivation of an intrinsic lineage program that drives both regenerative signaling during intestinal repair and EGFR-dependent tumorigenesis. Thus, our results shed light on CRC lineage plasticity as an adaptive escape mechanism from EGFR-targeted therapy and suggest opportunities to preemptively target residual disease.
Semen Ejaculates Characteristics, in vitro Fertility and Their Interrelationships in Sahiwal Bull Semen

This study aimed at determining the physico-morphological attributes, in vitro fertility and their interrelationships in semen of Sahiwal bulls. Semen samples were collected weekly for 6 weeks from ten mature Sahiwal bulls divided randomly into 5 groups. The mean (±SEM) of ejaculate volume (mL), mass activity (score 0-5), progressive sperm motility (%), sperm concentration (10 6 /mL), live sperm (%), abnormal sperm (%), intact acrosome (%), hypo-osmotic swelling (HOS) positive sperm (%), sperm penetration distance (SPD, mm) were 4.28, 3.17, 76.73, 1185.53, 83.37, 9.97, 82.70, 79.00 and 56.85, respectively. The bulls varied significantly (P<0.05) in all their ejaculates characteristics Moreover, HOS positive sperm also had significant (P<0.01) positive correlation with mass activity (r=0.756), progressively motile sperm (r=0.374), live sperm (r=0.395) and SPD (r=0.681), and negative correlation with abnormal sperm (r=-0.463). Sperm penetration distance has significant (P<0.05) positive correlation with mass activity (r=0.776), progressively motile sperm (r=0.653), sperm concentration (r=0.365) and HOS positive sperm (r=0.681), and negative correlation with intact acrosome (r=-0.415). Overall semen quality of Sahiwal bulls was found optimum for use in breeding programme.
Weed Control from Herbicide Combinations with Glyphosate1

Greenhouse studies were initiated to evaluate glyphosate alone and tank-mixed with acifluorfen, CGA 277476, chlorimuron, cloransulam-methyl, fomesafen, imazaquin, or pyrithiobac on seedling johnsongrass, broadleaf signalgrass, pitted morningglory, and hemp sesbania. Johnsongrass and broadleaf signalgrass control by glyphosate was not affected by the selective herbicides applied in mixtures. Pitted morningglory control by glyphosate ranged from 0% with 280 g ai/ha to 67% with 840 g/ha. There was an additive effect when selective herbicides were added to 280 g/ha glyphosate 2 wk after treatment (WAT). When acifluorfen was added to 560 g/ha glyphosate, pitted morningglory control 2 WAT increased to 100% compared with 55% with glyphosate alone. Similarly, the addition of fomesafen or acifluorfen to 840 g/ha glyphosate controlled pitted morningglory 2 WAT by 90 and 98%, respectively, compared with 67% with glyphosate alone. Only tank mixtures of acifluorfen, CGA 277476, or fomesafen, and 840 g/ha glyphosate reduced fresh weight compared with glyphosate alone 4 WAT. Acifluorfen, CGA 277476, and fomesafen controlled pitted morningglory by 85 to 100% when added to 1,120 g/ha glyphosate. Both acifluorfen and fomesafen effectively controlled hemp sesbania without the addition of glyphosate 2 WAT. Chlorimuron and pyrithiobac added to 1,120 g/ha glyphosate increased hemp sesbania control to 88 and 99%, respectively, compared with 45% with glyphosate alone 2 WAT. CGA 277476, cloransulam-methyl, imazaquin, and pyrithiobac were antagonistic to hemp sesbania fresh weight reduction when compared with the expected response, but fresh weights were still reduced more than with the same rate of glyphosate alone. Nomenclature: Acifluorfen; CGA-277476, 2-[[[[(4,6-dimethyl-2-pyrimidinyl)amino]carbonyl]amino]sulfonyl]-3-oxetanyl ester; chlorimuron; cloransulam-methyl; fomesafen; glyphosate; imazaquin; pyrithiobac; broadleaf signalgrass, Brachiaria platyphylla (Griseb.) Nash. #3 ECHCG; hemp sesbania, Sesbania exaltata (Raf.) Rydb. ex. A. W. Hill # SEBEX; johnsongrass, Sorghum halepense (L.) Pers. # SORHA; pitted morningglory, Ipomoea lacunosa L. # IPOLA. Additional index words: Additive effects, herbicide antagonism, tank mixtures. Abbreviations: ALS, acetolactate synthase; WAT, weeks after treatment.
Functional immune mapping with deep-learning enabled phenomics applied to immunomodulatory and COVID-19 drug discovery

Development of accurate disease models and discovery of immune-modulating drugs is challenged by the immune system’s highly interconnected and context-dependent nature. Here we apply deep-learning-driven analysis of cellular morphology to develop a scalable “phenomics” platform and demonstrate its ability to identify dose-dependent, high-dimensional relationships among and between immunomodulators, toxins, pathogens, genetic perturbations, and small and large molecules at scale. High-throughput screening on this platform demonstrates rapid identification and triage of hits for TGF-β- and TNF-α-driven phenotypes. We deploy the platform to develop phenotypic models of active SARS-CoV-2 infection and of COVID-19-associated cytokine storm, surfacing compounds with demonstrated clinical benefit and identifying several new candidates for drug repurposing. The presented library of images, deep learning features, and compound screening data from immune profiling and COVID-19 screens serves as a deep resource for immune biology and cellular-model drug discovery with immediate impact on the COVID-19 pandemic.
ICSI in cases of sperm DNA damage: beneficial effect of oral antioxidant treatment

Background Most studies examining the use of ICSI for cases of elevated sperm DNA fragmentation report poor pregnancy and implantation rates. ICSI with testicular sperm samples has recently been suggested for these cases. Here we test a less invasive approach based on oral antioxidant treatment prior to ICSI with ejaculated spermatozoa. Methods Thirty-eight men with an elevated (> or =15%) percentage of DNA-fragmented spermatozoa in the ejaculate were treated with antioxidants (1 g vitamin C and 1 g vitamin E daily) for 2 months after one failed ICSI attempt. In 29 (76%) of these cases this treatment led to a decrease in the percentage of DNA-fragmented spermatozoa, and a second ICSI attempt was performed. Outcomes of the two attempts were compared. Results No differences in fertilization and cleavage rates or in embryo morphology were found between the ICSI attempts performed before and after the antioxidant treatment. However, a marked improvement of clinical pregnancy (48.2% versus 6.9%) and implantation (19.6% versus 2.2%) rates was observed after the antioxidant treatment as compared with the pretreatment ICSI outcomes. Conclusions Oral antioxidant treatment appears to improve ICSI outcomes in those patiens with sperm DNA damage, in whom this treatment reduces the percentage of damaged spermatozoa.
Ecophysiological Analysis on Effect of Planting Pattern on Biomass Production and Grain Yield in Rice

Increasing the biomass productivity of rice is a critical research target for improving the yield potential. This paper reviews ecophysiological studies on biomass production as affected by agronomic techniques and cultivars. In addition, we examined the effects of the planting pattern on the biomass production using cv. Takanari, a high-yielding and lodging resistant cultivar. The results showed that greater biomass production and grain yield were observed in plants with the combination of one plant per hill, high hill density and square hill arrangement. The factors responsible for high biomass production in this combination are; (1) vigorous tiller increase at the tillering stage resulting in higher capture of solar radiation, (2) erect leaves in the canopy after the panicle formation stage resulting in an improved light-intercepting character or smaller extinction coefficient, and (3) larger nitrogen accumulation during the ripening period resulting in a smaller decline of photosynthesis as well as a smaller midday and afternoon depression of photosynthesis possibly related to the larger water uptake ability of roots owing to better root-system development. Our results implied that an improvement in biomass production and yield is possible by optimizing the planting pattern and nitrogen management using high-yielding and lodging resistant cultivars in transplanted and direct-sown rice.
Developing methods for measuring national distributions and densities of wild mammals using camera traps: A Kosovo study

Understanding the distributions and density of wild mammals is integral to the implementation of wildlife management strategies, particularly for controlling diseases and conservation management. Recent advances in camera trap technology together with the development of the Random Encounter Model have provided a non-invasive method for estimating mammal densities. In addition, the development of citizen science initiatives have advanced ecological data collection. This study describes a national camera trap survey delivered by local stakeholders in eleven forest sites in Kosovo from 2014 to 2015 to measure the distributions and abundance of medium to large wild mammals as part of the Control and/or eradication of animal diseases project. The Random Encounter Model was used to calculate density data for each species, which appear realistic when compared to densities found in other European countries. The study particularly focussed on the red fox (Vulpes vulpes) and the grey wolf (Canis lupus) as potential vectors of rabies and wild boar (Sus scrofa) as a vector of classical swine fever. These species were found to be three of the most widely distributed species in Kosovo and were present at the majority of sites at high densities. The camera survey also provided information on species of conservation concern such as the Eurasian brown bear (Ursus arctos) and provided the first physical evidence of a live Eurasian golden jackal (Canis aureus) in Kosovo. Although sources of bias were identified, these estimates are likely to be more accurate than those devised from methods such as hunting bags and the findings of this study suggest that, with a moderate amount of development, camera trapping implemented by local stakeholders can be used as an effective and practicable method to estimate national distributions and population sizes of medium to large sized wild mammals.
Threshold accumulation of a constitutive protein explains E. coli cell-division behavior in nutrient upshifts

Significance The mechanism leading to cell division in the bacterium Escherichia coli is unknown, but we know that it results in adding a roughly constant size every cell cycle, regardless of size at birth. While most available studies try to infer information on cell division from steadily dividing cells in constant nutrient conditions, this study leverages a high-resolution device to monitor single-cell growth division upon nutrient changes. Comparing these data with different mathematical models, we are able to discriminate among fundamentally different mechanisms of cell-division control, and we show that the data support a model where an unregulated protein accumulates to a threshold and triggers division. Despite a boost of recent progress in dynamic single-cell measurements and analyses in Escherichia coli, we still lack a mechanistic understanding of the determinants of the decision to divide. Specifically, the debate is open regarding the processes linking growth and chromosome replication to division and on the molecular origin of the observed “adder correlations,” whereby cells divide, adding roughly a constant volume independent of their initial volume. In order to gain insight into these questions, we interrogate dynamic size-growth behavior of single cells across nutrient upshifts with a high-precision microfluidic device. We find that the division rate changes quickly after nutrients change, much before growth rate goes to a steady state, and in a way that adder correlations are robustly conserved. Comparison of these data to simple mathematical models falsifies proposed mechanisms, where replication–segregation or septum completions are the limiting step for cell division. Instead, we show that the accumulation of a putative constitutively expressed “P-sector divisor” protein explains the behavior during the shift.
Video Laryngoscopy Improves the Success of Neonatal Tracheal Intubation for Novices but Not for Experienced Medical Staff

Background: There is limited evidence on the use of video laryngoscopy (VL) in neonatal tracheal intubation (NTI) during neonatal resuscitation. In this study, we aimed to compare the difference between direct laryngoscopy (DL) and VL in NTI of trainees during neonatal resuscitation training. Materials and Methods: A prospective observational study was conducted during a neonatal resuscitation training course to examine three circumstances: NTI by experienced medical staff (EMS) and less-experienced medical staff (LEMS) in a neonatal resuscitation scenario; NTI by EMS and LEMS with an ongoing chest compression; and NTI by midwives who were novices in the procedure. The trainees were given scenarios or were shown demonstrations on newborn simulation manikins and were required to perform an NTI on a simulation manikin using DL and/or VL. The mean intubation time and success rate of intubation were measured. Results: The mean NTI time for EMS using VL (24.1 ± 7.2 s) was significantly longer than that using DL intubation (18.1 ± 6.9 s, P < 0.001), whereas there was no significant difference between using VL and DL for LEMS. EMS spent slightly less time on NTI than did LEMS using both VL and DL, but there were no statistically significant differences (both p > 0.05). The NTI success rate for EMS using VL (48.0%, 12/25) was significantly lower than that using DL (88.0%, 22/25, P = 0.004), while the NTI success rate for LEMS using VL (68.2%, 15/22 vs. 40.9%, 9/22) was higher than that using DL, but there was no statistical significance. When NTI was required with ongoing chest compressions, there was no significant difference in the mean NTI time and success rate between using VL and DL for EMS or LEMS. In the group of midwives who were novices in NTI, after they watched a demonstration teaching NTI, the intubation time using VL (19.6 ± 9.0 s) was significantly shorter than that using DL (28.0 ± 6.7 s, P < 0.001). The success rate of NTI using VL was significantly higher (96.2%; 25/26) than that using DL (69.2%; 18/26). Conclusion: The video laryngoscopy could be an effective training tool for inexperienced staff in developing the skill of tracheal intubation.
One-Time Acute Heat Treatment Is Effective for Attenuation of the Exaggerated Exercise Pressor Reflex in Rats With Femoral Artery Occlusion

The purpose of this study was to determine the effects of one-time acute heat treatment (HT) on the exaggerated exercise pressor reflex in a model of peripheral arterial insufficiency induced by ligation of the femoral artery and was to further examine the underlying mechanism of ATP-P2X3 signal activity during this process. The blood pressure (BP) response to static muscle contraction and muscle tendon stretch was recorded to determine the exercise pressor reflex. Also, αβ-methylene ATP (αβ-me ATP) was injected into the arterial blood supply of the hindlimb muscles to stimulate P2X3 receptors in the muscle afferent nerves. To process one-time acute HT, a heating pad was placed locally on the hindlimb and the muscle temperature (Tm) was increased by ~1.5°C and maintained for 5 min. Compared with control rats, a greater mean arterial pressure (MAP) response to muscle contraction was observed in rats with femoral occlusion in a pre-heat control session (28 ± 2 mmHg in occluded rats/n = 12 vs. 18 ± 2 mmHg in control rats/n = 9; p < 0.05). The one-time acute HT attenuated the amplification of the BP response in rats with femoral artery occlusion (MAP response: 19 ± 8 mmHg in occluded rats + HT/n = 11; p < 0.05 vs. occluded rats). In contrast, HT did not significantly attenuate amplification of MAP response to muscle stretch and αβ-me ATP injection in rats with femoral artery occlusion and controls (all p > 0.05). Our data suggest that one-time acute HT selectively attenuates the amplified pressor response induced by activation of the metabolic and mechanical components of the reflex in rats after femoral artery occlusion. The suppressing effects of acute HT on the exaggerated exercise pressor reflex are likely mediated through a reduction in metabolites (e.g., ATP) stimulating the muscle afferent nerves in contracting muscle, but unlikely through direct alteration of P2X receptors per se.
The Evolution of the Continental Crust and the Onset of Plate Tectonics

The Earth is the only known planet where plate tectonics is active, and different studies have concluded that plate tectonics commenced at times from the early Hadean to 700 Ma. Many arguments rely on proxies established on recent examples, such as paired metamorphic belts and magma geochemistry, and it can be difficult to establish the significance of such proxies in a hotter, older Earth. There is the question of scale, and how the results of different case studies are put in a wider global context. We explore approaches that indicate when plate tectonics became the dominant global regime, in part by evaluating when the effects of plate tectonics were established globally, rather than the first sign of its existence regionally. The geological record reflects when the continental crust became rigid enough to facilitate plate tectonics, through the onset of dyke swarms and large sedimentary basins, from relatively high-pressure metamorphism and evidence for crustal thickening. Paired metamorphic belts are a feature of destructive plate margins over the last 700 Myr, but it is difficult to establish whether metamorphic events are associated spatially as well as temporally in older terrains. From 3.8 to 2.7 Ga, suites of high Th/Nb (subduction-related on the modern Earth) and low Th/Nb (non-subduction-related) magmas were generated at similar times in different locations, and there is a striking link between the geochemistry and the regional tectonic style. Archean cratons stabilized at different times in different areas from 3.1 to 2.5 Ga, and the composition of juvenile continental crust changed from mafic to more intermediate compositions. Xenon isotope data indicate that there was little recycling of volatiles before 3 Ga. Evidence for the juxtaposition of continental fragments back to ∼2.8 Ga, each with disparate histories highlights that fragments of crust were moving around laterally on the Earth. The reduction in crustal growth at ∼3 Ga is attributed to an increase in the rates at which differentiated continental crust was destroyed, and that coupled with the other changes at the end of the Archean are taken to reflect the onset of plate tectonics as the dominant global regime.
LncRNA DLX6-AS1 Promotes Malignant Phenotype and Lymph Node Metastasis in Prostate Cancer by Inducing LARGE Methylation

Long non-coding RNAs (lncRNAs) have recently become recognized as crucial players in cancer cellular events including proliferation, migration, and invasion. Herein, we investigated the potential role of lncRNA DLX6-AS1 in prostate cancer cell malignant behaviors and lymph node metastasis. A differentially expressed lncRNA DLX6-AS1 and its downstream regulatory gene (LARGE) were predicted by analysis in silico. RT-qPCR and western blot analysis results demonstrated that DLX6-AS1 was highly expressed, but LARGE was poorly expressed in prostate cancer tissues and cells. The online website indicated that DLX6-AS1 negatively targeted LARGE expression, which was validated by Pearson correlation analysis and MSP. ChIP, RIP, and RNA pull-down assays further suggested that DLX6-AS1 downregulated LARGE expression through recruitment of DNMT1 to its promoter. We induced DLX6-AS1/LARGE overexpression or knockdown to examine their effects through Edu and Transwell assays, which revealed that DLX6-AS1 overexpression accelerated proliferation, invasion, and migration of prostate cancer cells, and that overexpression of LARGE rescued these effects. Tumors xenografts studies confirmed that DLX6-AS1 promoted lymph node metastasis by regulating LARGE, as evidenced by enhanced expression of MMP-9, uPAR, and cathepsin B. In summary, DLX6-AS1 stimulated prostate cancer malignant progression and lymph node metastasis by inducing DNMT1-mediated LARGE methylation, highlighting a potential therapeutic target against prostate cancer.
Differential BUM-HMM: a robust statistical modelling approach for detecting RNA flexibility changes in high-throughput structure probing data

Combining RNA structure probing with high-throughput sequencing technologies has greatly enhanced our ability to analyze RNA structure at transcriptome scale. However, the high level of noise and variability encountered in these data call for the development of computational tools that robustly extract RNA structural information. Here we present diffBUM-HMM, a noise-aware model that enables accurate detection of RNA flexibility and conformational changes from high-throughput RNA structure-probing data. DiffBUM-HMM is compatible with a wide variety of high-throughput RNA structure probing data, taking into consideration biological variation, sequence coverage and sequence representation biases. We demonstrate that, compared to the existing approaches, diffBUM-HMM displays higher sensitivity while calling virtually no false positives. DiffBUM-HMM analysis of ex vivo and in vivo Xist SHAPE-MaP data detected many more RNA structural differences, involving mostly single-stranded nucleotides located at or near protein-binding sites. Collectively, our analyses demonstrate the value of diffBUM-HMM for quantitatively detecting RNA structural changes and reinforce the notion that RNA structure probing is a very powerful tool for identifying protein-binding sites.