Miracle-dz/UniFAR-FTUs huggingface dataset:
Impaired p53-Mediated DNA Damage Response Contributes to Microcephaly in Nijmegen Breakage Syndrome Patient-Derived Cerebral Organoids

Nijmegen Breakage Syndrome (NBS) is a rare autosomal recessive genetic disorder caused by mutations within NBN, a DNA-damage repair protein. Hallmarks of NBS include several clinical manifestations such growth retardation, chromosomal instability, immunodeficiency and progressive microcephaly. However, the etiology of microcephaly in NBS patients remains elusive. Here, we employed induced pluripotent stem cell-derived brain organoids from two NBS patients to analyze the underlying mechanisms of microcephaly. We show that NBS-organoids carrying the homozygous 647del5 NBN mutation are significantly smaller in size with disrupted cyto-architecture Patient-derived organoids exhibit premature differentiation together with neuronatin (NNAT) overexpression and key pathways related to DNA damage response and cell cycle are differentially regulated compared to controls. Moreover, we show that after exposure to bleomycin, NBS organoids undergo a delayed p53-mediated DNA damage response and aberrant trans-synaptic signalling, which ultimately leads to neuronal apoptosis. Our data provide insights into how mutations within NBN alters neurogenesis in NBS patients, thus providing a proof of concept that cerebral organoids are a valuable tool for studying DNA damage-related disorders.
Novel Chlamydiae and Amoebophilus endosymbionts are prevalent in wild isolates of the model social amoeba Dictyostelium discoideum

Amoebae interact with bacteria in diverse and multifaceted ways. Amoeba predation can serve as a selective pressure for the development of bacterial virulence traits. Bacteria may also adapt to life inside amoebae, resulting in symbiotic relationships (pathogenic or mutualistic). Indeed, amoebae are often infected with bacterial endosymbionts. Acanthamoeba and Hartmannella harbor symbionts from five distinct lineages within the Proteobacteria, Bacteroidetes, and Chlamydiae. Here, we PCR-screened an extensive collection of Dictyostelium discoideum wild isolates for the presence of bacterial symbionts. For the first time we found that obligate symbionts are surprisingly common in this highly-studied amoeba species, identified in 42% of screened isolates (N=730). Members of the environmental Chlamydiae are particularly prevalent. These strains are novel and phylogenetically distinct. We also found Amoebophilus symbionts in 8% of screened isolates (N=730). Under laboratory conditions, antibiotic-cured amoebae behave similarly to their endosymbiont-infected counterparts, suggesting that endosymbionts do not significantly impact host fitness, at least in the laboratory. We found several natural isolates were co-infected with different endosymbionts. The high prevalence and novelty of amoeba endosymbiont clades in the model organism D. discoideum opens the door to future research on the significance and mechanisms of amoeba-symbiont interactions. Significance statement In a large survey across the eastern US, we identify the presence and prevalence of novel strains of obligate intracellular symbionts from within the Chlamydiae, Amoebophilus, and Procabacter lineages in natural populations of the social amoeba Dictyostelium discoideum. We demonstrate that these symbionts do not affect amoeba fitness under standard laboratory conditions. High prevalences in natural populations and some non-random co-infection patterns suggest that these symbionts have environmental context-dependent effects. The presence of these novel bacterial strains that are highly diverged from known amoeba endosymbionts provides an opportunity to study host specificity and host-symbiont interactions in the well-studied D. discoideum model organism. It opens the door for exploring the evolutionary history of these widespread obligate symbionts that are associated with a large variety of hosts.
PD-L1 lncRNA splice promotes lung adenocarcinoma progression via enhancing c-Myc activity

Although blockade of programmed death-ligand 1 (PD-L1) to enhance T cell immune responses shows great promise in tumor immunotherapy, the efficacy of such immune-checkpoint inhibition strategy is limited for patients with solid tumors. The mechanism underlying the limited efficacy of PD-L1 inhibitors remains unclear. Here, we show that human lung adenocarcinoma, regardless of PD-L1 protein positive or negative, all produce a long non-coding RNA isoform of PD-L1 (PD-L1-lnc) via alternative splicing, which promotes lung adenocarcinoma proliferation and metastasis. PD-L1-lnc in various lung adenocarcinoma cells is significantly upregulated by IFNγ in a manner similar to PD-L1 mRNA. Both in vitro and in vivo studies demonstrate that PD-L1-lnc increases proliferation and invasion but decreases apoptosis of lung adenocarcinoma cells. Mechanistically, PD-L1-lnc directly binds to c-Myc and enhances c-Myc transcriptional activity downstream in lung adenocarcinoma cells. Our results provide targeting PD-L1-lnc−c-Myc axis as a novel strategy for lung cancer therapy.
Single-cell analyses identify circulating anti-tumor CD8 T cells and markers for their enrichment

The ability to monitor anti-tumor CD8+ T cell responses in the blood has tremendous therapeutic potential. Here, we used paired single-cell RNA sequencing and T cell receptor (TCR) sequencing to detect and characterize “tumor matching” (TM) CD8+ T cells in the blood of mice with MC38 tumors and melanoma patients using the TCR as a molecular barcode. TM cells showed increased activation compared to non-matching T cells in blood, and appeared less exhausted than matching counterparts in tumor. Importantly, PD-1, which has been used to identify putative circulating anti-tumor CD8+ T cells, showed poor sensitivity for identifying TM cells. By leveraging the transcriptome we identified candidate cell surface marker panels for TM cells in mice and melanoma patients, and validated NKG2D, CD39, and CX3CR1 in mice. These data demonstrate that the TCR can be used to identify tumor-relevant populations for comprehensive characterization, reveal unique transcriptional properties of TM cells, and develop marker panels for tracking and analysis of these cells. Summary Using single-cell RNA-sequencing coupled with TCR sequencing, we detected CD8+ T cell clones shared between blood and tumor in mice and melanoma patients, characterized these matching clones in blood and tumor, and identified potential biomarkers for their isolation in blood.
Continuous Rate Modelling of bacterial stochastic size dynamics

Bacterial division is an inherently stochastic process. However, theoretical tools to simulate and study the stochastic transient dynamics of cell-size are scarce. Here, we present a general theoretical approach based on the Chapman-Kolmogorov formalism to describe these stochastic dynamics including continuous growth and division events as jump processes. Using this approach, we analyze the effect of different sources of noise on the dynamics of the size distribution. Oscillations in the distribution central moments were found as consequence of the discrete translation invariance of the system with period of one doubling time, these oscillations are found in both the central moments of the size distribution and the auto-correlation function and do not disappear including stochasticity on division times or size heterogeneity on the population but only after include noise in either growth rate or septum position.
GM-CSF differentiation of human monocytes stabilizes macrophage state via oxidative signaling

Macrophages are central mediators of immunity that integrate diverse signals derived from differentiation cues, tissue location, and disease. Controlling macrophage state and function is an appealing therapeutic objective across many diseases including cancer, atherosclerosis, and tuberculosis. Despite the growing appreciation for the in vivo complexity of macrophage state, existing in vitro models of human monocyte-derived macrophages have used a limited number of individual perturbations to explore the complex phenotypic space that macrophages can occupy. Here, we leverage a tiered differentiation, activation, and stimulation strategy to generate libraries of in vitro monocyte-derived macrophages and examine the in vitro state space of macrophage function using high-dimensional technologies. Our tiered experimental approach further revealed a striking relationship between GM-CSF differentiation and IL-10 production. Cells that were differentiated with GM-CSF produced very low or undetectable levels of IL-10 independent of activation or stimulation condition. To nominate candidate regulators of this IL-10 response, we leverage unbiased single-cell mRNA sequencing to identify transcriptional networks associated with GM-CSF-derived cells. Using these data, we identify oxidative signaling pathways as upregulated in GM-CSF derived cells and demonstrate that scavenging of oxidative radicals can enhance IL-10 production in these cells. Collectively, these data underscore the complexity of monocyte-derived macrophage state over time and highlight a dominant role for GM-CSF in tuning macrophage inflammatory phenotype, metabolic state, and plasticity.
PYL8 ABA receptors of Phoenix dactylifera play a crucial role in response to abiotic stress and are stabilized by ABA (118)

The identification of those prevailing ABA receptors and molecular mechanisms that trigger drought adaptation in crops well adapted to harsh conditions such as date palm (Phoenix dactylifera, Pd) sheds light on plant-environment interactions. We reveal that PdPYL8-like receptors are predominantly expressed under abiotic stress, being Pd27 the most expressed receptor in date palm. Therefore, subfamily I PdPYL8-like receptors have been selected for ABA signaling during abiotic stress response in this crop. Biochemical characterization of PdPYL8-like and PdPYL1-like receptors revealed receptor- and ABA-dependent inhibition of PP2Cs, which triggers activation of the pRD29B-LUC reporter in response to ABA. PdPYLs efficiently abolish PP2C-mediated repression of ABA signaling, but loss of the Trp lock in the seed-specific AHG1-like phosphatase PdPP2C79 markedly impairs its inhibition by ABA receptors. Characterization of Arabidopsis transgenic plants that express PdPYLs shows enhanced ABA signaling in seed, root and guard cells. Specifically, Pd27 overexpressing (OE) plants showed lower ABA content and were more efficient than wild type to lower transpiration at negative soil water potential, leading to enhanced drought tolerance. Finally, PdPYL8-like receptors accumulate after ABA treatment, which suggests that ABA-induced stabilization of these receptors operates in date palm for efficient boosting of ABA signaling in response to abiotic stress. Highlight Date palm response to abiotic stress is triggered through PYL8-like ABA receptors that are stabilized by the hormone, which boosts plant adaptation to drought mediated by ABA.
Pattern of Suicide: A Review of Autopsies Conducted at Moi Teaching and Referral Hospital in Eldoret Kenya

Problem statement. Suicide is one of the ten leading causes of death in the world, accounting for more than 400,000 deaths annually. The pattern of suicide and the incidence of suicide vary from country to country. Cultural, religious and social values play some role in suicide. Currently, there is no data regarding the incidence of suicide in Kenya. Setting. Moi Teaching and Referral Hospital Mortuary. Study population. A seven-year retrospective study of all the autopsies performed at the Moi Teaching and Referral Hospital was analysed and the cases that were definitely determined as suicides were further studied. Objective. To characterize the pattern of suicide cases through autopsies conducted at MTRH mortuary between the years 2005 to 2012. Methodology. Retrospective descriptive cross-sectional study. Suicide cases were identified from the MTRH autopsy record books. From these record books, the autopsy number was used to retrieve the pathologists autopsy report. Data regarding age, gender and methods of suicide was retrieved and entered into a data collection form. Data analysis: Data collected was analysed using Stata version 10. Results. There were 213 autopsies performed. Majority were male 180(85%). The subjects had a median age of 29(IQR: 23–37) years. Organophosphate poisoning was the most preferred method followed by hanging. Organophosphate poisoning accounted for 195(91.54%) and hanging for 17(7.98%) of the subjects. Conclusion. The preferred methods of suicide were poisoning and hanging. The study may have missed some cases where the relatives could have declined for the postmortem procedure and hence the body released without postmortem examinations.
A small-molecule oral agonist of the human glucagon-like peptide-1 receptor

Peptide agonists of the glucagon-like peptide-1 receptor (GLP-1R) have revolutionized diabetes therapy, but their use has been limited by the requirement for injection. Here we describe the first effective, orally bioavailable small molecule GLP-1R agonists. A sensitized high-throughput screen identified a series of small molecule GLP-1R agonists that were optimized to promote endogenous GLP-1R signaling with nM potency. These small molecule agonists increased insulin levels in primates but not rodents, which is explained by a cryo-EM structure that revealed a binding pocket requiring primate-specific tryptophan 33. Importantly, oral administration of agonist PF-06882961 to healthy humans produced dose-dependent declines in serum glucose (NCT03309241). This opens the door to a new era of oral small molecule therapies that target the well-validated GLP-1R pathway for metabolic health. One Sentence Summary PF-06882961 is an orally administered small molecule that activates the GLP-1 receptor to lower blood glucose in humans.
Effect of growth regulators on in vitro complete plant regeneration in brinjal

Effect of growth regulators on shoot morphogenesis in hypocotyl and cotyledonary leaf explants, shoot elongation and root induction has been studied. Hypocotyl explants showed callus initiation and direct regeneration response after 3–5 and 13–15 days of culture initiation, respectively. Cotyledonary leaf explants showed callus initiation and callus-mediated shoot regeneration response after 7–8 days and 3 weeks of culture initiation. Growth regulators did not affect callus initiation response but they markedly influenced regeneration response. Culture medium (full-strength MS salts, vitamins, 3% sucrose and 0.8% agar) containing 2 μM and 0.05 μM NAA induced highest shoot regeneration in hypocotyl explants (65.71%), whereas culture medium containing 10 μM BAP and 0.5 μM NAA induced highest 18.33% shoot regeneration in cotyledonary leaf explants. Either increase or decrease in BAP concentration than this resulted in reduction in shoot regeneration response. Addition of BAP to shoot elongation medium was found beneficial for shoot elongation and shoot regeneration medium was efficient in shoot elongation also. Addition of auxins in root induction medium has reduced number of days taken for root induction and increased in number of roots and root length. In hardening, 90–95% of rooted shoots survived and all the plantlets were morphologically normal.
PHOTOSENSITIZATION IN SHEEP ASSOCIATED WITH INGESTION OF TRIBULUS TERRESTRIS IN AL-NAJAF DESERT, IRAQ

This study was conducted to investigate one of the most issues in Iraqi Awassi sheep by ingesting of Tribulus terrestris that disseminated in the Al-Najaf Desert. The Iraqi Awassi sheep is one of the most popular and economically important sheep in Iraq and the Middle East which survive on the low nutrition level. Nutrition also remains one of the major constraints to livestock production in the tropics, particularly the lack of protein during the dry season. Tribulus terrestris (Qutub) belongs to family Zygophyllaceae, it is a herbaceous, mat forming plant in nature and grows in warm dry tropics all over the world. A total of 75 blood samples were collected from jugular vein and placed into EDTA and plain tubes. Samples were divided in to two groups depending on the clinical signs, 45 sheep were clinically healthy and 30 sheep possessed clinical signs that are suggestive of photosensitization in Al-Najaf governorate, Iraq. The results showed that the total blood analyses, there were a significant increase (P > 0.05) in total leukocyte count and neutrophils, while, there was no significant difference in total red blood cells, PCV, Hb, lymphocytes, and eosinophil of affected sheep compared to the control. Furthermore, affected sheep had significantly higher levels of aspartate aminotransferase (AST), alkaline phosphatase (ALP), sorbitol dehydrogenase (SDH), total protein, total bilirubin, and serum urea nitrogen. In conclusion, the present study recorded that hematological, biochemical and pathological changes related with ingestion of toxic plant Tribulus terrestris in Al Najaf desert of Iraq, which causes photosensitization in affected sheep.
Effect of Rock Phosphate Enrichment and Azotobacter Inoculation on the Transformation of Nitrogen and Phosphorus during Composting

The effect of inoculation with Azotobacter and addition of varying levels of rock phosphate was studied on Nand P transformations during composting. Inoculation with Azotobacter at 30 and 60 days of composting increased NH4+, N03, and total N contents and decreased water soluble P and C:N ratio, whereas the inoculation done at the start of composting had no effect. Rock phosphate enrichment accelerated decompositiori, conserved N and improved N mineralization. Phosphorus from rock phosphate was solubilized during composting and transformed into available forms.
Effects of Environmental Cost on Thermoregulation in the Desert Iguana

The desert iguana (Dipsosaurus dorsalis) precisely thermoregulates in an operant conditioning apparatus, where it must walk 1 m to obtain a short-duration thermal reinforcement. The preferred body temperature depends on the duration of the thermal reinforcement (30-180 s) and on the ambient temperature (20 C or 30 C). Variation in preferred body temperature is not due to physiological constraintsexcept perhaps in the shortest-duration reinforcement at 20 C-but reflects motivational variation. The precision of thermoregulation depends on the thermal reinforcement duration, the ambient temperature, and the extent of the elevation of body temperature above ambient air temperature. The body temperature distributions were negatively skewed except under the short-duration thermal regimens. The stochastic dual-limit model of lizard behavioral thermoregulation closely predicts the observed frequency distribution of body temperatures only when the cost for thermoregulation is low (i.e., when there is high thermal reinforcement or high ambient temperature).
The effi cacy of baited and live capture pitfall traps in collecting large-bodied forest carabids.

Pitfall trapping is commonly used to sample epigaeic invertebrates throughout the world. However, this technique can be ineffective for capturing some species, whilst capturing high numbers of nontarget invertebrates. This study aims to improve the effi cacy of pitfall trapping for sampling Mecodema spp. (Coleoptera: Carabidae), but also examines the potential of live pitfall traps to reduce the by-catch of other invertebrates. Four types of pitfall traps were used in two separate sampling regimes: baited kill trap versus nonbaited kill trap, and chambered live trap versus non-chambered live trap, in regenerating kauri/broadleaf mixed forest (Waitakere Ranges, Auckland, New Zealand). Results show all four types of traps sampled different components of the invertebrate community. Baited kill traps caught extremely high numbers of some groups, particularly Diptera and Coleoptera, whereas non-baited kill traps caught far fewer individuals of these groups. Both types of live capture traps caught few individuals. Three genera of large-bodied Carabidae (Ctenognathus, Holcaspis and Mecodema) were caught in similarly low numbers in both baited and non-baited traps indicating that baiting with squid is ineffective as an attractant to increase catch rates of the genus Mecodema. Although baiting did not increase carabid catches it appears that live traps worked as well as kill traps, but live traps caught fewer invertebrates and therefore signifi cantly reduce the bycatch. A negative aspect of live pitfall trapping is the potential of captured invertebrates to prey upon each other. However, no predation was observed within the traps during this study.
Rectus Sheath Hematoma—A Rare and Dangerous Complication of Anticoagulation Therapy

Rectus sheath hematoma (RSH) is a rare bleeding site which can be life-threatening. Our aim was to analyze clinical features, diagnosis, treatment and outcome of these cases in a general hospital. Results: During a period of 24 months, 8 cases of RSH were diagnosed (0.1% of all inpatients). Mean age was 79.4 years (y, SD +/− 14.1). 75% were female. 7 patients (pts) were on therapy with oral anticoagulants (OAC), 2 had a history of additional therapy with aspirin (ASA), 4 had low molecular weight heparin (LMWH) for bridging of OAC therapy. 4 pts had INR values between 3.1 4.4. One pt with liver cirrhosis (Child A), mild thrombocytopenia had ASA and LMWH prophylactically. Five pts (63%) were coughing. Main symptom was localized pain in 7 pts. One pt was incidentally diagnosed on a CT scan performed for different reason. 7 pts had a palpable mass of the abdominal wall. 5 RSH were diagnosed with CT, 2 with ultrasound, 1 clinically. All pts were treated conservatively. In 7 pts vitamine K and Beriplex® was substituted to reverse OAC. 4 pts received blood transfusions (1 4 units). The mean change of hemoglobin (Hb) was 37 g/l (SD +/− 22 g/l). The renal function was impaired in 7 pts (mean creatinine clearance 51 ml/min +/− 12.4) and declined further. 3 out of 8 pts died (38%, age 90 92 y, all female). In these patients, the observed change in Hb was 42 58 g/l. 2 pts had combination of VKA and LMWH. 1 pt had VKA only. Conclusion: Acute abdominal pain in pts with any form of OAC or therapy to inhibit platelet function should always raise suspicion about RSH. Extensive blood loss, shock and aggravation of renal failure can be fatal. In majority of cases, the hematoma is palpable and should prompt further examination of the abdominal wall. It is crucial to normalize coagulation parameters and to correct intravascular volume depletion to avoid shock and further decline of renal failure. Corresponding author. T. Hoefflinghaus et al.
Global Journal of Psychology Research: New Trends and Issues

The present study was conducted to investigate the existence of any possible relationship between the cognitive reflection test (CRT), numeracy and academic majors. The statistical population of this study consisted of 117 freshmen studying under the faculties selected from the University of Tabriz. The generalised structural equation modelling technique was employed for data analysis. The research results indicated that CRT and numeracy had positive and significant effects on high school and university program selection. According to the research model and the higher CRT scores of engineering and medicine (two popular majors) than that of other majors, it appears that individuals with higher CRT and numeracy scores are more inclined to get accepted into these programs. Moreover, the relationship between CRT and numeracy was positive and significant, where CRT acted as the cause and numeracy as the effect. However, the reverse need not necessarily be true.