Miracle-dz/UniFAR-FTUs huggingface dataset:
CBX1 variants cause a neurodevelopmental syndrome due to facultative heterochromatin dysfunction

The heterochromatin protein 1 (HP1) family of proteins represents an essential structural component of heterochromatin formation and organization. Although HP1β, which is encoded by the CBX1 gene, is essential for brain development in mouse, no human disorders involving HP1 proteins have ever been reported. Through exome sequencing, we identified two heterozygous de novo CBX1 variants in two unrelated individuals with developmental delay, hypotonia and autistic features. Identified variants are in the known functional domain of HP1β, chromodomain, which mediates interaction with chromatin. We examined the effects of the variants using protein structural prediction models and molecular assays. Initial in silico analyses of these missense variants predict that they are highly pathogenic and disrupt protein structure for chromatin binding. Subsequent molecular assays confirmed that the identified variants abolished HP1β-chromatin interactions. Transcriptome and epigenome analyses of human patient-derived lymphoblastoid cell lines with RNA-seq and ATAC-seq, respectively, detected global transcriptional and chromatin organizational alterations, particularly in the context of facultative heterochromatin (i.e. reversibly repressed genomic regions), while chromatin organization was unchanged in constitutional heterochromatin. Overall, the genes harboring H3K27me3 were upregulated, while genes harboring H3K9me3 did not reveal transcriptional alterations. Chromatin was globally more open in the CBX1 mutant sample detected by ATAC-seq. These chromodomain HP1β variants highlight the importance of HP1β chromatin binding particularly in the functional regulation of facultative heterochromatin during neurocognitive development, and confirm the role of CBX1 in intellectual disability and autism spectrum disorder.
The receptor-like cytoplasmic kinase MAZZA and CLAVATA-family receptors interact in vivo, together mediating developmental processes in Arabidopsis thaliana

The receptor-like kinases (RLKs) CLAVATA1 (CLV1) and BARELY ANY MERISTEMs (BAM1 – 3) form the CLV-family (CLVf), which perceives peptides of the CLV3/EMBRYO SURROUNDING REGION (ESR)-related (CLE) family within various signaling pathways of Arabidopsis thaliana. CLE peptide signaling, which is required for meristem size control, vascular development, or pathogen responses, involves the formation of receptor complexes at the plasma membrane (PM). These complexes comprise RLKs and co-receptors in varying compositions depending on the signaling context and regulate target gene expression, such as WUSCHEL (WUS). How the CLE signal is transmitted intracellularly after perception at the PM is not known. Here, we found that the membrane-associated receptor-like cytoplasmic kinase (RLCK) MAZZA (MAZ) MAZ and additional members of the Pti1-like protein family interact in vivo with CLVf receptors. MAZ, which is widely expressed throughout the plant, localizes to the PM via posttranslational palmitoylation potentially enabling stimulus-triggered protein re-localization. We identified a role for a CLV1/MAZ signaling module during stomatal and root development, and redundancy could potentially mask other phenotypes of maz-1 mutants. We propose that RLCKs such as MAZ mediate CLVf signaling in a variety of developmental contexts, paving the way towards understanding the intracellular processes after CLE peptide perception.
Fibroblast Growth Factor Receptor 3 Amplified Metastatic Melanoma Treated With Erdafitinib

The treatment of metastatic melanoma has changed dramatically in the last decade with the introduction of immunotherapy and targeted therapy. A futile disease in the past is now treated with various options, resulting in improvement in progression-free and overall survivals, along with improvement in the quality of life. Having said that, the majority of patients with metastatic melanoma eventually succumb to the disease. Molecular profiling of each tumor in the advanced stage is standard of care now, as this would lead to individualized treatment options for each patient. Here, we present a rare case of fibroblast growth factor receptor 3 (FGFR 3) amplified metastatic melanoma, treated rather unconventionally with FGFR 3 inhibitor erdafitinib.
Evaluation of oral citrulline administration as a mitigation strategy for fescue toxicosis in sheep

Abstract Gestating ewes consuming ergot alkaloids, from endophyte-infected (E+) tall fescue seed, suffer from intrauterine growth restriction and produce smaller lambs. Arginine (Arg) supplementation has been shown to increase birth weight and oral citrulline (Cit) administration is reported to increase arginine concentrations. Two experiments were conducted to: 1) evaluate if oral supplementation with Cit or water, to ewes consuming E+ fescue seed, increases lamb birth weight and 2) determine the effectiveness of Cit and citrulline:malate as an oral drench and elevating circulating levels of Cit to determine levels and dose frequency. In experiment 1, gestating Suffolk ewes (n = 10) were assigned to one of two treatments [oral drench of citrulline–malate 2:1 (CITM; 81 mg/kg/d of citrulline) or water (TOX)] to start on d 86 of gestation and continued until parturition. Ewes on CITM treatment had decreased (P < 0.05) plasma Arg and Cit concentrations during gestation. At birth, lambs from CITM ewes had reduced (P < 0.05) crude fat and total fat but did not differ (P > 0.05) in birth weight from lambs born to TOX ewes. In experiment 2, nonpregnant Suffolk ewes (n = 3) were assigned to either oral citrulline (CIT; 81 mg/kg/d), citrulline–malate 2:1 (CITM; 81 mg/kg/d of citrulline), or water (CON) drench in a Latin Square design for a treatment period of 4 d with a washout period of 3 d. On d 4, blood samples were collected at 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 18 h post drench. Oral drenching of CIT and CITM increased (P < 0.0001) Cit concentrations within 2 h and levels remained elevated for 6 h. Apparent half-life of elimination for CIT and CITM were 8.484 and 10.392 h, respectively. Our results show that lamb birth weight was not altered with a single oral drench of citrulline–malate; however, lamb body composition was altered. The level and frequency of citrulline dosing may need to be greater in order to observe consistent elevation of Cit/Arg concentrations to determine its effectiveness in mitigating fescue toxicosis.
Notice of Retraction Impact of Moulds and Mycotoxins Contamination of the Broiler Concentrated Feeds at Different Storage Conditions

Abstract-The objective of the paper was to evaluate the influence of relative humidity (RH) and air temperature on mould growth and mycotoxin production in broiler concentrated feeds during the storage period. Air temperatures ranged at levels of 10, 20 and 30°C, and relative humidity ranged at levels of 65, 75 and 85% under storage conditions. The result showed that (1) the counts of moulds were 2.27 × 105, 5.12 × 105, 6.84 × 105, 2.57 × 105 cfu/g under storage conditions of 10°C, 65, 75 and 85% RH, 20°C, 65%RH on the 17th day, respectively. The levels of AflatoxinB1 (AFB1) were 10.2, 11.6, 12.0, 13.8 μg/kg, respectively. The levels of ochratoxin A (OTA) were 69.8, 68.9, 74.1, 75.4 μg/kg, respectively. The levels of deoxynivalenol (DON) were 1012, 1428, 1502, 2600 μg/kg, respectively. (2)The counts of moulds were 1.07 × 105, 1.21 × 105, 7.96 × 105 cfu/g under storage conditions of 20°C, 75% 85% RH, 30°C, 65% RH on the 10th day, respectively. The levels of AFB1 were 16.5, 12.0 μg/kg, 15.2 μg/kg, respectively. The levels of OTA were 73.6, 73.1, 78.1 μg/kg, respectively. The levels of DON were 1250, 1220, 2800 μg/kg, respectively. (3)The counts of moulds were 3.37 × 105, 4.00 × 105 cfu/g under storage conditions of 30°C, 75% 85%RH on the 5th day, respectively. The levels of AFB1 were 26.2, 11.7 μg/kg, respectively. The levels of OTA were 69.8, 77.2 μg/kg, respectively. The levels of DON were 3015, 1650 μg/kg, respectively. The total mould counts above were more than the limit of national feed standards. AFB1 and OTA did not exceed the limit. National feed standards did not clearly defined for feed corn and broiler concentrated feeds on the DON. (4) Species of F.moniliforme and P.viridicatum have been isolated and identified as the predominant moulds of some mould-contaminated broiler concentrated feeds.
Adsorption behavior of β-lactoglobulin onto polyethersulfone membrane surface

The adsorption of whey protein onto polyethersulfone (PES) membrane was investigated by static adsorption experiments to understand fouling mechanism and optimize the process condition to minimize the membrane fouling. Adsorption isotherm was applied to calculate the isotherm parameters such as adsorption capacity (KF) and surface heterogeneity (1/n). The KF values increased about 3.7 times at pH 3.0, 1.5 times at pH 5.2, and 2.3 times at pH 9.0 compared to that at pH 7.0. The hydrophobic interaction by dissociation of dimer structure of β-lactoglobulin to monomer structure at acidic and alkaline conditions showed the greatly increasing of the amount of protein adsorption by the protein and membrane interaction which might form the strong and rigid protein layer on the polymeric membrane surface. The addition of salt reduced the protein adsorption on PES membrane because of the interactions between charged protein molecules and salt ions.
Case report: potential treatment of metastatic amphicrine carcinoma of the rectum with FOLFOXIRI chemotherapy

ABSTRACT Amphicrine carcinoma (AmC) is a unique epithelial tumor displaying exocrine and endocrine features in the same cell. It shows an adenocarcinoma-like cellular form and has endocrine granules. There are few reports describing chemotherapy for AmC. Here, we describe a case with metastatic AmC from the rectum that was treated with FOLFOXIRI chemotherapy. A 64-year-old man was diagnosed with a submucosal lesion on the scar produced after an endoscopic mucosal resection, which had been performed for adenocarcinoma of the rectum 2 years before. The endoscopic submucosal dissection revealed AmC. The abdominoperineal resection including lymph nodes dissection was performed. Thereafter, computed tomography showed multiple liver metastases, and FOLFOXIRI was administered. The best overall response was partial response, and progression-free survival was 8.7 months. After 16.0 months since first-line chemotherapy the patient died. We can therefore conclude that FOLFOXIRI may be effective for AmC of the rectum.
Hematology Reference Intervals for Healthy Adults of the City of Sulaymaniyah, Iraq

Background Hematology laboratory analyses are essential in the diagnosis of and making decisions on clinical cases. Hematology results are only meaningful when reference made to a normal range of values for a particular population. These values are affected by race, diet, and lifestyle the society. Objective To establish the hematological reference values for adult residents of the city of Sulaymaniyah, Iraq. Methods Blood samples collected from 1133 healthy males and female volunteers were analyzed for complete blood count, serum iron, and vitamin B12 concentrations. After applying the exclusion criteria, the hematology results from 762 individuals comprising 313 males and 449 males were included in the study. Results The mean red blood cell count, hemoglobin concentration, hematocrit, and serum iron concentration were higher in males than females while the neutrophil and platelet counts and plateletcrit were higher in females than males. Conclusion This study for the first time recorded hematological reference intervals for residents of the city of Sulaymaniyah.
Physiologic Decompression of Lumbar Spinal Stenosis Through Anatomic Restoration Using Trans-Kambin Oblique Lateral Posterior Lumbar Interbody Fusion (OLLIF): A Retrospective Analysis

Introduction Lumbar spinal stenosis (LSS) is one of the most common indications for spinal surgery. Traditionally, decompression is achieved by removing bony and ligamentous structures through open surgery. However, recent studies have shown that symptomatic relief can be accomplished in many patients by increasing intervertebral and interpedicular height using fusion alone. In this study, we evaluate whether trans-Kambin oblique lateral lumbar interbody fusion (OLLIF) can effectively and safely relieve symptoms of LSS when an indication for fusion is present. Methods This is a retrospective single surgeon cohort study of 187 patients with LSS who underwent 189 OLLIF procedures between 2012 and August 2, 2019. Inclusion criteria for this study were age >18 years with symptoms of LSS, including pain, sensory, and motor deficits, and an additional indication for fusion, which included spondylolisthesis, degenerative disk disease, disk herniation, or scoliosis. Exclusion criteria were the bony obstruction of the approach, osteogenic spinal canal stenosis, large facet hypertrophy, and listhesis grade II or greater. The primary outcome was a change in the Oswestry Disability Index (ODI) one year after surgery. Secondary outcomes were the resolution of radiculopathy at the first follow-up visit and one year after surgery, complication rates, surgery time, blood loss, and hospital stay. Results ODI improved from 52% pre-op to 37% at the one-year follow-up. At the first follow-up, radiculopathy had resolved in 39% of patients, and 72% of patients experienced improvement of 50% or greater. One year after surgery, radiculopathy had resolved in 52% of patients and 74% experienced improvement of 50% or greater. Single-level surgeries required 56.4±21.5 minutes, with a mean hospital stay of 1.6‑±2.4 days. Nerve irritation occurred in 12% of patients at the first postoperative follow-up and persisted in 6.8% of patients one year after surgery. There was one case each of persistent weakness at one year, infection, and cage subsidence. Conclusion Trans-Kambin OLLIF delivers anatomic restoration of intradiscal and interpedicular distance, which results in physiologic decompression of lumbar spinal stenosis in patients undergoing lumbar fusion for degenerative or herniated disk disease, spondylolisthesis, or scoliosis. Amongst patients with LSS, OLLIF results in significant improvement of radiculopathy and patient-reported disability in the majority of patients with low rates of long-term complications. Unlike other minimally invasive surgery (MIS) fusions, OLLIF can be safely used from T12-S1.
Incidental detection of colorectal lesions on 18 F-FDG-PET/CT is associated with high proportion of malignancy: A study in 549 patients

Abstract Background and study aims Further diagnostics of incidental colorectal lesions on 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) is questionable. Therefore, we aimed to evaluate the clinical importance of incidentally detected colorectal lesions on FDG-PET/CT. Patients and methods In the North Denmark Region, a retrospective study was performed among 19,987 patients who had an FDG-PET/CT from January 2006 to December 2015. Among these patients, we identified patients with a colonoscopy within 12 months from the PET/CT scan and a description of incidental colorectal PET-avid lesions on the PET/CT. PET findings were compared with colonoscopy-detected lesions and eventually histopathology. Results Incidental PET-avid lesions were observed in 549 patients. Colonoscopy revealed lesions in 457 (83 %), among whom 338 patients had a final histopathological diagnosis. Malignant and premalignant lesions were found in 297 patients (54 % among patients with a PET-avid lesion). The lesions were cancer in 76 patients and adenoma in 221 patients of whom 30 had high-grade and 191 low-grade adenomas. The findings changed patient management in 166 cases (30 % of all patients with a PET-avid lesion). A colonoscopy-based surveillance program was initiated for 80 % of patients with high-grade adenoma. No patients with PET-avid lesions but normal colonoscopy developed colorectal cancer during 3 years of observation (median observation time 7 years). Conclusions Incidental colorectal FDG uptake was infrequently observed, but when present, it was associated with a high rate of malignant or premalignant lesions. Our results indicate that patients with incidental colorectal FDG uptake should be referred to diagnostic work-up including colonoscopy.
Severe Pancytopenia Induced by Valproic Acid

Valproic acid is commonly used to treat pediatric epilepsy. This drug is usually well-tolerated; its side effects are typically mild, with hepatotoxicity being the most widely recognized one. Bone marrow suppression is a rarely seen complication in patients with valproic acid levels more than 125 mcg/mL. Reported cases indicate an increased incidence of hematologic toxicity; however, evidence for management is limited. We report a case of bone marrow suppression induced by a high dose of valproic acid in a 10-year-old male.
EUS-guided intrahepatic biliary drainage: a large retrospective series and subgroup comparison between percutaneous drainage in hilar stenoses or postsurgical anatomy

Abstract Background and study aims Endoscopic ultrasound-guided intrahepatic biliary drainage (EUS-IBD) struggles to find a place in management algorithms, especially compared to percutaneous drainage (PTBD). In the setting of hilar stenoses or postsurgical anatomy data are even more limited. Patients and methods All consecutive EUS-IBDs performed in our tertiary referral center between 2012 – 2019 were retrospectively evaluated. Rendez-vous (RVs), antegrade stenting (AS) and hepatico-gastrostomies (HGs) were compared. The predefined subgroup of EUS-IBD patients with proximal stenosis/surgically-altered anatomy was matched 1:1 with PTBD performed for the same indications. Efficacy, safety and events during follow-up were compared. Results One hundred four EUS-IBDs were included (malignancies = 87.7 %). These consisted of 16 RVs, 43 ASs and 45 HGs. Technical and clinical success rates were 89.4 % and 96.2 %, respectively. Any-degree, severe and fatal adverse events (AEs) occurred in 23.3 %, 2.9 %, and 0.9 % respectively. Benign indications were more common among RVs while proximal stenoses, surgically-altered anatomy, and disconnected left ductal system among HGs. Procedures were shorter with HGs performed with specifically designed stents (25 vs. 48 minutes, P = 0.004) and there was also a trend toward less dysfunction with those stents (6.7 % vs. 30 %, P = 0.09) compared with previous approaches. Among patients with proximal stenosis/surgically-altered anatomy, EUS-IBD vs. PTBD showed higher rates of clinical success (97.4 % vs. 79.5 %, P = 0.01), reduced post-procedural pain (17.8 % vs. 44.4 %, p = 0.004), shorter median hospital stay (7.5 vs 11.5 days, P = 0.01), lower rates of stent dysfunction (15.8 % vs. 42.9 %, P = 0.01), and the mean number of reinterventions was lower (0.4 vs. 2.8, P < 0.0001). Conclusions EUS-IBD has high technical and clinical success with an acceptable safety profile. HGs show comparable outcomes, which are likely to further improve with dedicated tools. For proximal strictures and surgically-altered anatomy, EUS-IBD seems superior to PTBD.
Limiting DNA polymerase delta alters replication dynamics and leads to a dependence on checkpoint activation and recombination-mediated DNA repair

DNA polymerase delta (Pol δ) plays several essential roles in eukaryotic DNA replication and repair. At the replication fork, Pol δ is responsible for the synthesis and processing of the lagging-strand. At replication origins, Pol δ has been proposed to initiate leading-strand synthesis by extending the first Okazaki fragment. Destabilizing mutations in human Pol δ subunits cause replication stress and syndromic immunodeficiency. Analogously, reduced levels of Pol δ in Saccharomyces cerevisiae lead to pervasive genome instability. Here, we analyze how the depletion of Pol δ impacts replication origin firing and lagging-strand synthesis during replication elongation in vivo in S. cerevisiae. By analyzing nascent lagging-strand products, we observe a genome-wide change in both the establishment and progression of replication. S-phase progression is slowed in Pol δ depletion, with both globally reduced origin firing and slower replication progression. We find that no polymerase other than Pol δ is capable of synthesizing a substantial amount of lagging-strand DNA, even when Pol δ is severely limiting. We also characterize the impact of impaired lagging-strand synthesis on genome integrity and find increased ssDNA and DNA damage when Pol δ is limiting; these defects lead to a strict dependence on checkpoint signaling and resection-mediated repair pathways for cellular viability. SIGNIFICANCE STATEMENT DNA replication in eukaryotes is carried out by the replisome – a multi-subunit complex comprising the enzymatic activities required to generate two intact daughter DNA strands. DNA polymerase delta (Pol δ) is a multi-functional replisome enzyme responsible for synthesis and processing of the lagging-strand. Mutations in Pol δ cause a variety of human diseases: for example, destabilizing mutations lead to immunodeficiency. We titrate the concentration of Pol δ in budding yeast – a simple model eukaryote with conserved DNA replication machinery. We characterize several replication defects associated with Pol δ scarcity. The defects we observe provide insight into how destabilizing Pol δ mutations lead to genome instability.
Broadening the ecology of fear: non-lethal effects arise from diverse responses to predation and parasitism

The ecology of fear demonstrates how prey responses to avoid predation cause non-lethal effects at all ecological scales. Parasites also elicit defensive responses in hosts with associated non-lethal effects, which raises the longstanding, yet unresolved question of how non-lethal effects of parasites compare with those of predators. We developed a framework for systematically answering this question for all types of predator and parasite systems. Our framework predicts that trait responses and their non-lethal effects should be strongest from predators and parasites that do not kill individuals to feed on them, but which nevertheless damage fitness. Analysing trait response data on amphibians, which have been well-studied for this area of research, showed that individuals generally responded more directly to short-term predation risks than to parasitism. Apart from studies using amphibians, there have been few direct comparisons of responses to predation and parasitism, and none have incorporated responses to micropredators, parasitoids, or parasitic castrators, or examined their long-term consequences. Addressing these and other data gaps highlighted by our general framework can advance the field toward understanding how non-lethal effects shape real food webs, which contain multiple predator and parasite species.