bluuebunny/crossref_metadata_2025_split huggingface dataset:
DNA methylation variation along the cancer epigenome and the identification of novel epigenetic driver events
Authors: Heery Richard , Schaefer Martin H 
Published: November 2021

Abstract
While large-scale studies applying various statistical approaches have identified hundreds of mutated driver genes across various cancer types, the contribution of epigenetic changes to cancer remains more enigmatic. This is partly due to the fact that certain regions of the cancer genome, due to their genomic and epigenomic properties, are more prone to dysregulated DNA methylation than others. Thus, it has been difficult to distinguish which promoter methylation changes are really driving carcinogenesis from those that are mostly just a reflection of their genomic location. By developing a novel method that corrects for epigenetic covariates, we reveal a small, concise set of potential epigenetic driver events. Interestingly, those changes suggest different modes of epigenetic carcinogenesis: first, we observe recurrent inactivation of known cancer genes across tumour types suggesting a higher convergence on common tumour suppressor pathways than previously anticipated. Second, in prostate cancer, a cancer type with few recurrently mutated genes, we demonstrate how the epigenome primes tumours towards higher tolerance of other aberrations.
Management of obesity in kidney transplant candidates and recipients: A clinical practice guideline by the DESCARTES Working Group of ERA
Authors: Oniscu Gabriel C , Abramowicz Daniel , Bolignano Davide , Gandolfini Ilaria , Hellemans Rachel , Maggiore Umberto , Nistor Ionut , O'Neill Stephen , Sever Mehmet Sukru , Koobasi Muguet , Nagler Evi V 
Published: November 2021

ABSTRACT
The clinical practice guideline Management of Obesity in Kidney Transplant Candidates and Recipients was developed to guide decision-making in caring for people with end-stage kidney disease (ESKD) living with obesity. The document considers the challenges in defining obesity, weighs interventions for treating obesity in kidney transplant candidates as well as recipients and reflects on the impact of obesity on the likelihood of wait-listing as well as its effect on transplant outcomes. It was designed to inform management decisions related to this topic and provide the backdrop for shared decision-making. This guideline was developed by the European Renal Association’s Developing Education Science and Care for Renal Transplantation in European States working group. The group was supplemented with selected methodologists to supervise the project and provide methodological expertise in guideline development throughout the process. The guideline targets any healthcare professional treating or caring for people with ESKD being considered for kidney transplantation or having received a donor kidney. This includes nephrologists, transplant physicians, transplant surgeons, general practitioners, dialysis and transplant nurses. Development of this guideline followed an explicit process of evidence review. Treatment approaches and guideline recommendations are based on systematic reviews of relevant studies and appraisal of the quality of the evidence and the strength of recommendations followed the Grading of Recommendations Assessment, Development and Evaluation approach. Limitations of the evidence are discussed and areas of future research are presented.
Infectious Disease Images: A Remarkable, Free Resource
Authors: Radcliffe Christopher , Grant Matthew 
Published: November 2021

Abstract
Infectious Disease Images (idimages.org) features several hundred with a vast array of diagnoses. The website is organized by cases and images and boasts an atlas with scores of bacteria, viruses, fungi, parasites, and ectoparasites. As a free resource, Infectious Disease Images lends itself nicely to both learners and educators at all levels.
Can we harness digital technologies and physiology to hasten genetic gain in US maize breeding?
Authors: Diepenbrock Christine H , Tang Tom , Jines Michael , Technow Frank , Lira Sara , Podlich Dean , Cooper Mark , Messina Carlos 
Published: November 2021

Abstract
Plant physiology can offer invaluable insights to accelerate genetic gain. However, translating physiological understanding into breeding decisions has been an ongoing and complex endeavor. Here we demonstrate an approach to leverage physiology and genomics to hasten crop improvement. A half-diallel maize (Zea mays) experiment resulting from crossing 9 elite inbreds was conducted at 17 locations in the USA corn belt and 6 locations at managed stress environments between 2017 and 2019 covering a range of water environments from 377 to 760 mm of evapotranspiration and family mean yields from 542 to 1,874 g m−2. Results from analyses of 35 families and 2,367 hybrids using crop growth models linked to whole-genome prediction (CGM–WGP) demonstrated that CGM–WGP offered a predictive accuracy advantage compared to BayesA for untested genotypes evaluated in untested environments (r = 0.43 versus r = 0.27). In contrast to WGP, CGMs can deal effectively with time-dependent interactions between a physiological process and the environment. To facilitate the selection/identification of traits for modeling yield, an algorithmic approach was introduced. The method was able to identify 4 out of 12 candidate traits known to explain yield variation in maize. The estimation of allelic and physiological values for each genotype using the CGM created in silico phenotypes (e.g. root elongation) and physiological hypotheses that could be tested within the breeding program in an iterative manner. Overall, the approach and results suggest a promising future to fully harness digital technologies, gap analysis, and physiological knowledge to hasten genetic gain by improving predictive skill and definition of breeding goals.
Reinforcement of CHH methylation through RNA-directed DNA methylation ensures sexual reproduction in rice
Authors: Wang Lili , Zheng Kezhi , Zeng Longjun , Xu Dachao , Zhu Tianxin , Yin Yumeng , Zhan Huadong , Wu Yufeng , Yang Dong-Lei 
Published: November 2021

Abstract
DNA methylation is an important epigenetic mark that regulates the expression of genes and transposons. RNA-directed DNA methylation (RdDM) is the main molecular pathway responsible for de novo DNA methylation in plants. Although the mechanism of RdDM has been well studied in Arabidopsis (Arabidopsis thaliana), most mutations in RdDM genes cause no remarkable developmental defects in Arabidopsis. Here, we isolated and cloned Five Elements Mountain 1 (FEM1), which encodes RNA-dependent RNA polymerase 2 (OsRDR2) in rice (Oryza sativa). Mutation in OsRDR2 abolished the accumulation of 24-nt small interfering RNAs, and consequently substantially decreased genome-wide CHH (H = A, C, or T) methylation. Moreover, male and female reproductive development was disturbed, which led to sterility in osrdr2 mutants. We discovered that OsRDR2-dependent DNA methylation may regulate the expression of multiple key genes involved in stamen development, meiosis, and pollen viability. In wild-type (WT) plants but not in osrdr2 mutants, genome-wide CHH methylation levels were greater in panicles, stamens, and pistils than in seedlings. The global increase of CHH methylation in reproductive organs of the WT was mainly explained by the enhancement of RdDM activity, which includes OsRDR2 activity. Our results, which revealed a global increase in CHH methylation through enhancement of RdDM activity in reproductive organs, suggest a crucial role for OsRDR2 in the sexual reproduction of rice.
F-box protein EBF1 and transcription factor ABI5-like regulate banana fruit chilling-induced ripening disorder
Authors: Song Zunyang , Lai Xiuhua , Yao Yulin , Qin Jiajia , Ding Xiaochun , Zheng Qiuli , Pang Xuequn , Chen Weixin , Li Xueping , Zhu Xiaoyang 
Published: November 2021

Abstract
Cold stress adversely affects plant production, both qualitatively and quantitatively. Banana (Musa acuminata) is sensitive to cold stress and suffers chilling injury (CI) when stored under 11°C, causing abnormal fruit softening. However, the mechanism underlying the abnormal fruit softening due to CI remains obscure. This study uncovered the coordinated transcriptional mechanism of ethylene F-box (EBF1) protein and abscisic acid-insensitive 5 (ABI5)-like protein in regulating chilling-induced softening disorders of Fenjiao banana. Cold stress severely inhibited the transcript and protein levels of EBF1, ABI5-like, and fruit softening-related genes. The ABI5-like protein bound to the promoters of key starch and cell wall degradation-related genes such as β-amylase 8 (BAM8), pectate lyase 8 (PL8), and β-D-xylosidase23-like (XYL23-like) and activated their activities. EBF1 physically interacted with ABI5-like and enhanced the transcriptional activity of the key starch and cell wall degradation-related genes but did not ubiquitinate or degrade ABI5-like protein. This promoted fruit ripening and ameliorated fruit CI in a manner similar to the effect of exogenous abscisic acid treatment. The ectopic and transient overexpression of EBF1 and ABI5-like genes in tomato (Solanum lycopersicum) and Fenjiao banana accelerated fruit ripening and softening by promoting ethylene production, starch and cell wall degradation, and decreasing fruit firmness. EBF1 interacted with EIL4 but did not ubiquitinate or degrade EIL4, which is inconsistent with the typical role of EBF1/2 in Arabidopsis (Arabidopsis thaliana). These results collectively highlight that the interaction of EBF1 and ABI5-like controls starch and cell wall metabolism in banana, which is strongly inhibited by chilling stress, leading to fruit softening and ripening disorder.
An in situ sequencing approach maps PLASTOCHRON1 at the boundary between indeterminate and determinate cells
Authors: Laureyns Reinout , Joossens Jessica , Herwegh Denia , Pevernagie Julie , Pavie Benjamin , Demuynck Kirin , Debray Kevin , Coussens Griet , Pauwels Laurens , Van Hautegem Tom , Bontinck Michiel , Strable Josh , Nelissen Hilde 
Published: November 2021

Abstract
The plant shoot apex houses the shoot apical meristem, a highly organized and active stem-cell tissue where molecular signaling in discrete cells determines when and where leaves are initiated. We optimized a spatial transcriptomics approach, in situ sequencing (ISS), to colocalize the transcripts of 90 genes simultaneously on the same section of tissue from the maize (Zea mays) shoot apex. The RNA ISS technology reported expression profiles that were highly comparable with those obtained by in situ hybridizations (ISHs) and allowed the discrimination between tissue domains. Furthermore, the application of spatial transcriptomics to the shoot apex, which inherently comprised phytomers that are in gradual developmental stages, provided a spatiotemporal sequence of transcriptional events. We illustrate the power of the technology through PLASTOCHRON1 (PLA1), which was specifically expressed at the boundary between indeterminate and determinate cells and partially overlapped with ROUGH SHEATH1 and OUTER CELL LAYER4 transcripts. Also, in the inflorescence, PLA1 transcripts localized in cells subtending the lateral primordia or bordering the newly established meristematic region, suggesting a more general role of PLA1 in signaling between indeterminate and determinate cells during the formation of lateral organs. Spatial transcriptomics builds on RNA ISH, which assays relatively few transcripts at a time and provides a powerful complement to single-cell transcriptomics that inherently removes cells from their native spatial context. Further improvements in resolution and sensitivity will greatly advance research in plant developmental biology.
The a Priori Truth of Modal Rationalism
Authors: Cleeveley Harry 
Published: November 2021

AbstractModal rationalism is the claim that for any proposition p, if it is ideally conceivable that p, then there is a metaphysically possible world, W, in which p is true. If true, modal rationalism must itself be an a priori truth. Moreover, modal rationalism is true just if there are no strong a posteriori necessities. But are there any strong necessities? In this paper, I set out a transcendental argument to show that there cannot be any, because they are not genuinely conceivable. I argue that if it were ideally conceivable that there are strong necessities, then it would be impossible for us to have any modal knowledge of the world. Given that we do have some modal knowledge of the world, it follows that strong necessities are not ideally conceivable and therefore that modal rationalism itself is an a priori truth.
Measurement and Mitigation of Intracochlear Pressure Transients During Cochlear Implant Electrode Insertion
Authors: Banakis Hartl Renee M. , Greene Nathaniel T. 
Published: November 2021

Hypothesis:
High intracochlear pressure transients associated with cochlear implant placement are reduced with smaller, non-styleted arrays, and longer insertion durations.

Background:
With increasing focus on hearing preservation during cochlear implant surgery, atraumatic technique is of the utmost importance. Previous studies revealed that high intensity pressure transients can be generated during the insertion of implant electrodes. Resulting acoustic trauma may be one contributing factor to postoperative loss of residual hearing.

Methods:
Thirty ears in cadaveric specimens were surgically prepared with placement of intracochlear pressure sensors. Sequential implant insertions were made over 10, 30, or 60 seconds using seven randomly ordered electrode styles. Pressures were also measured during common post-insertion electrode manipulations and removal. Measurements were compared between electrode styles and characteristics using analysis of variance (ANOVA) and Pearson correlation.

Results:
Implant insertion and post-insertion manipulations produced high-intensity pressure transients with all electrodes tested, with some measurements exceeding 170 dB peak SPL. Average peak pressures were significantly lower for straight, non-stylet electrodes (p << 0.001). The likelihood of generating transients was lowest with the slowest insertions (p << 0.001).

Conclusions:
Cochlear implant insertion can generate transients in intralabyrinthine pressure levels equivalent to high intensity, impulsive acoustic stimuli known to cause hearing loss. Although transients were observed in all conditions, exposure may be mitigated by using non-styleted electrodes and slow insertion speeds. Additional surgical manipulations can also produce similar high-pressure events. Results from this investigation suggest that use of non-styleted electrodes, slow but steady insertion speeds, and avoidance of post-insertional manipulations are important to reduce cochlear trauma.
Resorbable Synthetic Ventral Hernia Repair in Contaminated Fields: Outcomes with Poly-4-Hydroxybutyrate Mesh
Authors: Christopher Adrienne N. , Morris Martin P. , Jia Hanna , Broach Robyn , Fischer John P. 
Published: November 2021

Background:
Hernia repair in the setting of contamination poses unique challenges, including complications such as recurrence and mesh infection. The ideal contaminated hernia repair including type of mesh use remains controversial. Poly-4-hydroxybutyrate is a biosynthetic scaffold for soft-tissue reinforcement and hernia repair and is potentially useful in contaminated hernia repair. The authors aim to describe postoperative outcomes, recurrence, and patient-reported outcomes after contaminated hernia repair with poly-4-hydroxybutyrate.

Methods:
Adult patients (≥18 years) undergoing a contaminated hernia repair with poly-4-hydroxybutyrate (Phasix) performed by a single plastic surgeon between January of 2015 and May of 2020 were identified. Patients with a ventral hernia defect and a Centers for Disease Control and Prevention wound class of II, III, or IV were included. Primary outcomes included recurrence, surgical-site infection, surgical-site occurrences, and surgical-site infection/occurrences requiring procedural interventions. As a secondary outcome, the authors assessed patient-reported outcomes as defined by the Abdominal Hernia-Q and Hernia-Related Quality of Life Survey.

Results:
Sixty patients were included with a median age of 52.5 and body mass index of 31 kg/m2. Median defect size was 300 cm2. Twenty-eight patients (46.7 percent) experienced a complication. The most common complications were surgical-site occurrence [n = 20 (33.3 percent)] and surgical-site infection [n = 10 (16.7 percent)]. Median follow-up was 24.2 months, with a recurrence rate of 8.3 percent (n = 4). Overall patient-reported outcomes improved postoperatively, and improvement was not affected by the presence of a complication.

Conclusions:
Poly-4-hydroxybutyrate use in contaminated hernia repair shows promising results with an acceptable safety profile. Although complications are frequent in this complex cohort, patient-reported outcomes improvement was significant even in patients with complications.

CLINICAL QUESTION/LEVEL OF EVIDENCE:
Therapeutic, IV.
An Update on the Diagnosis, Treatment, and Management of Occipital Neuralgia
Authors: Swanson Daniel , Guedry Ryan , Boudreaux Megan , Muhlenhaupt Emily , Kaye Alan D. , Viswanath Omar , Urits Ivan 
Published: November 2021

Abstract
This report intends to summarize the underlying pathophysiology, relevant symptoms, appropriate diagnostic workup, necessary imaging, and medical and surgical treatments of occipital neuralgia (ON). This was done through a comprehensive literature review of peer-reviewed literature throughout the most relevant databases. The current understanding of ON is that it causes neuropathic pain in the distribution of the greater occipital nerve, the lesser occipital nerve, the third occipital nerve or a combination of the 3. It is currently a subset of headaches although there is some debate if ON should be its own condition. Occipital neuralgia causes chronic, sharp, stabbing pain in the upper neck, back of the head, and behind the ears that can radiate to the front of the head. Diagnosis is typically clinical and patients present with intermittent, painful episodes associated with the occipital region and the nerves described above. Most cases are unilateral pain, however bilateral pain can be present and the pain can radiate to the frontal region and face. Physical examination is the first step in management of this disease and patients may demonstrate tenderness over the greater occipital and lesser occipital nerves. Anesthetics like 1% to 2% lidocaine or 0.25% to 0.5% bupivacaine can be used to block these nerves and antiinflammatory drugs like corticosteroids can be used in combination to prevent compressive symptoms. Other treatments like botulinum toxin and radiofrequency ablation have shown promise and require more research. Surgical decompression through resection of the obliquus capitis inferior is the definitive treatment however there are significant risks associated with this procedure.
Shock-Induced Endothelial Dysfunction is Present in Patients With Occult Hypoperfusion After Trauma
Authors: Kregel Heather R. , Hatton Gabrielle E. , Isbell Kayla D. , Henriksen Hanne H. , Stensballe Jakob , Johansson Per I. , Kao Lillian S. , Wade Charles E. 
Published: November 2021

ABSTRACT

Background:
Shock-induced endothelial dysfunction, evidenced by elevated soluble thrombomodulin (sTM) and syndecan-1 (Syn-1), is associated with poor outcomes after trauma. The association of endothelial dysfunction and overt shock has been demonstrated; it is unknown if hypoperfusion in the setting of normal vital signs (occult hypoperfusion [OH]) is associated with endothelial dysfunction. We hypothesized that sTM and Syn-1 would be elevated in patients with OH when compared to patients with normal perfusion.

Methods:
A single-center study of patients requiring highest-level trauma activation (2012–2016) was performed. Trauma bay arrival plasma Syn-1 and sTM were measured by enzyme-linked immunosorbent assay. Shock was defined as systolic blood pressure (SBP) <90 mm Hg or heart rate (HR) ≥120 bpm. OH was defined as SBP ≥ 90, HR < 120, and base excess (BE) ≤−3. Normal perfusion was assigned to all others. Univariate and multivariable analyses were performed.

Results:
Of 520 patients, 35% presented with OH and 26% with shock. Demographics were similar between groups. Patients with normal perfusion had the lowest Syn-1 and sTM, while patients with OH and shock had elevated levels. OH was associated with increased sTM by 0.97 ng/mL (95% CI 0.39–1.57, p = 0.001) and Syn-1 by 14.3 ng/mL (95% CI −1.5 to 30.2, p = 0.08). Furthermore, shock was associated with increased sTM by 0.64 (95% CI 0.02–1.30, p = 0.04) and with increased Syn-1 by 23.6 ng/mL (95% CI 6.2–41.1, p = 0.008).

Conclusions:
Arrival OH was associated with elevated sTM and Syn-1, indicating endothelial dysfunction. Treatments aiming to stabilize the endothelium may be beneficial for injured patients with evidence of hypoperfusion, regardless of vital signs.
Phenotypic distinctions of BLM- and RMI1-associated Bloom syndrome
Authors: Gönenc Ipek Ilgin , Elcioglu Nursel H. , Grijalva Carolina Martinez , Aras Seda , Großmann Nadine , Praulich Inka , Altmüller Janine , Kaulfuß Silke , Li Yun , Nürnberg Peter , Burfeind Peter , Yigit Gökhan , Wollnik Bernd 
Published: November 2021

AbstractBloom syndrome (BS) is an autosomal recessive disease with characteristic clinical features of primary microcephaly, growth deficiency, skin lesions, cancer predisposition, and immunodeficiency. Here, we report the clinical and molecular findings of eight patients from six families diagnosed with BS. We identified causative mutations in all families, three different homozygous mutations in BLM and one causative homozygous mutation in RMI1. The homozygous c.581_582delTT (p.Phe194*) and c.3164G>C (p.Cys1055Ser) mutations in BLM have already been reported in BS patients, while the c.572_573delGA (p.Arg191Lysfs*4) is novel. Interestingly, whole-exome sequencing revealed a homozygous loss-of-function mutation in RMI1 in two BS patients of a consanguineous Turkish family. All BS patients had primary microcephaly, intrauterine growth delay, and short stature, presenting the phenotypic hallmarks of BS. However, a narrow face, skin lesions, and upper airway infections were observed only in some of the patients. Overall, patients with homozygous BLM mutations had a more severe BS phenotype compared to patients carrying the homozygous RMI1 mutation, especially in terms of immunodeficiency and associated recurrent infections. Low-level immunoglobulins were observed in all BLM-mutated patients, emphasizing the immunodeficiency profile of the disease, which should be considered as an important phenotypic characteristic of BS, especially in the current Covid-19 pandemic era.