bluuebunny/crossref_metadata_2025 huggingface dataset:
When to Remove the Indwelling Catheter After Minimally Invasive Sacrocolpopexy? CARESS (CAtheter REmoval after Sacrocolpopexy Surgery)
Authors: Aslam Muhammad Faisal , Bazzi Ali A. , Hagglund Karen H. , Osmundsen Blake C.
Published: January 2020

Objective

The aim of the study was to determine the best practice guidelines regarding the use of indwelling catheters after minimally invasive sacrocolpopexy.

Methods

Multicenter (3 sites) randomized control trial comparing the standard overnight indwelling urethral catheterization (group 2) with removal of catheter immediately after surgery (group 1). Our primary outcome is the need for recatheterization. Secondary outcomes include the number of patients discharged with a catheter, length of hospital stay, number of urinary tract infections, patient satisfaction/pain scores, and whether patients would use the same treatment again.

Results

There were 32 patients (43.8%) in group 1 and 41 patients (56.2%) in group 2. On average, patients in group 1 required straight catheterization 0.8 (SD = 0.9) times versus 0.6 (SD = 0.9) times for group 2 (P = 0.239). The number of days with a catheter between the 2 groups was not statistically significant. There was no statistical significance between group 1 and group 2 in terms of operative time, times to leave the operating room, and hospital. Zero patients in group 1 and 2 patients in group 2 had a urinary tract infection. After dividing the groups based on whether or not they underwent a transvaginal tape procedure, the final results were similar.

Conclusions

We did not observe a difference in the risk of recatheterization or discharge home with a urinary catheter between the 2 groups. Addition of transvaginal tape to sacrocolpopexy did not show a difference in the risk of recatheterization. One reason for the lack of difference between the 2 groups could be due to a lack of power in our study.
Is Fluid Intake Associated With Fecal Incontinence in Women?
Authors: Halani Priyanka Kadam , Harvie Heidi S. , Arya Lily A. , Andy Uduak U.
Published: January 2020

Objective

The primary aim of this study was to determine if fecal incontinence (FI) is associated with self-reported fluid intake in women seeking care for pelvic floor disorders. The secondary aim was to determine the association between bowel symptoms and fluids associated with FI.

Methods

We conducted a retrospective cross-sectional study of women presenting for evaluation of pelvic floor disorders from 2009 to 2015. The presence of FI was defined as an affirmative response of any frequency to the question, “During the last 4 weeks, how often have you leaked or soiled yourself with stool?” Data on fluid intake and bowel symptoms were collected using the Questionnaire-based Voiding Diary and Colorectal-Anal Distress Inventory short form, respectively. The relationship between FI and quartiles of fluid intake, as well as the relationship between bowel symptoms and fluids associated with FI, was analyzed.

Results

Nine hundred twenty-four women were included: 379 (41%) with and 545 (59%) without FI. There was an association between FI and increasing total carbonated fluid intake (P = 0.009) and decreasing water intake (P = 0.009). The associations between FI and carbonated fluid intake and FI and water intake remained significant after controlling for patient characteristics (P < 0.05). There was a significant association between the symptom of straining to defecate and carbonated beverage intake (P = 0.046), which remained significant after controlling for patient characteristics (P < 0.001).

Conclusions

Consumption of carbonated beverages is associated with FI in women. Intake of carbonated fluids is associated with bowel symptoms that may exacerbate FI symptoms.
Plasma proteomics reveals markers of metabolic stress in HIV infected children with severe acute malnutrition
Authors: Gonzales Gerard Bryan , Njunge James M , Gichuki Bonface M , Wen Bijun , Potani Isabel , Voskuijl Wieger , Bandsma Robert H J , Berkley James A
Published: January 2020

HIV infection affects up to 30% of children presenting with severe acute malnutrition (SAM) in Africa and is associated with increased mortality. Children with SAM are treated similarly regardless of HIV status, although mechanisms of nutritional recovery in HIV and/or SAM are not well understood. We performed a secondary analysis of a clinical trial and plasma proteomics data among children with complicated SAM in Kenya and Malawi. Compared to children with SAM without HIV (n = 113), HIV-infected children (n = 54) had evidence (false discovery rate (FDR) corrected p<0.05) of metabolic stress, including enriched pathways related to inflammation and lipid metabolism. Moreover, we observed reduced plasma levels of zinc-α-2-glycoprotein, butyrylcholinesterase, and increased levels of complement C2 resembling findings in metabolic syndrome, diabetes and other non-communicable diseases. HIV was also associated (FDR corrected p<0.05) with higher plasma levels of inflammatory chemokines. Considering evidence of biomarkers of metabolic stress, it is of potential concern that our current treatment strategy for SAM regardless of HIV status involves a high-fat therapeutic diet. The results of this study suggest a need for clinical trials of therapeutic foods that meet the specific metabolic needs of children with HIV and SAM.
Spinach Growers Value Host Resistance and Synthetic Fungicides in the Fight against Downy Mildew
Authors: Choudhury Robin A. , McRoberts Neil
Published: January 2020

California spinach growers struggle to manage spinach downy mildew disease. The disease is especially difficult in the organic crop, which currently relies on resistant varieties to maintain disease-free crop. Alternative control measures are available, but it is not clear how growers perceive the efficacy of these methods. It is also not clear who growers contact to find out information on spinach downy mildew disease management. In this study, we conducted an online survey of people involved in spinach production, asking about their beliefs in the efficacy of different control methods and who they contact frequently to discuss spinach downy mildew control. We found that respondents were most positive about the efficacy of resistant varieties and synthetic pesticides, with much lower perceived efficacy for the practices of disking diseased fields, roguing diseased plants, and organic pesticides. Growers most frequently contacted pest control advisors (PCAs) about management strategies for spinach downy mildew. These results suggest that respondents are most confident about the efficacy of resistant varieties and synthetic pesticides and may be hesitant to adopt new control strategies like organic pesticides. The results also suggest that future extension efforts can be focused on PCAs to reach the most stakeholders with up to date research on downy mildew control.
AMPK activation by metformin promotes survival of dormant ER+ breast cancer cells
Authors: Hampsch Riley A. , Wells Jason D. , Traphagen Nicole A. , McCleery Charlotte F. , Fields Jennifer L. , Shee Kevin , Dillon Lloye M. , Pooler Darcy B. , Lewis Lionel D. , Demidenko Eugene , Huang Yina H. , Marotti Jonathan D. , Kinlaw William B. , Miller Todd W.
Published: January 2020

Purpose

Despite adjuvant anti-estrogen therapy for patients with estrogen receptor alpha (ER)-positive breast cancer, dormant residual disease can persist for years and eventually cause tumor recurrence. We sought to deduce mechanisms underlying the persistence of dormant cancer cells to identify therapeutic strategies.

Experimental Design

Mimicking the aromatase inhibitor-induced depletion of estrogen levels used to treat patients, we developed preclinical models of dormancy in ER+ breast cancer induced by estrogen withdrawal in mice. We analyzed tumor xenografts and cultured cancer cells for molecular and cellular responses to estrogen withdrawal and drug treatments. Publicly available clinical breast tumor gene expression datasets were analyzed for responses to neoadjuvant anti-estrogen therapy.

Results

Dormant breast cancer cells exhibited upregulated 5’ adenosine monophosphate-activated protein kinase (AMPK) levels and activity, and upregulated fatty acid oxidation. While the anti-diabetes AMPK-activating drug metformin slowed the estrogen-driven growth of cells and tumors, metformin promoted the persistence of estrogen-deprived cells and tumors through increased mitochondrial respiration driven by fatty acid oxidation. Pharmacologic or genetic inhibition of AMPK or fatty acid oxidation promoted clearance of dormant residual disease, while dietary fat increased tumor cell survival.

Conclusions

AMPK has context-dependent effects in cancer, cautioning against the widespread use of an AMPK activator across disease settings. The development of therapeutics targeting fat metabolism is warranted in ER+ breast cancer.

Statement of Translational Relevance

Dormant cancer cells that survive adjuvant therapy can ultimately give rise to recurrent/advanced tumors that frequently develop resistance to all approved therapies. Patients with early-stage estrogen receptor alpha (ER)-positive breast cancer are typically treated with surgical resection followed by ≥5 years of adjuvant anti-estrogen therapy that neutralizes ER and suppresses, but often does not eliminate, tumor-initiating cells. Estrogen withdrawal, which mimics aromatase inhibitor therapy, induced activation of the metabolic sensor 5’ adenosine monophosphate-activated protein kinase (AMPK) and upregulated fatty acid oxidation (FAO) in preclinical models. Treatment with the anti-diabetes AMPK-activating drug metformin or high dietary fat intake promoted survival of dormant ER+ breast cancer cells, while anti-anginal drugs that inhibit FAO induced clearance of dormant tumor cells. These findings caution against using AMPK modulators with anti-estrogens in patients with ER+ breast cancer, and warrant testing of FAO inhibitors as anti-cancer agents in combination with anti-estrogens.
Anin vivostrategy for knockdown of circular RNAs
Authors: Pamudurti Nagarjuna Reddy , Patop Ines Lucia , Krishnamoorthy Aishwarya , Ashwal-Fluss Reut , Bartok Osnat , Kadener Sebastian
Published: January 2020

Exonic circular RNAs (circRNAs) are highly abundant and evolutionarily conserved RNAs generated mostly from exons of protein-coding genes. Assaying the functions of circRNAs is not straightforward as common approaches for circRNA depletion tend to also alter the levels of mRNAs generated from the hosting gene. Here we describe a methodology for specific knockdown of circRNAsin vivowith tissue and cell resolution. We also describe an experimental and computational platform for determining the potential off-target effects as well as for verifying the obtained phenotypes. Briefly, we utilize miRNA-derived shRNAs targeted to the circRNA-specific back-splice junction to specifically downregulate the circRNA. We utilized this methodology to downregulate five circRNAs that are highly expressed in the fly nervous system. There were no effects on levels of the linear RNA or any RNA with complementarity to the expressed shRNA. Interestingly, downregulation of circCtrip resulted in developmental lethality that was recapitulated with a second shRNA. Moreover, we found that downregulation of individual circRNAs caused specific changes in the fly head transcriptome, suggesting roles for these circRNAs in the fly nervous system. Together, our results provide a methodological approach that enables the comprehensive study of circRNAs at the organismal and cell levels.
Interpretable Clinical Genomics with a Likelihood Ratio Paradigm
Authors: Robinson Peter N. , Ravanmehr Vida , Jacobsen Julius O.B. , Danis Daniel , Zhang Xingmin Aaron , Carmody Leigh C. , Gargano Michael , Thaxton Courtney L. ,   UNC Biocuration Core, Reese Justin , Holtgrewe Manuel , Köhler Sebastian , McMurry Julie A. , Haendel Melissa A. , Smedley Damian
Published: January 2020

Human Phenotype Ontology (HPO)-based analysis has become standard for genomic diagnostics of rare diseases. Current algorithms use a variety of semantic and statistical approaches to prioritize the typically long lists of genes with candidate pathogenic variants. These algorithms do not provide robust estimates of the strength of the predictions beyond the placement in a ranked list, nor do they provide measures of how much any individual phenotypic observation has contributed to the prioritization result. However, given that the overall success rate of genomic diagnostics is only around 25–50% or less in many cohorts, a good ranking cannot be taken to imply that the gene or disease at rank one is necessarily a good candidate. Likelihood ratios (LR) are statistics for summarizing diagnostic accuracy, providing a measure of how much more (or less) a patient with a disease has a particular test result compared to patients without the disease. Here, we present an approach to genomic diagnostics that exploits the LR framework to provide an estimate of (1) the posttest probability of candidate diagnoses; (2) the LR for each observed HPO phenotype, and (3) the predicted pathogenicity of observed genotypes. LIkelihood Ratio Interpretation of Clinical AbnormaLities (LIRICAL) placed the correct diagnosis within the first three ranks in 92.9% of 384 cases reports comprising 262 Mendelian diseases, with the correct diagnosis having a mean posttest probability of 67.3%. Simulations show that LIRICAL is robust to many typically encountered forms of genomic and phenomic noise. In summary, LIRICAL provides accurate, clinically interpretable results for phenotype-driven genomic diagnostics.
Non-pharmacological management of Alzheimer’s disease a qualitative study, in Mauritius
Authors: Goorah Smita , Dorkhy Geeta Devi
Published: January 2020

Introduction

The major form of dementia is Alzheimer’s disease (AD). In Mauritius it was estimated in 2015 that around 10,000 persons had Alzheimer’s disease from Alzheimer disease International report1. This represent 16% of the total population and it is expected to rise. Therefore, apart from pharmacological therapies, non-pharmacological treatment (NPT) which can improve cognitive performance such as cognitive training, occupational therapy, reminiscence therapy, are being highly investigated.

Aim and objective

To determine the outcome(s) and to highlight the effective strategies in the management of Alzheimer’s Disease in Mauritius using NPT. Information obtained from this research will add to the current knowledge and expansion.

Materials and methods

The only NGO in Mauritius is “Alzheimer’s Association”, from where the persons with AD were recruited. Non-interventional methods of qualitative study involving interviews of person with AD, lasting 30-45 minutes were audio-recorded. An informed consent from the carer or patient-relative prior to starting was ensured. Both semi-structured interviews and open-ended questions were used, relating to NPT. Thematic analysis in qualitative research, followed by coding and decoding raw data. Similar categories of data were grouped and themes emerged.

Results

In-depth responses of the person with AD related with their experiences, perceptions, opinions, feelings, and knowledge. Qualitative study (n=20) emerged with 6 main themes. Among these, dependency on family identified as an important theme. It has also been associated as an important form of cognitive and functional engagement for person with AD.

Discussion

Non-pharmacological interventions has an important role to prolong the active age of older individuals, as well as to maintain quality of life.

Conclusion

There is still a greater demand on the market for non-pharmacological interventions and Mauritius should plan and devise national guidelines to deal with this unmet proportion of elderly so as to curb for future health equality and stability.
Epidemiological identification of a novel infectious disease in real time: Analysis of the atypical pneumonia outbreak in Wuhan, China, 2019-20
Authors: Jung Sung-mok , Kinoshita Ryo , Thompson Robin N. , Hayashi Katsuma , Linton Natalie M. , Yang Yichi , Akhmetzhanov Andrei R. , Nishiura Hiroshi
Published: January 2020

Objective

Virological tests indicate that a novel coronavirus is the most likely explanation for the 2019-20 pneumonia outbreak in Wuhan, China. We demonstrate that non-virological descriptive characteristics could have determined that the outbreak is caused by a novel pathogen in advance of virological testing.

Methods

Characteristics of the ongoing outbreak were collected in real time from two medical social media sites. These were compared against characteristics of ten existing pathogens that can induce atypical pneumonia. The probability that the current outbreak is due to “Disease X” (i.e., previously unknown etiology) as opposed to one of the known pathogens was inferred, and this estimate was updated as the outbreak continued.

Results

The probability that Disease X is driving the outbreak was assessed as over 32% on 31 December 2019, one week before virus identification. After some specific pathogens were ruled out by laboratory tests on 5 Jan 2020, the inferred probability of Disease X was over 59%.

Conclusions

We showed quantitatively that the emerging outbreak of atypical pneumonia cases is consistent with causation by a novel pathogen. The proposed approach, that uses only routinely-observed non-virological data, can aid ongoing risk assessments even before virological test results become available.
Evaluation of the accuracy of a smartphone-based artificial intelligence system, PlantVillageNuru,in diagnosing of the viral diseases of cassava
Authors: Mrisho Latifa , Mbilinyi Neema , Ndalahwa Mathias , Ramcharan Amanda , Kehs Annalyse , McCloskey Peter , Murithi Harun , Hughes David , Legg James
Published: January 2020

Premise of the study

Nuruis an artificial intelligence system for diagnosis of plant diseases and pests developed as a public good by PlantVillage (Penn State University), FAO, IITA and CIMMYT. It provides a simple, inexpensive and robust means of conducting in-field diagnosis without requiring internet connection and provides real-time results and advice. The present work evaluates the effectiveness ofNuruas an in-field diagnostic tool by comparing the diagnosis capability ofNuruto that of cassava experts (researchers trained on cassava pests and diseases), agricultural extension agents and farmers.

Methods

The diagnosis capability ofNuruand that of the assessed individuals was determined by inspecting cassava plants in-field and by using the cassava symptom recognition assessment tool (CaSRAT) to score images of cassava leaves.

Results

Nuru’s accuracy for symptom recognition when using six leaves (74 - 88%, depending on the condition) was similar to that of experts, 1.5-times higher than agricultural extension agents and two-times higher than farmers.

Discussion

These findings suggests that Nuru can be an effective tool for in-field diagnosis of cassava diseases and has a potential of being a quick and cost-effective means of disseminating knowledge from researchers to agricultural extension agents and farmers.
Full-genome evolutionary analysis of the novel corona virus (2019-nCoV) rejects the hypothesis of emergence as a result of a recent recombination event
Authors: Paraskevis D. , Kostaki E.G. , Magiorkinis G. , Panayiotakopoulos G. , Tsiodras S.
Published: January 2020

Background

A novel coronavirus (2019-nCoV) associated with human to human transmission and severe human infection has been recently reported from the city of Wuhan in China. Our objectives were to characterize the genetic relationships of the 2019-nCoV and to search for putative recombination within the subgenus of sarbecovirus.

Methods

Putative recombination was investigated by RDP4 and Simplot v3.5.1 and discordant phylogenetic clustering in individual genomic fragments was confirmed by phylogenetic analysis using maximum likelihood and Bayesian methods.

Results

Our analysis suggests that the 2019-nCoV although closely related to BatCoV RaTG13 sequence throughout the genome (sequence similarity 96.3%), shows discordant clustering with the Bat-SARS-like coronavirus sequences. Specifically, in the 5’-part spanning the first 11,498 nucleotides and the last 3’-part spanning 24,341-30,696 positions, 2019-nCoV and RaTG13 formed a single cluster with Bat-SARS-like coronavirus sequences, whereas in the middle region spanning the 3’-end of ORF1a, the ORF1b and almost half of the spike regions, 2019-nCoV and RaTG13 grouped in a separate distant lineage within the sarbecovirus branch.

Conclusions

The levels of genetic similarity between the 2019-nCoV and RaTG13 suggest that the latter does not provide the exact variant that caused the outbreak in humans, but the hypothesis that 2019-nCoV has originated from bats is very likely. We show evidence that the novel coronavirus (2019-nCov) is not-mosaic consisting in almost half of its genome of a distinct lineage within the betacoronavirus. These genomic features and their potential association with virus characteristics and virulence in humans need further attention.
DNA methylation derived immune cell profiles, CpG markers of inflammation, and pancreatic cancer risk
Authors: Michaud Dominique S. , Ruan Mengyuan , Koestler Devin C. , Alonso Lola , Molina-Montes Esther , Pei Dong , Marsit Carmen J. , De Vivo Immaculata , Malats Núria , Kelsey Karl T.
Published: January 2020

Pancreatic cancer is projected to become the second most common cause of cancer death over the next 5 years. Since inflammation is thought to be a common trajectory for disease initiation, we sought to prospectively characterize immune profiles using DNA methylation markers to examine whether they play a key role in pancreatic cancer risk. In a nested case-control study pooling three U.S. prospective cohort studies, DNA methylation was measured in prediagnostic leukocytes of incident pancreatic cancer cases and matched controls using the Illumina MethylationEPIC array. Differentially methylated regions were used to predict immune cell types and CpGs previously associated with blood inflammatory markers were selected for the analysis. DNA methylation data from a retrospective case-control study conducted in Spain (PanGenEU) was used for independent replication of results. Immune cell proportions and ratio of cell proportions were not associated with pancreatic cancer risk in the nested case-control study. Methylation extent of CpGs residing in or near gene MNDA was significantly associated with pancreatic cancer risk in the nested case-control study and replicated in PanGenEU. In the nested case-control study, the associations were present 10 or more years prior to cancer diagnosis. Methylation of a promoter CpG of gene PIM-1 was associated with pancreatic cancer survival in both studies. We identified several CpGs that may play a role in pancreatic carcinogenesis using a targeted approach for the selection of inflammation-based CpGs in two large, independent studies conducted in different countries with distinct study designs.
Evolution of vertebrate gill covers via shifts in an ancient Pou3f3 enhancer
Authors: Barske Lindsey , Fabian Peter , Hirschberger Christine , Jandzik David , Square Tyler , Xu Pengfei , Nelson Nellie , Yu Haoze Vincent , Medeiros Daniel M. , Gillis J. Andrew , Crump J. Gage
Published: January 2020

Whereas the gill chambers of extant jawless vertebrates (lampreys and hagfish) open directly into the environment, jawed vertebrates evolved skeletal appendages that promote the unidirectional flow of oxygenated water over the gills. A major anatomical difference between the two jawed vertebrate lineages is the presence of a single large gill cover in bony fishes versus separate covers for each gill chamber in cartilaginous fishes. Here we find that these divergent gill cover patterns correlate with the pharyngeal arch expression of Pou3f3 orthologs. We identify a Pou3f3 arch enhancer that is deeply conserved from cartilaginous fish through humans but undetectable in lampreys, with minor sequence differences in the bony versus cartilaginous fish enhancers driving the corresponding single versus multiple gill arch expression patterns. In zebrafish, loss of Pou3f3 gene function disrupts gill cover formation, and forced expression of Pou3f3b in the gill arches generates ectopic skeletal elements resembling the multiple gill cover pattern of cartilaginous fishes. Emergence of this Pou3f3 enhancer >430 mya and subsequent modifications may thus have contributed to the acquisition and diversification of gill covers and respiratory strategies during gnathostome evolution.
AVibrio choleraeCore Genome Multilocus Sequence Typing Scheme to Facilitate the Epidemiological Study of Cholera
Authors: Liang Kevin Y. H. , Orata Fabini D. , Islam Mohammad Tarequl , Nasreen Tania , Alam Munirul , Tarr Cheryl L. , Boucher Yann F.
Published: January 2020

Core genome multilocus sequence typing (cgMLST) has gained popularity in recent years in epidemiological research and subspecies level classification. cgMLST retains the intuitive nature of traditional MLST but offers much greater resolution by utilizing significantly larger portions of the genome. Here, we introduce a cgMLST scheme forVibrio cholerae, a bacterium abundant in marine and freshwater environments and the etiologic agent of cholera. A set of 2,443 core genes ubiquitous inV. choleraewere used to analyze a comprehensive dataset of 1,262 clinical and environmental strains collected from 52 countries, including 65 newly sequenced genomes in this study. We established a sublineage threshold based on 133 allelic differences that creates clusters nearly identical to traditional MLST types, providing backwards compatibility to new cgMLST classifications. We also defined an outbreak threshold based on seven allelic differences that is capable of identifying strains from the same outbreak and closely related isolates which could give clues on outbreak origin. Using cgMLST, we confirmed the South Asian origin of modern epidemics and identified clustering affinity among sublineages of environmental isolates from the same geographic origin. Advantages of this method are highlighted by direct comparison with existing classification methods, such as MLST and single nucleotide polymorphism-based methods. cgMLST outperforms all existing methods in terms of resolution, standardization, and ease-of-use. We anticipate this scheme will serve as a basis for a universally applicable and standardized classification system forV. choleraeresearch and epidemiological surveillance in the future. This cgMLST scheme is publicly available on PubMLST (https://pubmlst.org/vcholerae/).

IMPORTANCE

ToxigenicVibrio choleraeof the O1 and O139 serogroups are the causative agent of cholera, an acute diarrheal disease that plagued the world for centuries, if not millennia. Here, we introduce a core genome multilocus sequence typing (cgMLST) scheme forV. cholerae. Using cgMLST, we established an outbreak threshold that can efficiently identify outbreak related strains and potential sources of introduction. We also defined a sublineage threshold that is similar to traditional MLST sequence type which will provide context to this new typing method by relating it to previous MLST results. cgMLST outperforms all existing methods in terms of resolution, standardization, and ease-of-use, making this scheme the most suitable method forV. choleraetyping and surveillance worldwide.
Loss of function of the mitochondrial peptidase PITRM1 induces proteotoxic stress and Alzheimer’s disease-like pathology in human cerebral organoids
Authors: Ivanyuk Dina , Pérez María José , Panagiotakopoulou Vasiliki , Di Napoli Gabriele , Brunetti Dario , Al-Shaana Rawaa , Kaeser Stephan A. , Jucker Mathias , Zeviani Massimo , Viscomi Carlo , Deleidi Michela
Published: January 2020

Mutations in pitrilysin metallopeptidase 1 (PITRM1), a mitochondrial protease involved in mitochondrial precursor processing and degradation, result in a slow-progressive syndrome, characterized by cerebellar ataxia, psychotic episodes and obsessive behavior as well as cognitive decline. To investigate the pathogenetic mechanisms of mitochondrial presequence processing, we employed cortical neurons and cerebral organoids generated from PITRM1 knockout human induced pluripotent stem cells (iPSCs). PITRM1 deficiency strongly induced mitochondrial unfolded protein response (UPRmt) and enhanced mitochondrial clearance in iPSC-derived neurons. Furthermore, we observed increased levels of amyloid precursor protein and amyloid β in PITRM1 knockout neurons. However, neither cell death nor protein aggregates were observed in 2D iPSC-derived cortical neuronal cultures. On the contrary, cerebral organoids generated from PITRM1 knockout iPSCs spontaneously developed over time pathological features of Alzheimer’s disease (AD), including accumulation of protein aggregates, tau pathology, and neuronal cell death. Importantly, we provide evidence for a protective role of UPRmtand mitochondrial clearance against impaired mitochondrial presequence processing and proteotoxic stress. In summary, we propose a novel concept of PITRM1-linked neurological syndrome whereby defects of mitochondrial presequence processing induce an early activation of UPRmtthat, in turn, modulates cytosolic quality control pathways. Thus our work supports a mechanistic link between mitochondrial function and common neurodegenerative proteinopathies.
Rapid event-related, BOLD, NHP: choose two out of three
Authors: Pelekanos Vassilis , Mok Robert M. , Joly Olivier , Ainsworth Matthew , Kyriazis Diana , Kelly Maria G. , Bell Andrew H. , Kriegeskorte Nikolaus
Published: January 2020

Human functional magnetic resonance imaging (fMRI) typically employs the blood-oxygen-level-dependent (BOLD) contrast mechanism. In non-human primates (NHP), contrast enhancement is possible using monocrystalline iron-oxide nanoparticles (MION) contrast agent, which has a more temporally extended response function. However, using BOLD fMRI in NHP is desirable for interspecies comparison, and the faster response of the BOLD signal promises to be beneficial to rapid event-related (rER) designs. Here, we used rER BOLD fMRI in macaque monkeys while viewing real-world images, and found visual responses and category-selectivity consistent with previous studies. However, activity estimates were very noisy, suggesting that the lower contrast-to-noise ratio of BOLD, suboptimal behavioural performance, and motion artefacts, in combination, render rER BOLD fMRI challenging in NHP. Previous studies have shown that rER monkey fMRI is possible with MION, despite its prolonged response function. To understand this, we conducted simulations of the BOLD and MION response during rER designs, and found that no matter how fast the design, the greater amplitude of the MION response outweighs the contrast loss caused by greater temporal smoothing. We conclude that although any two of the three elements (rER, BOLD, NHP) have been shown to work well, the combination of all three is particularly challenging.
An instructive role for IL7RA in the development of human B-cell precursor leukemia
Authors: Geron Ifat , Savino Angela Maria , Tal Noa , Brown John , Turati Virginia , James Chela , Sarno Jolanda , Lee Yu Nee , Gil Avigail Rein , Fishman Hila , Birger Yehudit , Muler Inna , Hameiri-Grossman Michal , Davis Kara Lynn , Marcu-Malina Victoria , Parnas Oren , Fischer Ute , Müschen Markus , Borkhardt Arndt , Kirsch Ilan Richard , Nagler Arnon , Enver Tariq , Izraeli Shai
Published: January 2020

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is preceded by a clinically silent pre-leukemia. Experimental models that authentically re-capitulate disease initiation and progression in human cells are lacking. We previously described activating mutations in interleukin 7 receptor alpha (IL7RA) that are associated with the poor-prognosis Philadelphia-like (Ph-like) subtype of BCP-ALL. Whether IL7RA signaling has a role in initiation of human BCP-ALL is unknown.

IL7RA is essential for mouse B-cell development; however, patients with truncatingIL7RAgermline mutations develop normal mature B-cell populations. Herein, we explore the consequences of aberrant IL7RA signaling activation in human hematopoietic progenitors on malignant B-cell development.

Transplantation of human cord-blood hematopoietic progenitors transduced with activated mutant IL7RA into NOD/LtSz-scid IL2Rγnullmice resulted in B-cell differentiation arrest with aberrant expression of CD34+and persistence of pro-B cells that survive despite failing to achieve productive rearrangement of immunoglobulin V(D)J gene segments. Activation of IL7RA signaling enhanced self-renewal and facilitated the development of a BCP-ALL in secondary transplanted mice. The development of leukemia was associated with spontaneous acquired deletions in CDKN2A/B and IKZF1 similar to what is observed in Ph-like BCP-ALL in humans. Single cell gene expression analysis suggested that pre-leukemic cells resided within a subpopulation of early B-cell precursors with CD34+CD10highCD19lowimmunophenotype.

The development of a bona fide BCP-ALL from IL7RA transduced cells supports the hypothesis that aberrant activation of the IL7RA pathway in human B-cell lineage progenitors has an instructive role by creating a pre-leukemic state which is vulnerable to transformation. These are the first demonstrations of a role for IL7RA in human B-cell differentiation and of a de-novo Ph-like BCP-ALL development from normal human hematopoietic progenitorsin vivo.
The complete chloroplast genome sequence of American elm (Ulmus americana) and comparative genomics of related species
Authors: Ebrahimi Aziz , Antonides Jennifer D. , Pinchot Cornelia C. , Slavicek James M. , Flower Charles E. , Woeste Keith E.
Published: January 2020

American elm,Ulmus americanaL., was cultivated widely in USA and Canada as a landscape tree, but the genome of this important species is poorly characterized. For the first time, we describe the sequencing and assembly of the chloroplast genomes of two American elm genotypes (RV16 and Am57845). The complete chloroplast genome ofU. americanaranged from 158,935-158,993 bp. The genome contains 127 genes, including 85 protein-coding genes, 34 tRNA genes and 8 rRNA genes. Between the two American elm chloroplasts we sequenced, we identified 240 sequence variants (SNPs and indels). To evaluate the phylogeny of American elm, we compared the chloroplast genomes of two American elms along with seven Asian elm species and twelve other chloroplast genomes available through the NCBI database. As expected,Ulmuswas closely related toMorusandCannabis, as all three genera are assigned to the Urticales. Comparison of American elm with Asian elms revealed thattrnH was absent from the chloroplast of American elm but not most Asian elms; conversely,petB,petD,psbL,trnK, andrps16 are present in the American elm but absent from all Asian elms. The complete chloroplast genome ofU. americanawill provide useful genetic resources for characterizing the genetic diversity ofU. americanaand potentially help to conserve natural populations of American elm.
Precise mapping of new group I introns in tRNA genes
Authors: Williams Kelly P.
Published: January 2020

Bacterial tRNA have been found interrupted at various positions in the anticodon loop by group I introns, in four types. The primary bioinformatic tool for group I intron discovery is a covariance model that can identify conserved features in the catalytic core and can sometimes identify the typical uridine residue at the -1 position, preceding the 5-prime splice site, but cannot identify the typical guanidine residue at the omega position, preceding the 3-prime splice site, to achieve precise mapping. One approach to complete the automation of group I intron mapping is to focus instead on the exons, which is enabled by the regularity of tRNAs. We develop a software module, within a larger package (tFind) aimed at mapping bacterial tRNA and tmRNA genes precisely, that expands this list of four known classes of intron-interrupted tRNAs to 21 cases. A new covariance model for these introns is presented. The wobble base pair formed by the -1 uridine is considered a determinant of the 5-prime splice site, yet one reasonably large new type bears a cytidine nucleotide at that position.
Cooperativity of membrane-protein and protein-protein interactions control membrane remodeling by epsin 1 and regulate clathrin-mediated endocytosis
Authors: Kroppen Benjamin , Teske Nelli , Yambire King F. , Denkert Niels , Murkhejee Indrani , Tarasenko Daryna , Jaipuria Garima , Zweckstetter Markus , Milosevic Ira , Steinem Claudia , Meinecke Michael
Published: January 2020

Membrane remodeling is a critical process for many membrane trafficking events, including clathrin-mediated endocytosis. Several molecular mechanisms for protein induced membrane curvature have been described in some detail. Contrary, the effect that the physico-chemical properties of the membrane has on these processes is far less well understood. Here, we show that the membrane binding and curvature-inducing ENTH domain of epsin1 is regulated by phosphatidylserine (PS). ENTH binds to membranes in a PI(4,5)P2-dependent manner but only induces curvature in the presence of PS. On PS-containing membranes, the ENTH domain forms rigid homo-oligomers and assembles into clusters. Membrane binding and membrane remodeling can be separated by structure-to-function mutants. Such oligomerization mutants bind to membranes but do not show membrane remodeling activity. In vivo they are not able to rescue defects in epidermal growth factor receptor (EGFR) endocytosis in epsin knock-down cells. Together, these data show that the membrane lipid composition is important for the regulation of protein-dependent membrane deformation during clathrin-mediated endocytosis.
Disparities in information on Long-Acting Reversible Contraceptives available to college students on student health center websites in USA
Authors: Kulkarni Anagha , Belsare Tejasvi , Shah Risha , Yu Yu Diana , Holschuh Carrie , Kakar Venoo , Modrek Sepideh , Smirnova Anastasia
Published: January 2020

Long Acting Reversible Contraceptive (LARC) methods are among the most effective birth control approaches for adolescent and young adults yet information on these methods is not widespread. We examine LARC information provided by Student Health Centers (SHC) websites from Universities across the USA to document disparities in access to information on these important contraception methods for college students. We find that compared to EC, Condoms, (plus Pap smear as control), LARC is mentioned less frequently than the others and 73% of schools have no LARC content on their SHC websites. There is no standardization in how the sexual and reproductive health information is organized on SHC websites, which might hinder access. When LARC information does exist, readability and accessibility vary. Universities having high rates of the student body who are African American or female are less likely to provide LARC information on their SHC website and universities situated in more rural settings are less likely to post LARC information on their websites.
Identifying Priority Landscapes for Conservation of Snow Leopards in Pakistan
Authors: Hameed Shoaib , ud Din Jaffar , Ali Hussain , Kabir Muhammad , Younas Muhammad , Hao Wang , Bischof Richard , Nawaz Muhammad Ali
Published: January 2020

Pakistan’s total estimated snow leopard habitat is about 80,000 km2of which about half is considered prime. However, this preliminary demarcation was not always in close agreement with the actual distribution—the discrepancy may be huge at the local and regional level. Recent technological developments like camera trapping and molecular genetics allow for collecting reliable presence records that could be used to construct realistic species distribution based on empirical data and advanced mathematical approaches like MaxEnt. Current study followed this approach to construct accurate distribution of the species in Pakistan. Moreover, movement corridors, among different landscapes, were also identified through the circuit theory. The habitat suitability map, generated from 384 presence points and 28 environmental variables, scored the snow leopard’s assumed range in Pakistan, from 0 to 0.97. A large shear of previously known range represented low-quality habitat, including areas in lower Chitral, Swat, Astore and Kashmir. Conversely, Khunjerab, Misgar, Chapursan, Qurumber, Broghil, and Central Karakoram represented high-quality habitats. Variables with higher contribution in the MaxEnt model were precipitation of driest month (34%), annual mean temperature (19.5%), mean diurnal range of temperature (9.8%), annual precipitation (9.4%) and river density (9.2). The validation texts suggest a good model fit, and strong prediction power.

The connectivity analysis revealed that the population in the Hindukush landscape appears to be more connected with the population in Afghanistan as compared to other populations in Pakistan. Similarly, the Pamir-Karakoram population is better connected with China and Tajikistan, while the Himalayan population was with the population in India.

Current study allows for proposing three model landscapes to be considered under GSLEP agenda as regional priority areas, to safeguard safeguard future of the species in the long run. These landsacpes fall in mountain ranges of the Himalaya, Hindu Kush and Karakoram-Pamir, respectively. We also identified gaps in existing protected areas network, and suggest new protected areas in Chitral and Gilgit-Baltistan to protect critical habitats of snow leopard in Pakistan.
Shikonin induces odontoblastic differentiation of dental pulp stem cells via AKT–mTOR signaling in the presence of CD44
Authors: Kajiura Kunihiro , Umemura Naoki , Ohkoshi Emika , Ohta Takahisa , Kondoh Nobuo , Kawano Satoshi
Published: January 2020

In our previous study, we demonstrated that hyaluronan induces odontoblastic differentiation of dental pulp stem cells via interactions with CD44. However, it remains unclear whether CD44 expression by dental pulp stem cells is required for odontoblastic differentiation. Therefore, we searched for a compound that induces odontoblastic differentiation of dental pulp stem cells, regardless of the chemical structure and function of hyaluronan, and examined whether CD44 is involved in the induction of odontoblastic differentiation by the compound. Because vitamin K analogues can promote bone formation and tissue calcification, we focused on derivatives of naphthoquinone, the skeleton of vitamin K; we verified whether those compounds could induce odontoblastic differentiation of dental pulp stem cells. We found that dentin sialophosphoprotein, a marker of odontoblasts, was expressed in dental pulp stem cells after treatment with shikonin. The shikonin-induced expression of dentin sialophosphoprotein was inhibited by PI3K, AKT, and mTOR inhibitors. In addition, in dental pulp stem cells transfected with siRNA against CD44, the shikonin-induced expression of dentin sialophosphoprotein was inhibited. Thus, shikonin can stimulate dental pulp stem cells to undergo odontoblastic differentiation through a mechanism involving the AKT–mTOR signaling pathway and CD44. Hyaluronan stimulated dental pulp stem cells to undergo CD44-mediated odontoblastic differentiation in our previous study; the present study indicated that CD44 is necessary for dental pulp stem cells to undergo odontoblastic differentiation. Although expression of CD44 is important for inducing odontoblastic differentiation of dental pulp stem cells, the relationship between the AKT–mTOR signaling pathway and CD44 expression, in the context of shikonin stimulation, has not yet been elucidated. This study suggested that shikonin may be useful for inducing odontoblastic differentiation of dental pulp stem cells, and that it may have clinical applications, including protection of dental pulp.
Antibiotic-induced DNA damage results in a controlled loss of pH homeostasis and genome instability
Authors: Booth James Alexander , Špírek Mário , Lobie Tekle Airgecho , Skarstad Kirsten , Krejci Lumir , Bjørås Magnar
Published: January 2020

Extracellular pH has been assumed to play little if any role in how bacteria respond to antibiotics and antibiotic resistance development. Here, we show that the intracellular pH ofEscherichia coliequilibrates to the environmental pH following antibiotic treatment. We demonstrate that this allows the environmental pH to influence the transcription of various DNA damage response genes and physiological processes such as filamentation. Using purified RecA and a known pH-sensitive mutant variant RecA K250R we show how pH can affect the biochemical activity of a protein central to control of the bacterial DNA damage response system. Finally, two different mutagenesis assays indicate that environmental pH affects antibiotic resistance development. Specifically, at environmental pH’s greater than six we find that mutagenesis plays a significant role in producing antibiotic resistant mutants. At pH’s less than or equal to 6 the genome appears more stable but extensive filamentation is observed, a phenomenon that has previously been linked to increased survival in the presence of macrophages.
Overarching control of autophagy and DNA damage response by CHD6 revealed by modeling a rare human pathology
Authors: Kargapolova Yulia , Rehimi Rizwan , Kayserili Hülya , Brühl Joanna , Zirkel Anne , Li Yun , Yigit Gökhan , Hoischen Alexander , Frank Stefan , Russ Nicole , Trautwein Jonathan , Laugsch Magdalena , Gusmao Eduardo Gade , Josipovic Natasa , Altmüller Janine , Nürnberg Peter , Längst Gernot , Kaiser Frank J. , Watrin Erwan , Brunner Han , Rada-Iglesias Alvaro , Kurian Leo , Wollnik Bernd , Bouazoune Karim , Papantonis Argyris
Published: January 2020

Members of the chromodomain-helicase-DNA binding (CHD) protein family are chromatin remodelers critically implicated in human pathologies, with CHD6 being one of its least studied members. Here, we discovered ade novo CHD6missense mutation in a patient clinically presenting the rare Hallermann-Streiff syndrome (HSS). We used genome editing to generate isogenic iPSC lines and model HSS in relevant cell types. We show that CHD6 binds a cohort of autophagy and stress response genes across cell types. The HSS-mutation affects CHD6 protein folding and impairs its ability to recruit co-factors in response to DNA damage or autophagy stimulation. This leads to an accumulation of DNA damage burden and to senescence-like phenotypes. By combining genomics and functional assays, we describe for the first time a molecular mechanism for the chromatin control of autophagic flux and genotoxic stress surveillance that applies broadly to human cell types and explains HSS onset.