bluuebunny/crossref_metadata_2025_split huggingface dataset:
Metastatic Donor-derived Malignancies Following Simultaneous Pancreas-kidney Transplant: Three Case Reports and Management Strategies
Authors: Amara Dominic , Wisel Steven A. , Braun Hillary J. , Collisson Eric A. , Friedlander Terence , Worner Giulia , Roll Garret R. , Hirose Ryutaro , Stock Peter G. 
Published: March 2021

Background.
Stopping immunosuppression in a transplant patient with donor-derived malignancy offers the theoretical benefit that reconstitution of the patient’s immune system will allow “rejection” of the malignancy, as the malignancy also originates from allogeneic tissue. However, this option exists with the caveat that the patient’s allograft(s) will likely be rejected too. In simultaneous pancreas-kidney (SPK) recipients, the normal continued functioning and possible absence of malignancy in either the unaffected kidney or pancreas further complicate this decision.

Methods.
The charts of 3 patients with donor-derived metastatic malignancies after SPK were retrospectively reviewed in detail. We provide treatment and management recommendations based on successful outcomes and a review of the existing literature.

Results.
Consistent with a broad review of the literature, in all 3 cases, complete immunosuppression cessation, removal of both grafts, and in 1 case treatment with an immune checkpoint inhibitor to augment the immune response was successful. One patient is doing well 1 year after successfully undergoing kidney retransplantation, while a second patient is active on the waitlist for SPK retransplantation after no evidence of metastatic disease for 2 years.

Conclusion.
The successful management of metastatic donor-derived malignancies requires allograft removal, immunosuppression cessation, and adjuvant therapy that includes occasional use of checkpoint inhibitors to augment the immune response.
Prediction of Postoperative Risk of Raised Intracranial Pressure After Spontaneous Skull Base Cerebrospinal Fluid Leak Repair
Authors: Buchowicz Bryce , Chen Benson S. , Bidot Samuel , Bruce Beau B. , Newman Nancy J. , Saindane Amit M. , Levy Joshua M. , Biousse Valérie ,   for the CSF-Leak Study Group
Published: March 2021

Background:
A relationship between idiopathic intracranial hypertension and spontaneous skull base cerebrospinal fluid (CSF) leaks has been proposed, by which CSF leak decreases intracranial pressure (ICP) and masks the symptoms and signs of elevated ICP. These patients are at risk of developing papilledema, symptoms of elevated ICP, or a recurrent CSF leak after CSF leak repair. The objective of this study was to assess whether radiographic signs of raised ICP on preoperative magnetic resonance or computed venography (MRI or CTV) are predictors of postoperative papilledema, recurrence of CSF leak, or need for CSF shunt surgery.

Methods:
We performed a retrospective review of systematically collected demographics, fundus examination, and presurgical brain MRI and magnetic resonance venography/computed tomography venography (MRV/CTV) in patients seen at 1 institution between 2013 and 2019 with spontaneous skull base CSF leak repair. Patients were divided into 2 groups depending on whether they developed papilledema, recurrent CSF leak, or required CSF shunting (Group 1) or not (Group 2).

Results:
Fifty-seven patients were included, among whom 19 were in Group 1. There was no difference in demographic characteristics or clinical features between patients in Group 1 and Group 2. Controlling for other imaging features, bilateral transverse venous sinus stenosis (TVSS) on preoperative imaging increased the odds of being in Group 1 by 4.2 times (95% confidence interval [CI], 1.04–21.2, P = 0.04), optic nerve tortuosity decreased the odds of being in Group 1 by 8.3 times (95% CI: 1.4–74.6, P = 0.02).

Conclusion:
Imaging of the intracranial venous system with MRV or CTV is warranted before repair of spontaneous CSF leak, as bilateral TVSS is an independent risk factor for postoperative papilledema, CSF leak recurrence, or need for a CSF shunting procedure.
Improved prime editors enable pathogenic allele correction and cancer modelling in adult mice
Authors: Liu Pengpeng , Liang Shun-Qing , Zheng Chunwei , Mintzer Esther , Zhao Yan G. , Ponnienselvan Karthikeyan , Mir Aamir , Sontheimer Erik J. , Gao Guangping , Flotte Terence R. , Wolfe Scot A. , Xue Wen 
Published: March 2021

AbstractPrime editors (PEs) mediate genome modification without utilizing double-stranded DNA breaks or exogenous donor DNA as a template. PEs facilitate nucleotide substitutions or local insertions or deletions within the genome based on the template sequence encoded within the prime editing guide RNA (pegRNA). However, the efficacy of prime editing in adult mice has not been established. Here we report an NLS-optimized SpCas9-based prime editor that improves genome editing efficiency in both fluorescent reporter cells and at endogenous loci in cultured cell lines. Using this genome modification system, we could also seed tumor formation through somatic cell editing in the adult mouse. Finally, we successfully utilize dual adeno-associated virus (AAVs) for the delivery of a split-intein prime editor and demonstrate that this system enables the correction of a pathogenic mutation in the mouse liver. Our findings further establish the broad potential of this genome editing technology for the directed installation of sequence modificationsin vivo, with important implications for disease modeling and correction.
3D models of Alzheimer’s disease patient microglia recapitulate disease phenotype and show differential drug responses compared to 2D
Authors: Cuní-López Carla , Quek Hazel , Oikari Lotta E. , Stewart Romal , Nguyen Tam Hong , Sun Yifan , Guo Christine C. , Lupton Michelle K. , White Anthony R. 
Published: March 2021

AbstractAlzheimer’s disease (AD) is an incurable neurodegenerative disorder with a rapidly increasing prevalence worldwide. Current approaches targeting hallmark pathological features of AD have had no consistent clinical benefit. Neuroinflammation is a major contributor to neurodegeneration and hence, microglia, the brain’s resident immune cells, are an attractive target for potentially more effective therapeutic strategies. However, there is no currentin vitromodel system that faithfully recapitulates patient-specific microglial characteristics. To address this shortcoming, we developed novel 3D models of monocyte-derived microglia-like cells (MDMi) from AD patients. MDMi in 3D exhibited mature microglial features, including a highly branched morphology and enhanced bonafide microglial marker expression compared to 2D. Moreover, AD MDMi in 3D co-cultures with neuro-glial cells showed altered cell-to-cell interactions, growth factor and cytokine secretion profiles and responses to amyloid-β. Drug screening assays in 3D AD MDMi revealed different cytokine responses compared to 2D. Our study demonstrates disease- and drug-specific responses in 3D MDMi models that are not apparent in 2D and presents a new 3D platform for more effective and personalised drug testing.
Heterochrony inorthodenticleexpression is associated with ommatidial size variation betweenDrosophilaspecies
Authors: Torres-Oliva Montserrat , Buchberger Elisa , Buffry Alexandra D. , Kittelmann Maike , Guerrero Genoveva , Sumner-Rooney Lauren , Gaspar Pedro , Bullinger Georg C. , Figueras Jimenez Javier , Casares Fernando , Arif Saad , Posnien Nico , Nunes Maria D. S. , McGregor Alistair P. , Almudi Isabel 
Published: March 2021

AbstractThe compound eyes of insects exhibit extensive variation in ommatidia number and size, which affects how they see and underlies adaptations in their vision to different environments and lifestyles. However, very little is known about the genetic and developmental bases of differences in compound eye size. We previously showed that the larger eyes ofDrosophila mauritianacompared toD. simulansis generally caused by differences in ommatidia size rather than number. Furthermore, we identified an X-linked chromosomal region inD. mauritianathat results in larger eyes when introgressed intoD. simulans. Here, we used a combination of fine-scale mapping and gene expression analysis to further investigate positional candidate genes on the X chromosome. We found earlier expression oforthodenticle (otd)during ommatidial maturation in third instar larvae inD. mauritianathan inD. simulans, and we show that this gene is required for the correct organisation and size of ommatidia inD. melanogaster. We discovered that the activity of anotdeye enhancer is consistent with the difference in the expression of this gene between species, with theD. mauritianaenhancer sequence driving earlier expression than that ofD. simulans. We also identified potential direct targets of Otd that are differentially expressed betweenD. mauritianaandD. simulansduring ommatidial maturation. Taken together, our results suggest that differential timing ofotdexpression contributes to natural variation in ommatidia size betweenD. mauritianaandD. simulans,which provides new insights into the mechanisms underlying the regulation and evolution of compound eye size in insects.
Characterisation of a novel ACE2-based therapeutic with enhanced rather than reduced activity against SARS-CoV2 variants
Authors: Ferrari Mathieu , Mekkaoui Leila , Ilca F. Tudor , Akbar Zulaikha , Bughda Reyisa , Lamb Katarina , Ward Katarzyna , Parekh Farhaan , Karattil Rajeev , Allen Christopher , Wu Philip , Baldan Vania , Mattiuzzo Giada , Bentley Emma M. , Takeuchi Yasuhiro , Sillibourne James , Datta Preeta , Kinna Alexander , Pule Martin , Onuoha Shimobi C. 
Published: March 2021

ABSTRACTThe human angiotensin-converting enzyme 2 acts as the host cell receptor for SARS-CoV-2 and the other members of theCoronaviridaefamily SARS-CoV-1 and HCoV-NL63. Here we report the biophysical properties of the SARS-CoV-2 spike variants D614G, B.1.1.7 and B.1.351 with affinities to the ACE2 receptor and infectivity capacity, revealing weaknesses in the developed neutralising antibody approaches. Furthermore, we report a pre-clinical characterisation package for a soluble receptor decoy engineered to be catalytically inactive and immunologically inert, with broad neutralisation capacity, that represents an attractive therapeutic alternative in light of the mutational landscape of COVID-19. This construct efficiently neutralised four SARS-CoV-2 variants of concern. The decoy also displays antibody-like biophysical properties and manufacturability, strengthening its suitability as a first-line treatment option in prophylaxis or therapeutic regimens for COVID-19 and related viral infections.
Tree canopy influences ground level atmospheric electrical and biogeochemical variability
Authors: Hunting Ellard R. , England Sam J. , Robert Daniel 
Published: March 2021

ABSTRACTStatic electric fields in the atmosphere are increasingly recognized to interact with various organisms over several levels of biological organization. Recently, a link between atmospheric electrical variations and biogeochemical processes has been established in the context of open fields, yet biological structures like trees produce substantial alterations in atmospheric electric properties. Here, we assess whether these structural changes affect the dynamics of both biogenic and abiotic electrical landscapes and their relation to geochemical processes. To this end, we theoretically assess how trees alter their surrounding electric fields and empirically compare the temporal dynamics of atmospheric potential gradients, positive ions in the near-ground level atmosphere and soil electrochemical properties in an open field and under a tree. The developed model of electric fields around trees provides insight into the extent to which trees shield underlying electric landscape, revealing that a substantial increase in atmospheric potential gradient only marginally affects the electric field under the canopy. We further show that soil electrochemical properties are tied to temporal dynamics of positive ions in the near-ground level atmosphere, and that the presence of a tree reduces the temporal variability in both ground level positive ions concentrations and soil redox potential. This suggests that a tree can have a stabilizing effect on drivers of temporal variability in atmospheric electricity and soil electro-chemistry, thereby likely indirectly influencing soil microorganisms and processes as well as electro-sensitive organisms that perceive and utilize atmospheric electric fields.
Co-condensation of proteins with single- and double-stranded DNA
Authors: Renger Roman , Morin Jose A. , Lemaitre Regis , Ruer-Gruss Martine , Jülicher Frank , Hermann Andreas , Grill Stephan W. 
Published: March 2021

SummaryBiomolecular condensates provide distinct compartments that can localize and organize biochemistry inside cells. Recent evidence suggests that condensate formation is prevalent in the cell nucleus. To understand how different components of the nucleus interact during condensate formation is an important challenge. In particular, the physics of co-condensation of proteins together with nucleic acids remains elusive. Here, we use optical tweezers to study how the prototypical prion-like protein Fused-in-Sarcoma (FUS) forms liquid-like assemblies in vitro, by co-condensing together with individual DNA molecules. Through progressive DNA unpeeling, buffer exchange and force measurements, we show that FUS adsorbing in a single layer on DNA effectively generates a sticky FUS-DNA polymer that can collapse to form a liquid-like FUS-DNA co-condensate. Condensation occurs at constant DNA tension for double-stranded DNA, which is a signature of phase separation. We suggest that co-condensation mediated by protein adsorption on nucleic acids is an important mechanism for intracellular compartmentalization.
Proprioception-based movement goals support imitation and are disrupted in apraxia
Authors: Isaacs Mitchell W. , Buxbaum Laurel J. , Wong Aaron L. 
Published: March 2021

ABSTRACTThe ability to imitate observed actions serves as an efficient method for learning novel movements and is specifically impaired (without concomitant gross motor impairments) in the neurological disorder of limb apraxia, a disorder common after left hemisphere stroke. Research with apraxic patients has advanced our understanding of how people imitate. However, the role of proprioception in imitation has been rarely assessed directly. Prior work has proposed that proprioceptively sensed body position is transformed into a visual format, supporting the attainment of a desired imitation goal represented visually (i.e., how the movement should look when performed). In contrast, we hypothesized a more direct role for proprioception: we suggest that movement goals are also represented proprioceptively (i.e., how a desired movement should feel when performed), and the ability to represent or access such proprioceptive goals is deficient in apraxia. Using a novel imitation task in which a robot cued meaningless trajectories proprioceptively or visually, we probed the role of each sensory modality. We found that patients with left hemisphere stroke were disproportionately worse than controls at imitating when cued proprioceptively versus visually. This proprioceptive versus visual disparity was associated with apraxia severity as assessed by a traditional imitation task, but could not be explained by general proprioceptive impairment or speed-accuracy trade-offs. These data suggest that successful imitation depends in part on the ability to represent movement goals in terms of how those movements should feel, and that deficits in this ability contribute to imitation impairments in patients with apraxia.
Testing for evolutionary change in restoration: a genomic comparison betweenex situ, native and commercial seed sources ofHelianthus maximiliani
Authors: Braasch Joseph E , Di Santo Lionel N , Tarble Zach , Prasifka Jarrad R , Hamilton Jill A 
Published: March 2021

AbstractGlobally imperiled ecosystems often depend upon collection, propagation, and storage of seed material for use in restoration. However, during the restoration process demographic changes, population bottlenecks, and selection can alter the genetic composition of seed material, with potential impacts for restoration success. The evolutionary outcomes associated with these processes have been demonstrated using theoretical and experimental frameworks, but no studies to date have examined the impact these processes have had on the seed material maintained for conservation and restoration. In this study, we compare genomic variation across seed sources used in conservation and restoration for the perennial prairie plantHelianthus maximiliani, a key component of restorations across North American grasslands. We compare individuals sourced from contemporary wild populations,ex situconservation collections, commercially produced restoration material, and two populations selected for agronomic traits. Overall, we observed thatex situand contemporary wild populations exhibited a similar genomic composition, while four of five commercial populations and selected lines were differentiated from each other and other seed source populations. Genomic differences across seed sources could not be explained solely by isolation by distance nor directional selection. We did find evidence of sampling effects forex situcollections, which exhibited significantly increased coancestry relative to commercial populations, suggesting increased relatedness. Interestingly, commercially sourced seed appeared to maintain an increased number of rare alleles relative toex situand wild contemporary seed sources. However, while commercial seed populations were not genetically depauperate, the genomic distance between wild and commercially produced seed suggests differentiation in the genomic composition could impact restoration success. Our results point towards the importance of genetic monitoring of species used for conservation and restoration as they are expected to be influenced by the evolutionary processes that contribute to divergence during the restoration process.
The radish Ogura fertility restorer impedes translation elongation along its cognate CMS-causing mRNA
Authors: Wang Chuande , Lezhneva Lina , Arnal Nadège , Quadrado Martine , Mireau Hakim 
Published: March 2021

AbstractThe control of mRNA translation has been increasingly recognized as a key regulatory step for gene control but clear examples in eukaryotes are still scarce. Nucleo-cytoplasmic male sterilities (CMS) represent ideal genetic models to dissect genetic interactions between the mitochondria and the nucleus in plants. This trait is determined by specific mitochondrial genes and is associated with a pollen sterility phenotype that can be suppressed by nuclear genes known as restorer-of-fertility (Rf) genes. In the study, we focused on the Ogura CMS system in rapeseed and showed that the suppression to male sterility by the PPR-B fertility restorer (also called Rfo) occurs through a specific inhibition of the translation of the mitochondria-encoded CMS-causing mRNAorf138. We also demonstrate that PPR-B binds within the coding sequence oforf138and acts as a ribosome blocker to specifically impede translation elongation along theorf138mRNA. Rfo is the first recognized fertility restorer shown to act this way. These observations will certainly facilitate the development of synthetic fertility restorers for CMS systems in which efficient natural Rfs are lacking.
REST is a major negative regulator of endocrine differentiation during pancreas organogenesis
Authors: Rovira Meritxell , Atla Goutham , Maestro Miguel Angel , Grau Vane , García-Hurtado Javier , Maqueda Maria , Mosquera Jose Luis , Kerr-Conte Julie , Pattou Francois , Ferrer Jorge 
Published: March 2021

SUMMARYUnderstanding genomic regulatory mechanisms of pancreas differentiation is relevant to the pathophysiology of diabetes mellitus, and to the development of replacement therapies. Numerous transcription factors promote β cell differentiation, although less is known about negative regulators. Earlier epigenomic studies suggested that the transcriptional repressor REST could be a suppressor of endocrine gene programs in the embryonic pancreas. However, pancreaticRestknock-out mice failed to show increased numbers of endocrine cells, suggesting that REST is not a major regulator of endocrine differentiation. Using a different conditional allele that enables profound REST inactivation, we now observe a marked increase in the formation of pancreatic endocrine cells. REST inhibition also promoted endocrinogenesis in zebrafish and mouse early postnatal ducts, and induced β-cell specific genes in human adult duct-derived organoids. Finally, we define REST genomic programs that suppress pancreatic endocrine differentiation. These results establish a crucial role of REST as a negative regulator of pancreatic endocrine differentiation.
MLL3/MLL4 Histone Methyltranferase Activity Dependent Chromatin Organization at Enhancers during Embryonic Stem Cell Differentiation
Authors: Kubo Naoki , Hu Rong , Ye Zhen , Ren Bing 
Published: March 2021

SUMMARYMLL3 (KMT2C) and MLL4 (KMT2D), the major mono-methyltransferases of histone H3 lysine 4 (H3K4), are required for cellular differentiation and embryonic development in mammals. We previously observed that MLL3/4 promote long-range chromatin interactions at enhancers, however, it is still unclear how their catalytic activities contribute to enhancer-dependent gene activation in mammalian cell differentiation. To address this question, we mapped histone modifications, long-range chromatin contacts as well as gene expression in MLL3/4 catalytically deficient mouse embryonic stem (ES) cells undergoing differentiation toward neural precursor cells. We showed that MLL3/4 activities are responsible for deposition of H3K4me1 modification and formation of long-range enhancer-promoter contacts at a majority of putative enhancers gained during cell differentiation, but are dispensable for most candidate enhancers found in undifferentiated ES cells that persist through differentiation. While transcriptional induction at most genes is unaltered in the MLL3/4 catalytically deficient cells, genes making more contacts with MLL3/4-dependent putative enhancers are disproportionately affected. These results support that MLL3/4 contributes to cellular differentiation through histone-methyltransferase-activity dependent induction of enhancer-promoter contacts and transcriptional activation at a subset of lineage-specific genes.
Engineering the AEG1 promoter from cotton to develop male sterile lines
Authors: Soni Kamlesh Kumar , Mehrotra Amita Kush , Burma Pradeep Kumar 
Published: March 2021

AbstractThis work reports on modifying the Upstream Regulatory Module (URM, 1.5 Kb region upstream of the open reading frame) ofAnther Expressing Gene 1(AEG1) from cotton to achieve anther specific activity.AEG1was identified in a previous study aimed to isolate a promoter with tapetum specific activity. Such a promoter could then be used to expressbarnaseandbarstargenes for developing male sterile and restorer lines for hybrid seed production in cotton. The AEG1 URM was observed to be active in tapetum as well as in roots making it unusable to drive the expression ofbarnasegene. Analysis of the URM showed the presence of several root specific motifs. Two modified AEG1 URMs were developed, by removing or mutating these motifs and its activity checked in tobacco. The activity of one of the modified URMs, AEG1(ΔBmut) was restricted to the anther tissue as observed using the reporter geneß-glucuronidase. The study also demonstrates that male sterile lines could be developed in tobacco using the AEG1(ΔBmut) URM to express thebarnasegene. This work thus shows the possibility of engineering promoters to achieve tissue specificity and to develop male sterile lines in cotton.