bluuebunny/crossref_metadata_2025_split huggingface dataset:
Variants in STXBP3 are Associated with Very Early Onset Inflammatory Bowel Disease, Bilateral Sensorineural Hearing Loss and Immune Dysregulation
Authors: Ouahed Jodie , Kelsen Judith R , Spessott Waldo A , Kooshesh Kameron , Sanmillan Maria L , Dawany Noor , Sullivan Kathleen E , Hamilton Kathryn E , Slowik Voytek , Nejentsev Sergey , Neves João Farela , Flores Helena , Chung Wendy K , Wilson Ashley , Anyane-Yeboa Kwame , Wou Karen , Jain Preti , Field Michael , Tollefson Sophia , Dent Maiah H , Li Dalin , Naito Takeo , McGovern Dermot P B , Kwong Andrew C , Taliaferro Faith , Ordovas-Montanes Jose , Horwitz Bruce H , Kotlarz Daniel , Klein Christoph , Evans Jonathan , Dorsey Jill , Warner Neil , Elkadri Abdul , Muise Aleixo M , Goldsmith Jeffrey , Thompson Benjamin , Engelhardt Karin R , Cant Andrew J , Hambleton Sophie , Barclay Andrew , Toth-Petroczy Agnes , Vuzman Dana , Carmichael Nikkola , Bodea Corneliu , Cassa Christopher A , Devoto Marcella , Maas Richard L , Behrens Edward M , Giraudo Claudio G , Snapper Scott B 
Published: April 2021

Abstract

Background and Aims
Very early onset inflammatory bowel disease [VEOIBD] is characterized by intestinal inflammation affecting infants and children less than 6 years of age. To date, over 60 monogenic aetiologies of VEOIBD have been identified, many characterized by highly penetrant recessive or dominant variants in underlying immune and/or epithelial pathways. We sought to identify the genetic cause of VEOIBD in a subset of patients with a unique clinical presentation.

Methods
Whole exome sequencing was performed on five families with ten patients who presented with a similar constellation of symptoms including medically refractory infantile-onset IBD, bilateral sensorineural hearing loss and, in the majority, recurrent infections. Genetic aetiologies of VEOIBD were assessed and Sanger sequencing was performed to confirm novel genetic findings. Western analysis on peripheral blood mononuclear cells and functional studies with epithelial cell lines were employed.

Results
In each of the ten patients, we identified damaging heterozygous or biallelic variants in the Syntaxin-Binding Protein 3 gene [STXBP3], a protein known to regulate intracellular vesicular trafficking in the syntaxin-binding protein family of molecules, but not associated to date with either VEOIBD or sensorineural hearing loss. These mutations interfere with either intron splicing or protein stability and lead to reduced STXBP3 protein expression. Knock-down of STXBP3 in CaCo2 cells resulted in defects in cell polarity.

Conclusion
Overall, we describe a novel genetic syndrome and identify a critical role for STXBP3 in VEOIBD, sensorineural hearing loss and immune dysregulation.
Improving 1-year mortality prediction in ACS patients using machine learning
Authors: Weichwald Sebastian , Candreva Alessandro , Burkholz Rebekka , Klingenberg Roland , Räber Lorenz , Heg Dik , Manka Robert , Gencer Baris , Mach François , Nanchen David , Rodondi Nicolas , Windecker Stephan , Laaksonen Reijo , Hazen Stanley L , von Eckardstein Arnold , Ruschitzka Frank , Lüscher Thomas F , Buhmann Joachim M , Matter Christian M 
Published: April 2021

Abstract

Background
The Global Registry of Acute Coronary Events (GRACE) score is an established clinical risk stratification tool for patients with acute coronary syndromes (ACS). We developed and internally validated a model for 1-year all-cause mortality prediction in ACS patients.

Methods
Between 2009 and 2012, 2’168 ACS patients were enrolled into the Swiss SPUM-ACS Cohort. Biomarkers were determined in 1’892 patients and follow-up was achieved in 95.8% of patients. 1-year all-cause mortality was 4.3% (n = 80). In our analysis we consider all linear models using combinations of 8 out of 56 variables to predict 1-year all-cause mortality and to derive a variable ranking.

Results
1.3% of 1’420’494’075 models outperformed the GRACE 2.0 Score. The SPUM-ACS Score includes age, plasma glucose, NT-proBNP, left ventricular ejection fraction (LVEF), Killip class, history of peripheral artery disease (PAD), malignancy, and cardio-pulmonary resuscitation. For predicting 1-year mortality after ACS, the SPUM-ACS Score outperformed the GRACE 2.0 Score which achieves a 5-fold cross-validated AUC of 0.81 (95% CI 0.78–0.84). Ranking individual features according to their importance across all multivariate models revealed age, trimethylamine N-oxide, creatinine, history of PAD or malignancy, LVEF, and haemoglobin as the most relevant variables for predicting 1-year mortality.

Conclusions
The variable ranking and the selection for the SPUM-ACS Score highlight the relevance of age, markers of heart failure, and comorbidities for prediction of all-cause death. Before application, this score needs to be externally validated and refined in larger cohorts.

Clinical Trial Registration
NCT01000701.
Identification of novel pentose transporters in Kluyveromyces marxianus using a new screening platform
Authors: Donzella Lorena , Varela Javier A , Sousa Maria João , Morrissey John P 
Published: April 2021

ABSTRACT
The capacity of yeasts to assimilate xylose or arabinose is strongly dependent on plasma membrane transport proteins. Because pentoses comprise a substantial proportion of available sugars in lignocellulosic hydrolysates, their utilisation is centrally important for the development of second generation biorefineries. Relatively few native pentose transporters have been studied and there is intense interest in expanding the repertoire. To aid the identification of novel transporters, we developed a screening platform in the native pentose-utilising yeast Kluyveromyces marxianus. This involved the targeted deletion of twelve transporters of the major facilitator superfamily (MFS) and application of a synthetic biology pipeline for rapid testing of candidate pentose transporters. Using this K. marxianus ΔPT platform, we identified several K. marxianus putative xylose or arabinose transporter proteins that recovered a null strain's ability to growth on these pentoses. Four proteins of the HGT-family were able to support growth in media with high or low concentrations of either xylose or arabinose, while six HXT-like proteins displayed growth only at high xylose concentrations, indicating solely low affinity transport activity. The study offers new insights into the evolution of sugar transporters in yeast and expands the set of native pentose transporters for future functional and biotechnological studies.
Drinking, eating and dancing: Swiss merchants’ lobbying in seventeenth- and eighteenth-century Lyon
Authors: Schnyder Marco 
Published: April 2021

Abstract
At the beginning of the eighteenth century, the Swiss formed the most important and numerous foreign merchant community in Lyon. As a result of centuries-old treaties, Swiss nationals benefited from several privileges in France. However, these privileges were increasingly threatened by French protectionist policies. In order to defend their rights, Swiss merchants adopted various strategies. In this article, the focus is on a particular form of lobbying: dinners and parties. The merchants themselves documented such events in their own writings. In general terms these sources offer an original research perspective on early modern urban food, drinking and ceremonial culture. More specifically, this article reveals not only the different facets of a foreign community’s agency in a protectionist context, but it also contributes to a better understanding of the internal relations within this merchant community, such as between its Protestant and Catholic members.
Mutation Rates and Selection on Synonymous Mutations in SARS-CoV-2
Authors: De Maio Nicola , Walker Conor R , Turakhia Yatish , Lanfear Robert , Corbett-Detig Russell , Goldman Nick 
Published: April 2021

Abstract
The COVID-19 pandemic has seen an unprecedented response from the sequencing community. Leveraging the sequence data from more than 140,000 SARS-CoV-2 genomes, we study mutation rates and selective pressures affecting the virus. Understanding the processes and effects of mutation and selection has profound implications for the study of viral evolution, for vaccine design, and for the tracking of viral spread. We highlight and address some common genome sequence analysis pitfalls that can lead to inaccurate inference of mutation rates and selection, such as ignoring skews in the genetic code, not accounting for recurrent mutations, and assuming evolutionary equilibrium. We find that two particular mutation rates, G →U and C →U, are similarly elevated and considerably higher than all other mutation rates, causing the majority of mutations in the SARS-CoV-2 genome, and are possibly the result of APOBEC and ROS activity. These mutations also tend to occur many times at the same genome positions along the global SARS-CoV-2 phylogeny (i.e., they are very homoplasic). We observe an effect of genomic context on mutation rates, but the effect of the context is overall limited. Although previous studies have suggested selection acting to decrease U content at synonymous sites, we bring forward evidence suggesting the opposite.
ALTERED MAIZE ENDOSPERM ADP-GLUCOSE PYROPHOSPHORYLASES FROM REVERTANTS OF A SHRUNKEN-2-DISSOCIATION ALLELE
Authors: Tuschall D M , Hannah L C 
Published: April 2021

ABSTRACT
Four phenotypically wild-type seeds were obtained from separate Activator-induced events in the Dissociation-inhibited allele sh2-ml (shrunken-2, mutable-1). Endosperm adenosine diphosphoglucose pyrophosphorylase, the enzyme controlled by sh2, was extracted and partially purified from the four revertants and was compared to enzyme produced by the progenitor Sh2 allele and the sh2-m allele.
The revertants contained 50 to 140% of the activity conditioned by the progenitor allele. Each of the revertants appears to be unique as judged by differences in Km(glucose-1-PO4), 3-phosphoglycerate(3-PGA) activation, and phosphate-inhibition. In one case the reversion event apparently increased the sensitivity of ADP-glucose pyrophosphorylate to 3-PGA activation.
[HOK], A NEW YEAST NON-MENDELIAN TRAIT, ENABLES A REPLICATION-DEFECTIVE KILLER PLASMID TO BE MAINTAINED
Authors: Wickner Reed B , Toh-E Akio 
Published: April 2021

ABSTRACT
The K1 killer plasmid, [KIL-k1], of Saccharomyces cerevisiae is a 1.25 × 106 dalton linear double-stranded RNA plasmid coding for a protein toxin and immunity to that toxin. The [KIL-sd1] plasmid is a replication-defective mutant of [KIL-k1] that depends on one of the recessive chromosomal superkiller (ski -) mutations for its maintenance (Toh-e and Wickner 1979). This report concerns a means by which [KIL-sd1] can be stably maintained in a SKI + host. Strains carrying a plasmid we call [HOK] (helper of killer) stably maintain [KIL-sd1]. [HOK] segregates 4 [HOK]:0 in meiotic crosses and is efficiently transferred by cytoplasmic mixing (heterokaryon formation). [HOK] depends for its maintenance on the products of PET18, MAK3, and MAK10, three chromosomal genes needed to maintain [KIL-k1], but is independent of 10 other MAK genes and of MKT1. [HOK] is not mitochondrial DNA and is unaffected by agents which convert ψ+ strains to ψ-. [HOK] is also distinct from the previously described plasmids [URE3], 20S RNA, 2 µ DNA, and [EXL]. Strains lacking [HOK] consistently have a four-fold lower copy number of L double-stranded RNA than strains carrying [HOK].
FORMATION OF F'TRP PLASMIDS IN ESCHERICHIA COLI K12
Authors: Van Gijsegem Frédérique , Toussaint Ariane 
Published: April 2021

ABSTRACT
From strains carrying two different F-prime factors, we recovered F′ derivatives that acquired the trp chromosomal region. These F′trp plasmids can be isolated at a frequency of 10-5 to 10-6. They were characterized genetically by looking at the size of the trp segment they acquired and at the location of that segment in the parental F′ plasmid. Results are discussed in relationship to possible transposition mechanisms.
EFFECT OF RADIATION DOSAGE ON EFFICIENCY OF CHLOROPLAST TRANSFER BY PROTOPLAST FUSION IN NICOTIANA
Authors: Menczel László , Galiba Gábor , Nagy Ferenc , Maliga Pál 
Published: April 2021

ABSTRACT
Chloroplasts of Nicotiana tabacum SR1 were transferred into Nicotiana plumbaginifolia by protoplast fusion. The protoplasts of the organelle donor were irradiated with different lethal doses using a 60Co source, to facilitate the elimination of their nuclei from the fusion products. After fusion induction, clones derived from fusion products and containing streptomycin-resistant N. tabacum SR1 chloroplasts were selected by their ability to green on a selective medium. When N. tabacum protoplasts were inactivated by iodoacetate instead of irradiation, the proportion of N. plumbaginifolia nuclear segregant clones was low (1-2%). Irradiation markedly increased this value: Using 50, 120, 210 and 300 J kg-1 doses, the frequency of segregant clones was 44, 57, 84 and 70 percent, respectively. Regeneration of resistant N. plumbaginifolia plants with SR1 chloroplasts indicated that plastids can be rescued from the irradiated cells by fusion with untreated protoplasts. Resistant N. plumbaginifolia plants that were regenerated (43 clones studied) had diploid (2n = 2X = 20) or tetraploid chromosome numbers and were identical morphologically to parental plants. The absence of aneuploids suggests that in these clones irradiation resulted in complete elimination of the irradiated N. tabacum nuclei. Resistance is inherited maternally (five clones tested). The demonstration of chloroplast transfer and the presence of N. tabacum plastids in the N. plumbaginifolia plants was confirmed by chloroplast DNA fragmentation patterns after EcoRI digestion.
FREQUENCIES OF NULL ALLELES AT ENZYME LOCI IN NATURAL POPULATIONS OF PONDEROSA AND RED PINE
Authors: Allendorf Fred W , Knudsen Kathy L , Blake George M 
Published: April 2021

ABSTRACT
Pinus ponderosa and P. resinosa population samples have mean frequencies of enzymatically inactive alleles of 0.0031 and 0.0028 at 29 and 27 enzyme loci, respectively. Such alleles are rare and are apparently maintained by selection-mutation balance. Ponderosa pine have much higher amounts of allozymic and polygenic phenotypic variation than red pine, yet both species have similar frequencies of null alleles. Thus, null alleles apparently do not contribute to polygenic variation, as has been suggested. The concordance between allozymic and polygenic variation adds support to the view that allozyme studies may be valuable in predicting the relative amount of polygenic variation in populations.
THE MATHEMATICS OF MOSAIC ANALYSIS III. ANALYSIS OF STRUCTURES WITH EXTENT IN TWO DIMENSIONS
Authors: Wyman Robert J , Costello Walter J , Koto Mary L 
Published: April 2021

ABSTRACT
This paper derives formulae for the use of mosaic analysis to determine the sizes, shapes and locations of structures that are not points but are extended areas on the blastoderm. We consider a male patch of any convex shape and size and a structure of any convex shape and size. The probability that these two intersect in a set of mosaics is simply one-quarter the product of their perimeters. From this perimeter formula we derive equations relating the frequency of mosaicism of a structure to its size and we derive a formula for the mapping of lethal foci. We then develop a method to locate the borders of a focus that covers an area on the blastoderm.
EVOLUTION OF A REGULATED OPERON IN THE LABORATORY
Authors: Hall Barry G 
Published: April 2021

ABSTRACT
The evolution of new metabolic functions is being studied in the laboratory using the EBG system of E. coli as a model system. It is demonstrated that the evolution of lactose utilization by lacZ deletion strains requires a series of structural and regulatory gene mutations. Two structural gene mutations act to increase the activity of ebg enzyme toward lactose, and to permit ebg enzyme to convert lactose into allolactose, an inducer of the lac operon. A regulatory mutation increases the sensitivity of the ebg repressor to lactose, and permits sufficient ebg enzyme activity for growth. The resulting fully evolved ebg operon regulates its own expression, and also regulates the synthesis of the lactose permease.
THE GENETICS OF A SMALL AUTOSOMAL REGION OF DROSOPHILA MELANOGASTER CONTAINING THE STRUCTURAL GENE FOR ALCOHOL DEHYDROGENASE. III. HYPOMORPHIC AND HYPERMORPHIC MUTATIONS AFFECTING THE EXPRESSION OF HAIRLESS
Authors: Ashburner Michael 
Published: April 2021

ABSTRACT
A lethal locus (1(2)br7;35B6-10), near Adh on chromosome arm 2L of D. melanogaster, is identified with Plunkett's dominant suppressor of Hairless (H). Of eight new alleles, seven act as dominant suppressors of H, the eighth is a dominant enhancer of H. One of the suppressor alleles is both a leaky lethal and a weak suppressor of H. Confirming Nash (1970), deletions of 1(2)br7 are dominant suppressors, and duplications are dominant enhancers of H. A simple model is proposed to account for the interaction of 1(2)br7 and H, assuming that amorphic (or hypomorphic) alleles of l(2)br7 suppress H and that hypermorphic alleles enhance H.
Recombination and replication of plasmid-like derivatives of a short section of the mitochondrial chromosome of Neurospora crassa.
Authors: Gross S R , Levine P H , Metzger S , Glaser G 
Published: April 2021

Abstract
The 21-kbp mitochondrial chromosome of the stp-ruv strain of Neurospora crassa undergoes regional amplification yielding plasmid-like supercoiled circles varying in size from subunit length to very high multimers. A comparison of the base sequence of the five plasmids studied, with the region of the chromosome from which they were derived, indicated that the amplified chromosomal segments were determined by a recombination-excision process near or within two structurally distinctive regions. One of these, consisting of nearly uninterrupted strings of Cs and Gs straddling tandem PstI site direct repeats, could form an extended hairpin loop with only a few mismatches. It was found at or near the 5' exchange point of all of the plasmids. An extended 35-bp sequence containing 17-bp direct repeats was the primary 3' site of exchange. Base sequence changes were found in the vicinity of exchange points. Most notable of these was a G insertion and T to C transition within a section of the 5' region likely to form a hairpin loop, suggesting the involvement of a mismatch repair-like mechanism in the recombination process. The sequence, TATATAGACATATA, was identified as a likely candidate for the site of replication initiation. A nearly identical sequence was found common to all of the corresponding plasmids of Podospora anserina and was reported near the presumed replication origin of the Drosophila yakuba mitochondrial chromosome. A search of GenBank revealed a remarkable association of the consensus sequence, TATATAGAXATATA, with the plus strand of organelle DNA.
Localization of murine X and autosomal sequences homologous to the human Y located testis-determining region.
Authors: Mitchell M , Simon D , Affara N , Ferguson-Smith M , Avner P , Bishop C 
Published: April 2021

Abstract
Recently a candidate gene for the primary testis-determining factor (TDF) encoding a zinc finger protein (ZFY) has been cloned from the human Y chromosome. A highly homologous X-linked copy has also been identified. Using this human sequence it is possible to identify two Y loci, an X and an autosomal locus in the mouse (Zfy-1, Zfy-2, Zfx and Zfa, respectively). Suprisingly ZFY is more homologous to the mouse X and autosomal sequences than it is to either of the Y-linked loci. Both Zfy-1 and Zfy-2 are present in the Sxr region of the Y but Zfy-2 is absent in the Sxr deletion variant Sxrb (or Sxr") suggesting it is not necessary for male determination. Extensive backcross analyses map Zfa to mouse chromosome 10 and Zfx to a 5-cM interval between anonymous X probe MDXS120 and the tabby locus (Ta). We also show that the mouse androgen receptor locus (m-AR) believed to underlie the testicular feminization mutation (Tfm) shows complete linkage to Zfx. Comparative mapping indicates that in man these genes lie in separate conserved DNA segments.
A set of lacZ mutations in Escherichia coli that allow rapid detection of specific frameshift mutations.
Authors: Cupples C G , Cabrera M , Cruz C , Miller J H 
Published: April 2021

Abstract
We have used site-directed mutagenesis to alter bases in lacZ near the region encoding essential residues in the active site of beta-galactosidase. The altered sequences generate runs of six or seven identical base pairs which create a frameshift, resulting in a Lac- phenotype. Reversion to Lac+ in each strain can occur only by a specific frameshift at these sequences. Monotonous runs of A's (or of T's on the opposite strand) and G's (or C's) have been constructed, as has an alternating -C-G- sequence. These specific frameshift indicator strains complement a set of six previously described strains which detect each of the base substitutions. We have examined a variety of mutagens and mutators for their ability to cause reversion to Lac+. Surprisingly, frameshifts are well stimulated at many of these runs by ethyl methanesulfonate, N-methyl-N'-nitro-N-nitrosoguanidine and 2-amino-purine, mutagens not widely known to induce frameshifts. A comparison of ethyl methanesulfonate, N-methyl-N'-nitro-N-nitrosoguanidine and 2-aminopurine frameshift specificity with that found with a mutH strain suggests that these mutagens partially or fully saturate or inactivate the methylation-directed mismatch repair system and allow replication errors leading to frameshifts to escape repair. This results in a form of indirect mutagenesis, which can be detected at certain sites.
TRK2 is required for low affinity K+ transport in Saccharomyces cerevisiae.
Authors: Ko C H , Buckley A M , Gaber R F 
Published: April 2021

Abstract
TRK1, the gene encoding the high affinity K+ transporter in Saccharomyces cerevisiae, is nonessential due to the existence of a functionally independent low affinity transporter. To identify the gene(s) encoding the low affinity K+ transporter, we screened trk1 delta cells for mutants (Kla-) that require higher concentrations of K+ in the medium to support growth. trk1 delta trk2 mutants require up to tenfold higher concentrations of K+ to exhibit normal growth compared to trk1 delta TRK2 cells. K+ and 86Rb+ transport assays demonstrate that the mutant phenotype is due to defective K+ transport (uptake). Each of 38 independent mutants contains a mutation in the same gene, TRK2. Cells deficient for both high and low affinity K+ transport (trk1 delta trk2) exhibit hypersensitivity to low extracellular pH that can be suppressed by high concentrations of K+ but not Na+. TRK1 completely suppresses both the K+ transport defect and low pH hypersensitivity of trk2 cells, suggesting that TRK1 and TRK2 are functionally independent.
Direct selection for mutants with increased K+ transport in Saccharomyces cerevisiae.
Authors: Vidal M , Buckley A M , Hilger F , Gaber R F 
Published: April 2021

Abstract
Saccharomyces cerevisiae cells containing a deletion of TRK1, the gene encoding the high affinity potassium transporter, retain only low affinity uptake of this ion and consequently lose the ability to grow in media containing low levels (0.2 mM) of potassium. Using a trk1 delta strain, we selected spontaneous Trk+ pseudorevertants that regained the ability to grow on low concentrations of potassium. The revertants define three unlinked extragenic suppressors of trk1 delta. Dominant RPD2 mutations and recessive rpd1 and rpd3 mutations confer increased potassium uptake in trk1 delta cells. Genetic evidence suggests that RPD2 mutations are alleles of TRK2, the putative low affinity transporter gene, whereas rpd1 and rpd3 mutations increase TRK2 activity: (1) RPD2 mutations are closely linked to trk2, and (2) trk2 mutations are epistatic to both rpd1 and rpd3. rpd1 maps near pho80 on chromosome XV and rpd3 maps on the left arm of chromosome XIV, closely linked to kre1.