bluuebunny/crossref_metadata_2025_split huggingface dataset:
Biallelic CACNA2D1 loss-of-function variants cause early-onset developmental epileptic encephalopathy
Authors: Dahimene Shehrazade , von Elsner Leonie , Holling Tess , Mattas Lauren S , Pickard Jess , Lessel Davor , Pilch Kjara S , Kadurin Ivan , Pratt Wendy S , Zhulin Igor B , Dai Hongzheng , Hempel Maja , Ruzhnikov Maura R Z , Kutsche Kerstin , Dolphin Annette C 
Published: February 2022

Abstract
Voltage-gated calcium (CaV) channels form three subfamilies (CaV1–3). The CaV1 and CaV2 channels are heteromeric, consisting of an α1 pore-forming subunit, associated with auxiliary CaVβ and α2δ subunits. The α2δ subunits are encoded in mammals by four genes, CACNA2D1–4. They play important roles in trafficking and function of the CaV channel complexes. Here we report biallelic variants in CACNA2D1, encoding the α2δ-1 protein, in two unrelated individuals showing a developmental and epileptic encephalopathy. Patient 1 has a homozygous frameshift variant c.818_821dup/p.(Ser275Asnfs*13) resulting in nonsense-mediated mRNA decay of the CACNA2D1 transcripts, and absence of α2δ-1 protein detected in patient-derived fibroblasts. Patient 2 is compound heterozygous for an early frameshift variant c.13_23dup/p.(Leu9Alafs*5), highly probably representing a null allele and a missense variant c.626G&gt;A/p.(Gly209Asp). Our functional studies show that this amino-acid change severely impairs the function of α2δ-1 as a calcium channel subunit, with strongly reduced trafficking of α2δ-1G209D to the cell surface and a complete inability of α2δ-1G209D to increase the trafficking and function of CaV2 channels. Thus, biallelic loss-of-function variants in CACNA2D1 underlie the severe neurodevelopmental disorder in these two patients. Our results demonstrate the critical importance and non-interchangeability of α2δ-1 and other α2δ proteins for normal human neuronal development.
Analysis of Denosumab by a Validated CZE Method and Determination of Sialic Acids by the RP–HPLC Method
Authors: Dumoncel Rafaela Ferreira Perobelli , Xavier Bruna , Cardoso Júnior Clóvis Dervil Appratto , da Silva Francielle Santos , Motta Luís Gustavo Jung , Cavalheiro Thaís Neuhaus , Dalmora Sérgio Luiz 
Published: February 2022

Abstract
A capillary zone electrophoresis (CZE) method was developed and validated to quantitate the monoclonal antibody denosumab (DmAb) and its charge variants in pharmaceutical products, demonstrating excellent precision, linearity and accuracy. Separations were obtained with migration times of 11.3 min for DmAb and the calibration curve was linear in the range of 0.95–20 mg/mL. The analytical comparability of seven batches of Prolia® showed mean differences of the estimated content/potencies of 1.87% lower, and 0.84 and 1.21% higher compared with the size-exclusion and reversed-phase liquid chromatography (SE–HPLC and RP–HPLC) methods and the osteoclast antiproliferative bioassay, respectively, with non-significant differences (P &gt; 0.05). An RP–HPLC method with fluorescence detection (RP–HPLC–F), performed on a Kinetex® EVO C18 column (5 μm, 100 Å, 250 mm × 4.6 mm), was optimized to determine the levels of sialic acids of DmAb biomolecules, giving mean concentrations of 0.16 and 0.17 μg N-acetylneuraminic acid/mg DmAb for Prolia® and Xgeva® pharmaceutical products, respectively. The results demonstrated the capability of each one of the methods, and their use in combination constitutes a strategy to monitor instability, thereby assuring the quality and the batch-to-batch consistency of the biotechnology-derived medicine.
A review on antimicrobial peptides databases and the computational tools
Authors: Ramazi Shahin , Mohammadi Neda , Allahverdi Abdollah , Khalili Elham , Abdolmaleki Parviz 
Published: February 2022

Abstract
Antimicrobial Peptides (AMPs) have been considered as potential alternatives for infection therapeutics since antibiotic resistance has been raised as a global problem. The AMPs are a group of natural peptides that play a crucial role in the immune system in various organisms AMPs have features such as a short length and efficiency against microbes. Importantly, they have represented low toxicity in mammals which makes them potential candidates for peptide-based drugs. Nevertheless, the discovery of AMPs is accompanied by several issues which are associated with labour-intensive and time-consuming wet-lab experiments. During the last decades, numerous studies have been conducted on the investigation of AMPs, either natural or synthetic type, and relevant data are recently available in many databases. Through the advancement of computational methods, a great number of AMP data are obtained from publicly accessible databanks, which are valuable resources for mining patterns to design new models for AMP prediction. However, due to the current flaws in assessing computational methods, more interrogations are warranted for accurate evaluation/analysis. Considering the diversity of AMPs and newly reported ones, an improvement in Machine Learning algorithms are crucial. In this review, we aim to provide valuable information about different types of AMPs, their mechanism of action and a landscape of current databases and computational tools as resources to collect AMPs and beneficial tools for the prediction and design of a computational model for new active AMPs.
Impacts of Winter Annual Cover Crops and Neonicotinoid Seed Treatments on Arthropod Diversity in Mississippi Soybean
Authors: Whalen D A , Catchot A L , Gore J , Cook D R , Barton B T , Brown R L , Irby J T , Speights C J 
Published: February 2022

Abstract
Winter annual cover crops can be planted before soybean in Mississippi for many agronomic reasons. Incorporating winter annual cover crops into soybean production changes the seasonal hosts within fields. Some studies suggest that reducing tillage and using diverse species of cover crops can increase arthropod diversity and predator activity. Neonicotinoid seed treatments are often implemented to combat early season insect pests in soybean that follow cover crops, but negative effects on the environment such as reductions in biodiversity are often attributed to these compounds. We conducted an experiment to measure the effects on the diversity of the soybean epigeal and foliar communities when incorporating cover crops as well as insecticidal seed treatments into Mississippi soybean growing systems. Our results showed that legume cover crops had significant impacts on the epigeal community diversity of soybean planted behind them. These cover crops, especially hairy vetch, supported a more diverse foliar community before termination. To prevent increases in herbivorous arthropods, neonicotinoid seed treatments can be used without affecting epigeal predators such as beetles, ants, and spiders. The neonicotinoid seed treatments affected arthropod diversity, but the reductions were mainly caused by decreases in herbivorous pest insects that fed on treated soybean plants.
Craniofacial changes from 13 to 62 years of age
Authors: Al-Taai Nameer , Persson Maurits , Ransjö Maria , Levring Jäghagen Eva , Fors Ronny , Westerlund Anna 
Published: February 2022

Summary

Background
In long-term studies of orthodontic, orthognathic, and prosthodontic treatments, control subjects are needed for comparison.

Objectives
To study the craniofacial (skeletal, soft tissue, and dental) changes that occur in untreated subjects with normal occlusion between 13 and 62 years of age.

Materials/Methods
Thirty subjects with a Class I normal occlusion and harmonious facial profile were studied. X-ray examinations were performed at 13 (T1), 16 (T2), 31 (T3), and 62 (T4) years of age, and data were obtained from cephalograms. In total, 53 angular and linear parameters were measured using superimposition-based and conventional cephalometric methods to describe the craniofacial changes.

Results
The jaws showed significant anterior growth from T1 to T2, and significant retrognathism from T3 to T4. The anterior face height and jaw dimensions increased significantly until T3. Significant posterior rotation of the mandible and opening of the vertical jaw relation, in addition to significant retroclination of the incisors and straightening of the facial profile, were found from T3 to T4.

Limitations
Given the small sample size at T4, it was not possible to analyse the gender dimension.

Conclusions/Implications
Craniofacial changes continue up to the sixth decade of life. These changes are consistent, albeit to a lesser extent, with the adolescent growth patterns for most of the studied parameters, with the exceptions of incisor inclination, sagittal jaw position, vertical jaw relation and inclination, and posterior face height.
Quantifying the Value of Log Sorting Based on the Location of Timber Harvest Sites Across Wisconsin
Authors: Wysocki Adam , Gautam Shuva , Rijal Baburam , Doruska Paul , Burns Kevin 
Published: February 2022

Abstract

It is generally understood that sorting logs based on grade generates maximum value for all stakeholders. However, the benefits of sorting logs may depend on the location of a timber sale and distances to manufacturing mills. The objective is to quantify the potential value of log sorting through scenario-based analysis in different areas with divergent forest and mill types. An optimization model was developed to allocate logs from the timber sale to the highest profit-yielding mills. Factors considered by the model included logging and transportation cost, timber sale tract-to-mill distances, mills’ acceptance criteria, and price at the mill gate. Four timber sales from across Wisconsin were selected for the study. Three scenarios were tested, with each scenario yielding different proportions of log sorts. The results showed that log sorting increased profit by up to $41.10 per cord in certain locations but was not profitable in other locations.

Study Implications
The methods proposed in this study can help foresters and landowners increase the value of harvested timber. Practitioners can use the proposed method to systematically assess the gain or loss in profit associated with log sorting at each timber sale. It also provides directives on the best mill for each log sort to be sent. The proposed method should be adopted to minimize underutilization of timber, especially in areas where profits are marginal.
Characterizing the gene–environment interaction underlying natural morphological variation in Neurospora crassa conidiophores using high-throughput phenomics and transcriptomics
Authors: Krach Emily K , Skaro Michael , Wu Yue , Arnold Jonathan 
Published: February 2022

Abstract
Neurospora crassa propagates through dissemination of conidia, which develop through specialized structures called conidiophores. Recent work has identified striking variation in conidiophore morphology, using a wild population collection from Louisiana, United States of America to classify 3 distinct phenotypes: Wild-Type, Wrap, and Bulky. Little is known about the impact of these phenotypes on sporulation or germination later in the N. crassa life cycle, or about the genetic variation that underlies them. In this study, we show that conidiophore morphology likely affects colonization capacity of wild N. crassa isolates through both sporulation distance and germination on different carbon sources. We generated and crossed homokaryotic strains belonging to each phenotypic group to more robustly fit a model for and estimate heritability of the complex trait, conidiophore architecture. Our fitted model suggests at least 3 genes and 2 epistatic interactions contribute to conidiophore phenotype, which has an estimated heritability of 0.47. To uncover genes contributing to these phenotypes, we performed RNA-sequencing on mycelia and conidiophores of strains representing each of the 3 phenotypes. Our results show that the Bulky strain had a distinct transcriptional profile from that of Wild-Type and Wrap, exhibiting differential expression patterns in clock-controlled genes (ccgs), the conidiation-specific gene con-6, and genes implicated in metabolism and communication. Combined, these results present novel ecological impacts of and differential gene expression underlying natural conidiophore morphological variation, a complex trait that has not yet been thoroughly explored.
Genome-scale patterns in the loss of heterozygosity incidence in Saccharomyces cerevisiae
Authors: Tutaj Hanna , Pirog Adrian , Tomala Katarzyna , Korona Ryszard 
Published: February 2022

Abstract
Former studies have established that loss of heterozygosity can be a key driver of sequence evolution in unicellular eukaryotes and tissues of metazoans. However, little is known about whether the distribution of loss of heterozygosity events is largely random or forms discernible patterns across genomes. To initiate our experiments, we introduced selectable markers to both arms of all chromosomes of the budding yeast. Subsequent extensive assays, repeated over several genetic backgrounds and environments, provided a wealth of information on the genetic and environmental determinants of loss of heterozygosity. Three findings stand out. First, the number of loss of heterozygosity events per unit time was more than 25 times higher for growing than starving cells. Second, loss of heterozygosity was most frequent when regions of homology around a recombination site were identical, about a half-% sequence divergence was sufficient to reduce its incidence. Finally, the density of loss of heterozygosity events was highly dependent on the genome’s physical architecture. It was several-fold higher on short chromosomal arms than on long ones. Comparably large differences were seen within a single arm where regions close to a centromere were visibly less affected than regions close, though usually not strictly adjacent, to a telomere. We suggest that the observed uneven distribution of loss of heterozygosity events could have been caused not only by an uneven density of initial DNA damages. Location-depended differences in the mode of DNA repair, or its effect on fitness, were likely to operate as well.
Hearing and Mobility in Aging—The Moderating Role of Neuropsychological Function
Authors: Pupo Daniel A , Small Brent J , Deal Jennifer A , Armstrong Nicole M , Simonsick Eleanor M , Resnick Susan M , Lin Frank R , Ferrucci Luigi , Tian Qu 
Published: February 2022

Abstract

Background
In older persons, neuropsychological function, especially sensorimotor function, is strongly associated with mobility. Hearing impairment is related to poor mobility, and we hypothesize that such relationships would be stronger in persons with compromised sensorimotor function than those with preserved sensorimotor function.

Methods
We analyzed 601 cognitively normal (Mini-Mental State Examination ≥24 or free of cognitive impairment/dementia) Baltimore Longitudinal Study of Aging participants aged 50 or older with concurrent data on hearing (better ear pure-tone average [PTA]), mobility (6 m usual gait, 400 m endurance walk), and neuropsychological function including attention via Trail Making Test (TMT)-A, executive function via the difference between TMT-A and B, and Digit Symbol Substitution Test, and manual dexterity via Pegboard performance. We examined the association of PTA, each cognitive measure, and their interaction with mobility using multivariable linear regression, adjusted for covariates.

Results
After covariate adjustment, there were significant interactions between PTA and all cognitive measures in the association with 400 m endurance walking speed as the outcome. There was also a significant interaction between PTA and pegboard nondominant hand performance in the association with 6 m gait as the outcome. In all these cases, the PTA–mobility relationship was stronger among participants with lower cognition.

Conclusion
Impaired hearing more strongly relates to poor mobility among those with compromised neuropsychological performance, especially manual dexterity reflecting the motor–cognitive interface and sensorimotor function, than those with preserved neuropsychological performance. Future longitudinal studies are needed to test whether hearing impairment more strongly predicts mobility decline over time in older persons with compromised neuropsychological function.
Multi-ancestry genome-wide association study of gestational diabetes mellitus highlights genetic links with type 2 diabetes
Authors: Pervjakova Natalia , Moen Gunn-Helen , Borges Maria-Carolina , Ferreira Teresa , Cook James P , Allard Catherine , Beaumont Robin N , Canouil Mickaël , Hatem Gad , Heiskala Anni , Joensuu Anni , Karhunen Ville , Kwak Soo Heon , Lin Frederick T J , Liu Jun , Rifas-Shiman Sheryl , Tam Claudia H , Tam Wing Hung , Thorleifsson Gudmar , Andrew Toby , Auvinen Juha , Bhowmik Bishwajit , Bonnefond Amélie , Delahaye Fabien , Demirkan Ayse , Froguel Philippe , Haller-Kikkatalo Kadri , Hardardottir Hildur , Hummel Sandra , Hussain Akhtar , Kajantie Eero , Keikkala Elina , Khamis Amna , Lahti Jari , Lekva Tove , Mustaniemi Sanna , Sommer Christine , Tagoma Aili , Tzala Evangelia , Uibo Raivo , Vääräsmäki Marja , Villa Pia M , Birkeland Kåre I , Bouchard Luigi , Duijn Cornelia M , Finer Sarah , Groop Leif , Hämäläinen Esa , Hayes Geoffrey M , Hitman Graham A , Jang Hak C , Järvelin Marjo-Riitta , Jenum Anne Karen , Laivuori Hannele , Ma Ronald C , Melander Olle , Oken Emily , Park Kyong Soo , Perron Patrice , Prasad Rashmi B , Qvigstad Elisabeth , Sebert Sylvain , Stefansson Kari , Steinthorsdottir Valgerdur , Tuomi Tiinamaija , Hivert Marie-France , Franks Paul W , McCarthy Mark I , Lindgren Cecilia M , Freathy Rachel M , Lawlor Deborah A , Morris Andrew P , Mägi Reedik 
Published: February 2022

Abstract
Gestational diabetes mellitus (GDM) is associated with increased risk of pregnancy complications and adverse perinatal outcomes. GDM often reoccurs and is associated with increased risk of subsequent diagnosis of type 2 diabetes (T2D). To improve our understanding of the aetiological factors and molecular processes driving the occurrence of GDM, including the extent to which these overlap with T2D pathophysiology, the GENetics of Diabetes In Pregnancy Consortium assembled genome-wide association studies of diverse ancestry in a total of 5485 women with GDM and 347 856 without GDM. Through multi-ancestry meta-analysis, we identified five loci with genome-wide significant association (P &lt; 5 × 10−8) with GDM, mapping to/near MTNR1B (P = 4.3 × 10−54), TCF7L2 (P = 4.0 × 10−16), CDKAL1 (P = 1.6 × 10−14), CDKN2A-CDKN2B (P = 4.1 × 10−9) and HKDC1 (P = 2.9 × 10−8). Multiple lines of evidence pointed to the shared pathophysiology of GDM and T2D: (i) four of the five GDM loci (not HKDC1) have been previously reported at genome-wide significance for T2D; (ii) significant enrichment for associations with GDM at previously reported T2D loci; (iii) strong genetic correlation between GDM and T2D and (iv) enrichment of GDM associations mapping to genomic annotations in diabetes-relevant tissues and transcription factor binding sites. Mendelian randomization analyses demonstrated significant causal association (5% false discovery rate) of higher body mass index on increased GDM risk. Our results provide support for the hypothesis that GDM and T2D are part of the same underlying pathology but that, as exemplified by the HKDC1 locus, there are genetic determinants of GDM that are specific to glucose regulation in pregnancy.
Thyroid function, pernicious anemia and erythropoiesis: a two-sample Mendelian randomization study
Authors: Kjaergaard Alisa D , Teumer Alexander , Marouli Eirini , Deloukas Panos , Kuś Aleksander , Sterenborg Rosalie , Åsvold Bjørn O , Medici Marco , Ellervik Christina 
Published: February 2022

Abstract
Autoimmune thyroid disease (AITD) and pernicious anemia (PA) often coexist, but the directionality is unknown. In a two-sample Mendelian randomization (MR) analysis, using summary statistics from large genome-wide association studies (GWASs) in Europeans (N = 49 269–755 406), we examined the genetic associations between thyroid function, PA and markers of erythropoiesis. We performed inverse variance weighted random-effects MR, several sensitivity MR analyses, and bidirectional MR and MR Steiger for directionality. AITD and PA were associated bidirectionally (P ≤ 8 × 10−6). Neither euthyroid thyroid stimulating hormone (TSH) nor free thyroxine (FT4) were causally associated with PA. One standard deviation (SD) increase in euthyroid FT4 regulated by genetic variants in deiodinases 1 and 2 genes (DIO1/DIO2), corresponding to low-normal free triiodothyronine (FT3) levels, was causally associated with a pernicious/macrocytic anemia pattern, i.e. decreased erythrocyte counts (rank-based inverse normal transformed β = −0,064 [95% confidence interval: −0,085, −0,044], P = 8 × 10−10) and hemoglobin (−0.028 [−0.051, −0.005], P = 0.02) and increased mean corpuscular hemoglobin (0.058 [0.025, 0.091], P = 5 × 10−4) and mean corpuscular volume levels (0.075 [0.052, 0.098], P = 1 × 10−8). Meanwhile, subclinical hyperthyroidism mirrored that pattern. AITD was causally associated with increased erythrocyte distribution width (P = 0.007) and decreased reticulocyte counts (P ≤ 0.02), whereas high-normal FT4 regulated by DIO1/DIO2 variants was causally associated with decreased bilirubin (−0.039 (−0.064, −0.013), P = 0.003). In conclusion, the bidirectional association between AITD and PA suggests a shared heritability for these two autoimmune diseases. AITD was causally associated with impaired erythropoiesis and not autoimmune hemolysis. Additionally, in euthyroid individuals, local regulation of thyroid hormones by deiodinases likely plays a role in erythropoiesis.
Grafting: a potential method to reveal the differential accumulation mechanism of secondary metabolites
Authors: Dong Ding , Shi Ya-Na , Mou Zong-Min , Chen Sui-Yun , Zhao Da-Ke 
Published: February 2022

Abstract
Plant secondary metabolites make a great contribution to the agricultural and pharmaceutical industries. Their accumulation is determined by the integrated transport of target compounds and their biosynthesis-related RNA, protein, or DNA. However, it is hard to track the movement of these biomolecules in vivo. Grafting may be an ideal method to solve this problem. The differences in genetic and metabolic backgrounds between rootstock and scion, coupled with multiple omics approaches and other molecular tools, make it feasible to determine the movement of target compounds, RNAs, proteins, and DNAs. In this review, we will introduce methods of using the grafting technique, together with molecular biological tools, to reveal the differential accumulation mechanism of plant secondary metabolites at different levels. Details of the case of the transport of one diterpene alkaloid, fuziline, will be further illustrated to clarify how the specific accumulation model is shaped with the help of grafting and multiple molecular biological tools.