bluuebunny/crossref_metadata_2025 huggingface dataset:
Destabilizing NF1 variants act in a dominant negative manner through neurofibromin dimerization
Authors: Young Lucy C. , Goldstein de Salazar Ruby , Han Sae-Won , Huang Zi Yi Stephanie , Merk Alan , Drew Matthew , Darling Joseph , Wall Vanessa , Grisshammer Reinhard , Cheng Alice , Allison Madeline R. , Sale Matthew J. , Nissley Dwight V. , Esposito Dominic , Ognjenovic Jana , McCormick Frank
Published: January 2023

The majority of pathogenic mutations in the neurofibromatosis type I (
NF1
) gene reduce total neurofibromin protein expression through premature truncation or microdeletion, but it is less well understood how loss-of-function missense variants drive NF1 disease. We have found that patient variants in codons 844 to 848, which correlate with a severe phenotype, cause protein instability and exert an additional dominant-negative action whereby wild-type neurofibromin also becomes destabilized through protein dimerization. We have used our neurofibromin cryogenic electron microscopy structure to predict and validate other patient variants that act through a similar mechanism. This provides a foundation for understanding genotype–phenotype correlations and has important implications for patient counseling, disease management, and therapeutics.
Rubble pile asteroids are forever
Authors: Jourdan Fred , Timms Nicholas E. , Nakamura Tomoki , Rickard William D. A. , Mayers Celia , Reddy Steven M. , Saxey David , Daly Luke , Bland Phil A. , Eroglu Ela , Fougerouse Denis
Published: January 2023

Rubble piles asteroids consist of reassembled fragments from shattered monolithic asteroids and are much more abundant than previously thought in the solar system. Although monolithic asteroids that are a kilometer in diameter have been predicted to have a lifespan of few 100 million years, it is currently not known how durable rubble pile asteroids are. Here, we show that rubble pile asteroids can survive ambient solar system bombardment processes for extremely long periods and potentially 10 times longer than their monolith counterparts. We studied three regolith dust particles recovered by the Hayabusa space probe from the rubble pile asteroid 25143 Itokawa using electron backscatter diffraction, time-of-flight secondary ion mass spectrometry, atom probe tomography, and
40
Ar/
39
Ar dating techniques. Our results show that the particles have only been affected by shock pressure of ca. 5 to 15 GPa. Two particles have
40
Ar/
39
Ar ages of 4,219 ± 35 and 4,149 ± 41 My and when combined with thermal and diffusion models; these results constrain the formation age of the rubble pile structure to ≥4.2 billion years ago. Such a long survival time for an asteroid is attributed to the shock-absorbent nature of rubble pile material and suggests that rubble piles are hard to destroy once they are created. Our results suggest that rubble piles are probably more abundant in the asteroid belt than previously thought and provide constrain to help develop mitigation strategies to prevent asteroid collisions with Earth.
The LexTALE as a measure of L2 global proficiency
Authors: Puig-Mayenco Eloi , Chaouch-Orozco Adel , Liu Hong , Martín-Villena Fernando
Published: January 2023

The role of proficiency is widely discussed in multilingual language acquisition research, and yet, there is little consensus as to how one should operationalize it in our empirical investigations. The present study assesses the validity of the LexTALE (Lemhöfer & Broersma, 2012) as a ‘quick and valid’ measure of global proficiency. We first provide an overview review of how the LexTALE has been used since its publication, showing that although the test has gained popularity in the last few years, its reliability has not been thoroughly examined. Thus, herein we present results of a partial replication of Lemhöfer and Broersma (2012), where we empirically assess the validity of the LexTALE as a measure of L2 global proficiency in two groups of learners of English with various degrees of proficiency (L1 Spanish, n = 288; L1 Chinese, n = 266). Results indicate that if we are to use LexTALE in our investigations, we should do so with caution as the analyses show that irrespective of the L1 and level of proficiency of the targeted participants, its reliability as a measure of global proficiency is under question evidenced by the low and moderate correlations found with a standardised measure of global proficiency.
Myosin-binding protein C stabilizes, but is not the sole determinant of SRX myosin in cardiac muscle
Authors: Nelson Shane , Beck-Previs Samantha , Sadayappan Sakthivel , Tong Carl , Warshaw David M.
Published: January 2023

The myosin super-relaxed (SRX) state is central to striated muscle metabolic and functional regulation. In skeletal muscle, SRX myosin are predominantly colocalized with myosin-binding protein C (MyBP-C) in the sarcomere C-zone. To define how cardiac MyBP-C (cMyBP-C) and its specific domains contribute to stabilizing the SRX state in cardiac muscle, we took advantage of transgenic cMyBP-C null mice and those expressing cMyBP-C with a 271-residue N-terminal truncation. Utilizing super-resolution microscopy, we determined the lifetime and subsarcomeric location of individual fluorescent-ATP turnover events within isolated cardiac myofibrils. The proportion of SRX myosin demonstrated a gradient along the half-thick filament, highest in the P- and C-zones (72 ± 9% and 71 ± 6%, respectively) and lower in the D-zone (45 ± 10%), which lies farther from the sarcomere center and lacks cMyBP-C, suggesting a possible role for cMyBP-C in stabilizing the SRX. However, myofibrils from cMyBP-C null mice demonstrated an ∼40% SRX reduction, not only within the now cMyBP-C-free C-zone (49 ± 9% SRX), but also within the D-zone (22 ± 5% SRX). These data suggest that the influence of cMyBP-C on the SRX state is not limited to the C-zone but extends along the thick filament. Interestingly, myofibrils with N-terminal truncated cMyBP-C had an SRX content and spatial gradient similar to the cMyBP-C null, indicating that the N terminus of cMyBP-C is necessary for cMyBP-C’s role in enhancing the SRX gradient along the entire thick filament. Given that SRX myosin exist as a gradient along the thick filament that is highest in the C-zone, even in the absence of cMyBP-C or its N-terminus, an inherent bias must exist in the structure of the thick filament to stabilize the SRX state.
Improving the linearity of synaptic plasticity of single-walled carbon nanotube field-effect transistors via CdSe quantum dots decoration
Authors: Zhang Yantao , Wang Zhong , Liu Jia , Wan Xianjie , Yu Zhou , Zhang Guohe , Han Chuanyu , Li Xin , Liu Weihua
Published: January 2023

The linearity of synaptic plasticity of single-walled carbon nanotube field-effect transistor (SWCNT FET) was improved by CdSe quantum dots decoration. The linearity of synaptic plasticity in SWCNT FET with decorating QDs was further improved by reducing the P-type doping level from the atmosphere. The synaptic behavior of SWCNT FET is found to be dominated by the charging and discharging processes of interface traps and surface traps, which are predominantly composed of H2O/O2 redox couples. The improved synaptic behavior is mainly due to the reduction of the interface trap charging process after QDs decoration. The inherent correlation between the device synaptic behavior and the electron capture process of the traps are investigated through charging-based trap characterization. This study provides an effective scheme for improving linearity and designing new-type SWCNT synaptic devices.
The smallest bimolecular mass action reaction networks admitting Andronov–Hopf bifurcation
Authors: Banaji Murad , Boros Balázs
Published: January 2023

We address the question of which small, bimolecular, mass action chemical reaction networks (CRNs) are capable of Andronov–Hopf bifurcation (from here on abbreviated to ‘Hopf bifurcation’). It is easily shown that any such network must have at least three species and at least four irreversible reactions, and one example of such a network with exactly three species and four reactions was previously known due to Wilhelm. In this paper, we develop both theory and computational tools to fully classify three-species, four-reaction, bimolecular CRNs, according to whether they admit or forbid Hopf bifurcation. We show that there are, up to a natural equivalence, 86 minimal networks which admit nondegenerate Hopf bifurcation. Amongst these, we are able to decide which admit supercritical and subcritical bifurcations. Indeed, there are 25 networks which admit both supercritical and subcritical bifurcations, and we can confirm that all 25 admit a nondegenerate Bautin bifurcation. A total of 31 networks can admit more than one nondegenerate periodic orbit. Moreover, 29 of these networks admit the coexistence of a stable equilibrium with a stable periodic orbit. Thus, fairly complex behaviours are not very rare in these small, bimolecular networks. Finally, we can use previously developed theory on the inheritance of dynamical behaviours in CRNs to predict the occurrence of Hopf bifurcation in larger networks which include the networks we find here as subnetworks in a natural sense.
Anisotropic edge-preserving network for resolution enhancement in unidirectional Cartesian magnetic particle imaging
Authors: Shang Yaxin , Liu Jie , Liu Yanjun , Zhang Bo , Wu Xiangjun , Zhang Liwen , Tong Wei , Hui Hui , Tian Jie
Published: January 2023

Objective. Magnetic particle imaging (MPI) is a novel imaging modality. It is crucial to acquire accurate localization of the superparamagnetic iron oxide nanoparticles distributions in MPI. However, the spatial resolution of unidirectional Cartesian trajectory MPI exhibits anisotropy, which blurs the boundaries of MPI images and makes precise localization difficult. In this paper, we propose an anisotropic edge-preserving network (AEP-net) to alleviate the anisotropic resolution of MPI. Methods. AEP-net resolve the resolution anisotropy by constructing an asymmertic convolution. To recover the edge information, we design the uncertainty region module. In addition, we evaluated the performance of the proposed AEP-net model by using simulations and experimental data. Results. The results show that the AEP-net model alleviates the anisotropy of the unidirectional Cartesian trajectory and preserves edge details in the MPI image. By comparing the visualization results and the metrics, we demonstrate that our method is superior to other methods. Significance. The proposed method produces accurate visualization in unidirectional Cartesian devices and promotes accurate quantization, which promote the biomedical applications using MPI.
Pseudo standard entanglement structure cannot be distinguished from standard entanglement structure
Authors: Arai Hayato , Hayashi Masahito
Published: January 2023

An experimental verification of the maximally entangled state ensures that the constructed state is close to the maximally entangled state, but it does not guarantee that the state is exactly the same as the maximally entangled state. Further, the entanglement structure is not uniquely determined in general probabilistic theories even if we impose that the local subsystems are fully equal to quantum systems. Therefore, the existence of the maximally entangled state depends on whether the standard entanglement structure (SES) is valid. To examine this issue, we introduce pseudo SES as a structure of quantum composite system under natural assumptions based on the existence of projective measurements and the existence of approximations of all maximally entangled standard states. Surprisingly, there exist infinitely many pseudo SESs different from the SES. In our setting, any maximally entangled state can be arbitrarily approximated by an entangled state that belongs to our obtained pseudo standard entanglement structure. That is, experimental verification does not exclude the possibility of our obtained pseudo standard entanglement structure that is different from the standard entanglement structure. On the other hand, such pseudo structures never possess global unitary symmetry, i.e. global unitary symmetry is essential condition for the SES.
Electron correlation dynamics in atomic Kr excited by XUV pulses and controlled by NIR laser pulses of variable intensity
Authors: Roos Andreas H , Hoque Ziaul , Klimešová Eva , Ben Ltaief Ltaief , Medina Cristian , Jurkovičová Lucie , Albrecht Martin , Finke Ondřej , Hort Ondřej , Nejdl Jaroslav , Mudrich Marcel , Andreasson Jakob , Krikunova Maria
Published: January 2023

We have investigated the possibility to track and control correlation dynamics of valence electrons in krypton (Kr) initiated by the absorption of one extreme ultraviolet (XUV) photon. In this investigation, pump-probe experiments have been performed where monochromatized single high-harmonics at photon energies 29.6, 32.8, and 35.9 eV have been used as pump to populate different intermediate excited states. A temporally delayed near-infrared (NIR) pulse probes the population of various decay channels via the detection of Kr2+ ion yields and its transient profiles. We observe that by varying the NIR pulse intensity within a range from

0.3
×

10

13

to

2.6
×

10

13

W cm−2, the shape of the Kr2+ transient profile changes significantly. We show that by varying the intensity of the NIR pulse, it is possible—(i) to control the ratio between sequential and non-sequential double ionization of Kr; (ii) to selectively probe quantum beating oscillations between Kr

+
∗

satellite states that are coherently excited within the bandwidth of the XUV pulse; and (iii) to specifically probe the relaxation dynamics of doubly excited (Kr

∗
∗

) decay channels. Our studies show that the contribution of different ionization and decay channels (i)–(iii) can be altered by the NIR pulse intensity, thus demonstrating an efficient way to control the ionization dynamics in rare gas atoms.
The halo bispectrum multipoles in redshift space
Authors: Rizzo Federico , Moretti Chiara , Pardede Kevin , Eggemeier Alexander , Oddo Andrea , Sefusatti Emiliano , Porciani Cristiano , Monaco Pierluigi
Published: January 2023

We present the analysis of the halo bispectrum in redshift-space in terms of its multipoles, monopole, quadrupole and hexadecapole, measured from a large set of simulations. We fit such measurements with a tree-level model in perturbation theory that depends on linear and nonlinear bias parameters as well as on the growth rate f of density fluctuations. The likelihood analysis takes advantage of a very large set of mock catalogs, enabling a robust estimation of the covariance properties for all multipoles. We compare the numerical estimate of the covariance matrix to its Gaussian prediction finding discrepancies of 10% or less for all configurations with the sole exception of the squeezed triangles in the monopole case. We find the range of validity of the tree-level model, for the total simulation volume of about
1000 h
-3Gpc3, reaches a maximum wavenumber of 0.08 h Mpc-1 for the monopole, while it is limited to 0.06 and 0.045 h Mpc-1 respectively for quadrupole and hexadecapole. Despite this, the addition of the quadrupole to the analysis allows for significant improvements on the determination of the model parameters and specifically on f, similarly to the power spectrum case. Finally, we compare our numerical estimate for the full covariance with its theoretical prediction in the Gaussian approximation and find the latter to work remarkably well in the context of simulation boxes with periodic boundary condition.
Multipacting study for fundamental power coupler of a superconducting cavity
Authors: Tang Yungai , Wu Cong-Feng , Wang Lin , Zhang Shancai , Feng Guangyao , Li Weimin , Tan Mingsheng , Zhang Kai
Published: January 2023

The research work of Hefei Advanced Light Facility (HALF) is
in progress. A 499.8 MHz superconducting cavity will be used in the
HALF RF system. The preliminary RF design and thermal analysis for
the fundamental power coupler (FPC) of HALF 499.8 MHz
superconducting cavity have been completed. Multipacting (MP) is one
of the major causes of the breakdown in many high power input
couplers and RF cavities, thus, MP simulation for our FPC is
necessary. In this paper, the MP simulation for the FPC was
performed by using the CST. The MP performance of the FPC was
studied. The formation process of the MP in the FPC was investigated
and the physical mechanism of the delay of the MP establishment was
analyzed. The simulation results show that MP will occur when the
power level is higher than 175 kW, and the MP location is near the
ceramic. Therefore, MP suppression is required in the FPC. In order
to suppress the MP, the effect of the biasing DC electric voltage to
MP in the FPC was analyzed in this paper. The simulation results
indicates that the biasing DC electric voltage not only can suppress
the MP, but also can excites new MP in the coupler. Thus, it is
crucial to select the appropriate biasing DC electric voltage for
the MP suppression in the coupler. The results show that the MP in
the FPC can be suppressed very well by using 2 kV or 3 kV biasing
DC electric voltage.
A Study on Site Specific Ground Response Analysis in Bihar
Authors: Noolu Venkatesh , Paluri Yeswanth
Published: January 2023

The influence of local soil conditions on earthquake earthquakes is assessed using seismic site response analysis. Earthquakes are natural phenomena that have claimed the lives and property of millions of people over the centuries. As a result, classifying these strong ground motions, predicting their damage potential, and suggesting mitigation measures become critical. The present study area is Kanti (Muzaffarpur), which is located in north Bihar and covers a geographical area of 3,132 square kilometres and lies between North Latitude 250 54’00”-260 23’00” and East Longitude 84053’00”- 85045’00” which falls in seismic zone IV of IS 1893: 2016. The geotechnical characterization of the site has been investigated using borehole data collected from various locations. The bedrock depth could not be determined due to a lack of deep boreholes, but traces of rock found in the collected data suggest rock outcrops in this region. According to geotechnical characterization, the soil profile in the region is dominated by silty sands, clayey silts, and poorly graded soils. DEEPSOIL software was used to estimate peak ground acceleration. Peak ground acceleration has been estimated using equivalent linear analysis with soil layer depth, bulk density, shear wave velocities, and damping as inputs.
A novel extrusion-based 3D bioprinting system for skeletal muscle tissue engineering
Authors: Fornetti E , De Paolis F , Fuoco C , Bernardini S , Giannitelli S M , Rainer A , Seliktar D , Magdinier F , Baldi J , Biagini R , Cannata S , Testa S , Gargioli C
Published: January 2023

Three-dimensional (3D) bioprinting is an emerging technology, which turned out to be an optimal tool for tissue engineering approaches. To date, different printing systems have been developed. Among them, the extrusion-based approach demonstrated to be the most suitable for skeletal muscle tissue engineering, due to its ability to produce and deposit printing fibers in a parallel pattern that well mimic the native skeletal muscle tissue architecture. In tissue bioengineering, a key role is played by biomaterials, which must possess the key requisite of ‘printability’. Nevertheless, this feature is not often well correlated with cell requirements, such as motives for cellular adhesion and/or absorbability. To overcome this hurdle, several efforts have been made to obtain an effective bioink by combining two different biomaterials in order to reach a good printability besides a suitable biological activity. However, despite being efficient, this strategy reveals several outcomes limitations. We report here the development and characterization of a novel extrusion-based 3D bioprinting system, and its application for correction of volumetric muscle loss (VML) injury in a mouse model. The developed bioprinting system is based on the use of PEG-Fibrinogen, a unique biomaterial with excellent biocompatibility, well-suited for skeletal muscle tissue engineering. With this approach, we obtained highly organized 3D constructs, in which murine muscle progenitors were able to differentiate into muscle fibers arranged in aligned bundles and capable of spontaneously contracting when cultured in vitro. Furthermore, to evaluate the potential of the developed system in future regenerative medicine applications, bioprinted constructs laden with either murine or human muscle progenitors were transplanted to regenerate the Tibialis Anterior muscle of a VML murine model, one month after grafting.
Elevated-temperature wear behavior of Ti6Al4V alloy: microstructural evolution and properties change in subsurfaces and mild-severe wear transition
Authors: An J , Zhang S G , Du D H , Chen H X
Published: January 2023

Dry sliding wear behavior of Ti6Al4V alloy was studied at elevated temperatures of 50 °C–400 °C. The constituent phases and morphologies of worn surfaces were examined to evaluate the roles of oxide layers and wear mechanisms in mild-severe wear transition (M-SWT). Microstructural evolution and hardness change in subsurfaces were also investigated to reveal the most fundamental reason for M-SWT. The results showed that M-SWT happened via severe plastic deformation (SPD) within 20 °C–350 °C, while mild wear prevailed via a protective mechanically mixed layer (MML) containing multiple oxide phases at 400 °C. Large surface plastic deformation and frictional heat activated dynamic recrystallization (DRX) softening in subsurface, which resulted in M-SWT. The critical load for M-SWT presented an approximate linear relationship with testing temperature within 20 °C–250 °C, from which a critical temperature of 555.8 °C for M-SWT was obtained by linearly fitting method. It was thought as the critical temperature for DRX realization in surface layer, and it was utilized to calculate the transition loads at 300 °C and 350 °C.
Evaluation of deep learning based implanted fiducial markers tracking in pancreatic cancer patients
Authors: Ahmed Abdella M , Gargett Maegan , Madden Levi , Mylonas Adam , Chrystall Danielle , Brown Ryan , Briggs Adam , Nguyen Trang , Keall Paul , Kneebone Andrew , Hruby George , Booth Jeremy
Published: January 2023

Real-time target position verification during pancreas stereotactic body radiation therapy (SBRT) is important for the detection of unplanned tumour motions. Fast and accurate fiducial marker segmentation is a Requirement of real-time marker-based verification. Deep learning (DL) segmentation techniques are ideal because they don’t require additional learning imaging or prior marker information (e.g., shape, orientation). In this study, we evaluated three DL frameworks for marker tracking applied to pancreatic cancer patient data. The DL frameworks evaluated were (1) a convolutional neural network (CNN) classifier with sliding window, (2) a pretrained you-only-look-once (YOLO) version-4 architecture, and (3) a hybrid CNN-YOLO. Intrafraction kV images collected during pancreas SBRT treatments were used as training data (44 fractions, 2017 frames). All patients had 1-4 implanted fiducial markers. Each model was evaluated on unseen kV images (42 fractions, 2517 frames). The ground truth was calculated from manual segmentation and triangulation of markers in orthogonal paired kV/MV images. The sensitivity, specificity, and area under the precision-recall curve (AUC) were calculated. In addition, the mean-absolute-error (MAE), root-mean-square-error (RMSE) and standard-error-of-mean (SEM) were calculated for the centroid of the markers predicted by the models, relative to the ground truth. The sensitivity and specificity of the CNN model were 99.41% and 99.69%, respectively. The AUC was 0.9998. The average precision of the YOLO model for different values of recall was 96.49%. The MAE of the three models in the left-right, superior-inferior, and anterior-posterior directions were under 0.88 ± 0.11 mm, and the RMSE were under 1.09 ± 0.12 mm. The detection times per frame on a GPU were 48.3, 22.9, and 17.1 milliseconds for the CNN, YOLO, and CNN-YOLO, respectively. The results demonstrate submillimeter accuracy of marker position predicted by DL models compared to the ground truth. The marker detection time was fast enough to meet the requirements for real-time application.
Wood and bark structure inBuddleja: anatomical background of stem morphology
Authors: Frankiewicz K E , Chau J H , Baczyński J , Wdowiak A , Oskolski A
Published: January 2023

Bark (all tissues outside of the vascular cambium) has been extensively studied in recent years, especially its anatomy and physiology. Macromorphological bark characters can be important taxonomically for many plant groups, including the genus Buddleja (Scrophulariaceae). However, the relationship between macroscopic bark appearance and its microscopic structure remains obscure, hampering the use and interpretation of bark traits in plant taxonomy and phylogenetics as well as in other fields of botany. We studied micro- and macrostructure of bark in the species of Buddleja representing wide taxonomic and geographic diversity to identify general relationships between bark anatomy and morphology. We also examined Buddleja xylem and discussed the importance of anatomical traits for understanding the relationships between clades in this genus. The smooth bark surface in sect. Gomphostigma and the outgroup (Freylinia spp.) relates to the small number of periderms of superficial origin and limited sclerification. This allows for the retention of visible lenticels. In the rest of Buddleja, bark sloughs off and division of labour is present: collapsed phloem undergoes sclerification and acts as a protective layer, while thin-walled phellem forms the separation layers. A similar pattern is found in some groups (e.g. Lonicera), but in others (e.g. Vitis and the species of Eucalyptus with stringy bark), the pattern is inversed. Wood and bark anatomy supports a sister relationship between the southern African section Gomphostigma and the rest of Buddleja but is taxonomically uninformative among remaining clades. Limited development of periderms and sclerification allows for the retention of a smooth bark surface and conspicuous lenticels. Sloughing off of bark requires division of labour into a lignified protective layer and a thin-walled separation layer. These two functions are never served by a single tissue but are rather divided between phloem and periderm. How more subtle features (e.g. size and shape of fissures) are determined requires further study. Simultaneously, bark anatomy could be a useful source of data to complement molecular phylogenetic studies in a total evidence approach for systematics.
Characterizing the Network Structure of Post-Concussion Symptoms
Authors: Goodwin Grace J , Salva Christine E , Rodrigues Jessica , Maietta Julia , Kuwabara Hana C , Ross Staci , Kinsora Thomas F , Allen Daniel N
Published: January 2023

Objective

Assessment of post-concussion symptoms is implemented at secondary, post-secondary, and professional levels of athletics. Network theory suggests that disorders can be viewed as a set of interacting symptoms that amplify, reinforce, and maintain one another. Examining the network structure of post-concussion symptoms may provide new insights into symptom comorbidity and may inform targeted treatment. We used network analysis to examine the topology of post-concussion symptoms using the Post-Concussion Symptom Scale (PCSS) in high school athletes with recent suspected sport-related concussion.

Method

Using a cross-sectional design, the network was estimated from Post Concussion Symptom Scale scores from 3,292 high school athletes, where nodes represented symptoms and edges represented the association between symptoms. Node centrality was calculated to determine the relative importance of each symptom in the network.

Results

The network consisted of edges within and across symptom domains. “Difficulty concentrating” and “dizziness” were the most central symptoms in the network. Although not highly central in the network, headaches were the highest rated symptom.

Conclusions

The interconnectedness among symptoms supports the notion that post-concussion symptoms are interrelated and mutually reinforcing. Given their central role in the network, “difficulty concentrating” and “dizziness” are expected to affect the activation and persistence of other post-concussion symptoms. Interventions targeting difficulties with concentration and dizziness may help alleviate other symptoms. Our findings could inform the development of targeted treatment with the aim of reducing overall symptom burden. Future research should examine the trajectory of post-concussion symptom networks to advance the clinical understanding of post-concussive recovery.
Multivariate Base Rates of Low Score on Neuropsychological Tests of Individuals with Coca Paste Use Disorder
Authors: Vergara-Moragues Esperanza , Barreto María Rocío Acosta , Rivera Diego , Santiago-Ramajo Sandra , González-Saiz Francisco , Lasprilla Juan Carlos Arango
Published: January 2023

Objective

The aim of this study was to determine the prevalence of low scores on eight commonly used neuropsychological tests to evaluate learning and memory, language, and executive functions in individuals with coca paste use disorders (CPUD) and to identify the differences with respect to a group of healthy nonconsuming subjects (HCs).

Methods

162 Colombian adults with CPUD and a group of 162 Colombian adult HCs participated in this comparative study. Eight tests (eighteen test scores) were grouped into three categories: learning and memory, language, and executive functions. Each participant was categorized based on the number of low scoring tests in specific percentile cut-off groups (25th, 16th, 10th, 5th, and 2nd).

Results

In the learning and memory domain, 89.5% of individuals with CPUD and 55.6% of HCs scored below the 25th percentile on at least one of the five test scores, in the language domain, 80.7% of individuals with CPUD and 58% of HCs and in the executive function domain, 92% of individuals with CPUD and 67.3% of HCs. Having two or more scores below the 10th percentile or 10 or more at the 5th percentile shows an optimal cut-off for determining the sensitivity and specificity for discriminating between the two groups.

Conclusions

The individuals with CPUD had a higher percentage of low scores than the HCs in the domains of learning and memory, language, and executive function. It is important for clinicians to be aware of low scores in individuals with CPUD to avoid false-positive diagnoses of cognitive impairment.
cvlr: finding heterogeneously methylated genomic regions using ONT reads
Authors: Raineri Emanuele , Alberola i Pla Mariona , Dabad Marc , Heath Simon
Published: January 2023

Nanopore reads encode information on the methylation status of cytosines in CpG dinucleotides. The length of the reads makes it comparatively easy to look at patterns consisting of multiple loci; here, we exploit this property to search for regions where one can define subpopulations of molecules based on methylation patterns. As an example, we run our clustering algorithm on known imprinted genes; we also scan chromosome 15 looking for windows corresponding to heterogeneous methylation. Our software can also compute the covariance of methylation across these regions while keeping into account the mixture of different types of reads.

Availability and implementation

https://github.com/EmanueleRaineri/cvlr.

Contact

simon.heath@cnag.crg.eu

Supplementary information

Supplementary data are available at Bioinformatics Advances online.
Faltwerk: a library for spatial exploratory data analysis of protein structures
Authors: Viehweger Adrian
Published: January 2023

Proteins are fundamental building blocks of life and are investigated in a broad range of scientific fields, especially in the context of recent progress using in silico structure prediction models and the surge of resulting protein structures in public databases. However, exploratory data analysis of these proteins can be slow because of the need for several methods, ranging from geometric and spatial analysis to visualization. The Python library faltwerk provides an integrated toolkit to perform explorative work with rapid feedback. This toolkit includes support for protein complexes, spatial analysis (point density or spatial autocorrelation), ligand binding site prediction and an intuitive visualization interface based on the grammar of graphics.

Availability and implementation

faltwerk is distributed under the permissive BSD-3 open source license. Source code and documentation, including an extensive common-use case tutorial, can be found at github.com/phiweger/faltwerk; binaries are available from the pypi repository.
Cistrome Explorer: an interactive visual analysis tool for large-scale epigenomic data
Authors: L’Yi Sehi , Keller Mark S , Dandawate Ariaki , Taing Len , Chen Chen-Hao , Brown Myles , Meyer Clifford A , Gehlenborg Nils
Published: January 2023

The regulation of genes by cis-regulatory elements (CREs) is complex and differs between cell types. Visual analysis of large collections of chromatin profiles across diverse cell types, integrated with computational methods, can reveal meaningful biological insights. We developed Cistrome Explorer, a web-based interactive visual analytics tool for exploring thousands of chromatin profiles in diverse cell types. Integrated with the Cistrome Data Browser database which contains thousands of ChIP-seq, DNase-seq and ATAC-seq samples, Cistrome Explorer enables the discovery of patterns of CREs across cell types and the identification of transcription factor binding underlying these patterns.

Availability and implementation

Cistrome Explorer and its source code are available at http://cisvis.gehlenborglab.org/ and released under the MIT License. Documentation can be accessed via http://cisvis.gehlenborglab.org/docs/.

Supplementary information

Supplementary data are available at Bioinformatics online.
Phosformer: an explainable transformer model for protein kinase-specific phosphorylation predictions
Authors: Zhou Zhongliang , Yeung Wayland , Gravel Nathan , Salcedo Mariah , Soleymani Saber , Li Sheng , Kannan Natarajan
Published: January 2023

Motivation

The human genome encodes over 500 distinct protein kinases which regulate nearly all cellular processes by the specific phosphorylation of protein substrates. While advances in mass spectrometry and proteomics studies have identified thousands of phosphorylation sites across species, information on the specific kinases that phosphorylate these sites is currently lacking for the vast majority of phosphosites. Recently, there has been a major focus on the development of computational models for predicting kinase–substrate associations. However, most current models only allow predictions on a subset of well-studied kinases. Furthermore, the utilization of hand-curated features and imbalances in training and testing datasets pose unique challenges in the development of accurate predictive models for kinase-specific phosphorylation prediction. Motivated by the recent development of universal protein language models which automatically generate context-aware features from primary sequence information, we sought to develop a unified framework for kinase-specific phosphosite prediction, allowing for greater investigative utility and enabling substrate predictions at the whole kinome level.

Results

We present a deep learning model for kinase-specific phosphosite prediction, termed Phosformer, which predicts the probability of phosphorylation given an arbitrary pair of unaligned kinase and substrate peptide sequences. We demonstrate that Phosformer implicitly learns evolutionary and functional features during training, removing the need for feature curation and engineering. Further analyses reveal that Phosformer also learns substrate specificity motifs and is able to distinguish between functionally distinct kinase families. Benchmarks indicate that Phosformer exhibits significant improvements compared to the state-of-the-art models, while also presenting a more generalized, unified, and interpretable predictive framework.

Availability and implementation

Code and data are available at https://github.com/esbgkannan/phosformer.

Supplementary information

Supplementary data are available at Bioinformatics online.
Binding peptide generation for MHC Class I proteins with deep reinforcement learning
Authors: Chen Ziqi , Zhang Baoyi , Guo Hongyu , Emani Prashant , Clancy Trevor , Jiang Chongming , Gerstein Mark , Ning Xia , Cheng Chao , Min Martin Renqiang
Published: January 2023

Motivation

MHC Class I protein plays an important role in immunotherapy by presenting immunogenic peptides to anti-tumor immune cells. The repertoires of peptides for various MHC Class I proteins are distinct, which can be reflected by their diverse binding motifs. To characterize binding motifs for MHC Class I proteins, in vitro experiments have been conducted to screen peptides with high binding affinities to hundreds of given MHC Class I proteins. However, considering tens of thousands of known MHC Class I proteins, conducting in vitro experiments for extensive MHC proteins is infeasible, and thus a more efficient and scalable way to characterize binding motifs is needed.

Results

We presented a de novo generation framework, coined PepPPO, to characterize binding motif for any given MHC Class I proteins via generating repertoires of peptides presented by them. PepPPO leverages a reinforcement learning agent with a mutation policy to mutate random input peptides into positive presented ones. Using PepPPO, we characterized binding motifs for around 10 000 known human MHC Class I proteins with and without experimental data. These computed motifs demonstrated high similarities with those derived from experimental data. In addition, we found that the motifs could be used for the rapid screening of neoantigens at a much lower time cost than previous deep-learning methods.

Availability and implementation

The software can be found in https://github.com/minrq/pMHC.

Supplementary information

Supplementary data are available at Bioinformatics online.
Selection of p53 pathway in adaptive evolution and reproductive isolation in incipient sympatric speciation ofDrosophilaat Evolution Canyon
Authors: Zhao Yang , Song Li , Wang Junying , Fang Xiaodong , Li Kexin , Han Lijuan , Beiles Avigdor , Cao Yi-Bin , Nevo Eviatar
Published: January 2023

Sympatric speciation (SS) refers to the origin of new species within a freely breeding population. The ‘Evolution Canyon’ (EC) in Israel is a natural microsite model for SS of species across phylogenies from viruses and bacteria to mammals, adapting to, and speciating in, interslope microclimates. The cosmopolitan Drosophila melanogaster at EC I, Mount Carmel, is undergoing incipient SS in response to sharply divergent interslope microclimate stresses, including solar radiation, temperature, humidity and pathogenicity. We demonstrated here a selective interslope divergence of single nucleotide polymorphism (SNP) distribution in the Drosophila p53 pathway. This involves a total of 71 genes, which are associated with DNA repair, heat response, and fungal and bacterial resistant pathways. This distribution pattern links the previously observed thermotolerance and ageing divergence of D. melanogaster between the opposite canyon slopes: the south-facing slope (SFS, or African slope: tropical, savannoid and dry) and the abutting north-facing slope (NFS, or European slope; temperate, forested, cool and humid). The genes with interslope-significant differential SNPs link the p53 pathway with pathways related to the responses to microclimates through protein-protein interaction. Moreover, for the first time we provide evidence that the p53 pathway is linked to reproductive isolation, and is thus actively participating in incipient SS of D. melanogaster. This is the first demonstration of a link between the p53 pathway and reproductive isolation, thereby contributing to adaptive incipient sympatric speciation.
Recent natural hybridization inElymusandCampeiostachysof Triticeae: evidence from morphological, cytological and molecular analyses
Authors: Wu Dan-Dan , Liu Xiao-Yan , Yu Zheng-Hao , Tan Lu , Lu Jia-Le , Cheng Yi-Ran , Sha Li-Na , Fan Xing , Kang Hou-Yang , Wang Yi , Zhou Yong-Hong , Zhang Chang-Bing , Zhang Hai-Qin
Published: January 2023

Natural hybrids in Triticeae have been frequently reported from the Qinghai–Tibet plateau, but minor variation in morphological features and homoploid hybridization have made it difficult to identify the origin and genome constitution of hybrids between Elymus and Campeiostachys. Specimens were investigated using morphology, cytogenetics and phylogenetic analyses to uncover the genome constitution and origin of ten putative natural hybrids (SH01-SH10) from the Qinghai–Tibet plateau. SH01, SH02, SH03, SH05 and SH06 (2n = 5x = 35, StStHHY) originated from Campeiostachys breviaristata (2n = 6x = 42, StStHHYY) and Elymus sibiricus (2n = 4x = 28, StStHH); SH04 and SH07 (2n = 5x = 35, StStHHY) originated from C. nutans (2n = 6x = 42, StStHHYY) and E. sibiricus; SH08 (2n = 5x = 35, StStHHY) originated from C. dahurica var. tangutorum (2n = 6x = 42, StStHHYY) and E. sibiricus; and SH09 and SH10 (2n = 4x = 28, StStHH) were the homoploid hybrids of E. sibiricus and an unknown Elymus sp. (2n = 4x = 28, StStHH). Karyotype variations in SH04 and SH07 might originate from the maternal progenitor. Frequent hybridization in the Qinghai–Tibet plateau might result from factors such as genome constitution, pollination habits, overlapping flowering stage, sympatric distribution and unique ecological conditions.
Phylogeographic patterns ofDeschampsia cespitosa(Poaceae) in Europe inferred from genomic data
Authors: Xue Zhiqing , Chiapella Jorge O , Paun Ovidiu , Volkova Polina , Peintinger Markus , Wasowicz Pawel , Tikhomirov Nikita , Grigoryan Maksim , Barfuss Michael H J , Greimler Josef
Published: January 2023

The highly variable tufted hairgrass Deschampsia cespitosa is a tussock-forming plant especially of cool and humid environments. Although common and widespread, its phylogeographic structure and the significance of polyploidy for its evolution are poorly understood. Here we used a phylogenomic approach to study the genetic structure of this species in Europe and how the polyploid cytotypes/subspecies are related to the diploids. Using genomic data (RADseq and whole plastid sequencing) we found a highly divergent Iberian group, including the Spanish Deschampsia cespitosa subsp. cespitosa (diploid and tetraploid) and the Macaronesian island endemic diploid Deschampsia argentea. Moreover, we found substantial divergence of pseudoviviparous tetraploids (Deschampsia cespitosa subspp. neoalpina and rhenana) from seminiferous tetraploids (except Deschampsia cespitosa subsp. littoralis) and all diploids of the remaining European samples. The divergent pseudoviviparous tetraploids (D. cespitosa subspp. neoalpina and rhenana) and the seminiferous tetraploid D. cespitosa subsp. littoralis probably represent periglacial and relict lineages of unknown origin regarding auto- and/or allo-polyploidy, whereas other seminiferous tetraploid variants of D. cespitosa are always nested in the diploid D. cespitosa, suggesting multiple autopolyploid origins. An analysis after excluding the Iberian Group and the highly divergent tetraploids revealed five genetic groups with overlapping geographical patterns. However, the recovered geographical structure, the overall low genetic divergence and the diffuse genetic structure point to recolonization from various refugial areas and secondary contact. Effective wind dispersal of pollen and seeds in an open early post-glacial tundra landscape and, finally, increasing human impact on dispersal of this grass since the Neolithic, may have enhanced admixture and resulted in the complex patterns detected today.
Phylogenetics of the Andean tree genusRuagea(Meliaceae): implications for taxonomy
Authors: Rojas-Andrés Blanca M , Lihanova Yuliia , Pennington Terence D , Muellner-Riehl Alexandra N
Published: January 2023

Ruagea (Meliaceae) comprises c. 15 species of small or medium-sized trees distributed in Central and South America, predominantly in montane rain forest and cloud forest of the Andes. The taxonomic position of Ruagea has changed several times in the past, and it was previously included in Guarea. Ruagea is currently accepted as a separate genus based on morphology and molecular phylogenetic analyses at the family level. However, its monophyly has not been accurately tested, and phylogenetic relationships among species are still largely unknown. In addition, delimitation of species boundaries is not straightforward due to morphological diversity within species. Here, we present the first phylogenetic reconstruction of Ruagea based on two nuclear ribosomal (ITS, ETS) and two plastid DNA regions (rps4-trnT, psbA-trnH). Our results show that Ruagea is monophyletic and composed of four main clades (A, B, C and D). Clade D, comprising the Ecuadorian endemic R. membranacea and a potentially new species from Colombia, is sister to the rest of the genus. Our results demonstrate that R. membranacea and R. insignis are monophyletic and provide support for the recognition of two new species with divergent morphologies. The delimitation of the remaining species remains unresolved as they are recovered as either poly- or paraphyletic. Our results highlight the complexity of the taxonomy of Ruagea, as found in other rainforest taxa, and the need for further detailed analyses to delimit these taxa. This study provides the first and most extensive phylogenetic analysis of the genus so far, representing a contribution towards understanding the evolutionary history of Ruagea.
Association analysis of 10 candidate genes causing Mendelian calcium nephrolithiasis in the INCIPE study: a South European general population cohort
Authors: Santoro Gloria , Lombardi Gianmarco , Andreola Stefano , Salvagno Gian Luca , Treccani Mirko , Locatelli Elena , Ferraro Pietro Manuel , Lippi Giuseppe , Malerba Giovanni , Gambaro Giovanni
Published: January 2023

Background

Idiopathic calcium nephrolithiasis (ICN) is a common condition with a complex phenotype influenced by both environmental and genetic factors. In our study we investigated the association of allelic variants with the history of nephrolithiasis.

Methods

We genotyped and selected 10 candidate genes potentially related to ICN from 3046 subjects participating in the INCIPE survey cohort (Initiative on Nephropathy, of relevance to public health, which is Chronic, possibly in its Initial stages, and carries a Potential risk of major clinical End-points), a study enrolling subjects from the general population in the Veneto region in Italy.

Results

Overall, 66 224 variants mapping on the 10 candidate genes were studied. A total of 69 and 18 variants in INCIPE-1 and INCIPE-2, respectively, were significantly associated with stone history (SH). Only two variants, rs36106327 (chr20:54 171 755, intron variant) and rs35792925 (chr20:54 173 157, intron variant) of the CYP24A1 gene were observed to be consistently associated with ICN. Neither variant has been previously reported in association with renal stones or other conditions. Carriers of CYP24A1 variants showed a significant increase in the ratio of 1,25 (OH)2 vitamin D to 25 (OH) vitamin D compared with controls (P = .043). Although not associated with ICN in this study, the rs4811494 CYP24A1 variant that was reported to be causative of nephrolithiasis was very prevalent in heterozygosity (20%).

Conclusion

Our data suggest a possible role for CYP24A1 variants in the risk of nephrolithiasis. Genetic validation studies in larger sample sets will be necessary to confirm our findings.