bluuebunny/crossref_metadata_2025 huggingface dataset:
Understanding Psychiatric Illness Through Natural Language Processing (UNDERPIN): Rationale, Design, and Methodology
Authors: Kishimoto Taishiro , Nakamura Hironobu , Kano Yoshinobu , Eguchi Yoko , Kitazawa Momoko , Liang Kuo-ching , Kudo Koki , Sento Ayako , Takamiya Akihiro , Horigome Toshiro , Yamasaki Toshihiko , Sunami Yuki , Kikuchi Toshiaki , Nakajima Kazuki , Tomita Masayuki , Bun Shogyoku , Momota Yuki , Sawada Kyosuke , Murakami Junichi , Takahashi Hidehiko , Mimura Masaru
Published: December 2021

Introduction

Psychiatric disorders are diagnosed according to diagnostic criteria such as the DSM-5 and ICD-11. Basically, psychiatrists extract symptoms and make a diagnosis by conversing with patients. However, such processes often lack objectivity. In contrast, specific linguistic features can be observed in some psychiatric disorders, such as a loosening of associations in schizophrenia. The purposes of the present study are to quantify the language features of psychiatric disorders and neurocognitive disorders using natural language processing and to identify features that differentiate disorders from one another and from healthy subjects.

Methods

This study will have a multi-center prospective design. Major depressive disorder, bipolar disorder, schizophrenia, anxiety disorder including obsessive compulsive disorder and, major and minor neurocognitive disorders, as well as healthy subjects will be recruited. A psychiatrist or psychologist will conduct 30-to-60-min interviews with each participant and these interviews will be recorded using a microphone headset. In addition, the severity of disorders will be assessed using clinical rating scales. Data will be collected from each participant at least twice during the study period and up to a maximum of five times.

Discussion

The overall goal of this proposed study, the Understanding Psychiatric Illness Through Natural Language Processing (UNDERPIN), is to develop objective and easy-to-use biomarkers for diagnosing and assessing the severity of each psychiatric disorder using natural language processing. As of August 2021, we have collected a total of >900 datasets from >350 participants. To the best of our knowledge, this data sample is one of the largest in this field.

Trial registration

UMIN000032141, University Hospital Medical Information Network (UMIN).
The structural role of SARS-CoV-2 genetic background in the emergence and success of spike mutations: the case of the spike A222V mutation
Authors: Ginex Tiziana , Marco-Marín Clara , Wieczór Miłosz , Mata Carlos P. , Krieger James , López-Redondo Maria Luisa , Francés-Gómez Clara , Ruiz-Rodriguez Paula , Melero Roberto , Sánchez-Sorzano Carlos Óscar , Martínez Marta , Gougeard Nadine , Forcada-Nadal Alicia , Zamora-Caballero Sara , Gozalbo-Rovira Roberto , Sanz-Frasquet Carla , Bravo Jeronimo , Rubio Vicente , Marina Alberto ,   The IBV-Covid19-Pipeline, Geller Ron , Comas Iñaki , Gil Carmen , Coscolla Mireia , Orozco Modesto , Llácer José Luis , Carazo José-Maria
Published: December 2021

The S:A222V point mutation, within the G clade, was characteristic of the 20E (EU1) SARS-CoV-2 variant identified in Spain in early summer 2020. This mutation has now reappeared in the Delta subvariant AY.4.2, raising questions about its specific effect on viral infection. We report combined serological, functional, structural and computational studies characterizing the impact of this mutation. Our results reveal that S:A222V promotes an increased RBD opening and slightly increases ACE2 binding as compared to the parent S:D614G clade. Finally, S:A222V does not reduce sera neutralization capacity, suggesting it does not affect vaccine effectiveness.
Decrowding Expansion Pathology: Unmasking Previously Invisible Nanostructures and Cells in Intact Human Brain Pathology Specimens
Authors: Valdes Pablo A. , Yu Chih-Chieh (Jay) , Aronson Jenna , Zhao Yongxin , Bernstock Joshua D. , Bhere Deepak , An Bobae , Viapiano Mariano S. , Shah Khalid , Chiocca E. Antonio , Boyden Edward S.
Published: December 2021

Proteins are densely packed in cells and tissues, where they form complex nanostructures. Expansion microscopy (ExM) variants have been used to separate proteins from each other in preserved biospecimens, improving antibody access to epitopes. Here we present an ExM variant, decrowding expansion pathology (dExPath), which can expand proteins away from each other in human brain pathology specimens, including formalin-fixed paraffin-embedded (FFPE) clinical specimens. Immunostaining of dExPath-expanded specimens reveals, with nanoscale precision, previously unobserved cellular structures, as well as more continuous patterns of staining. This enhanced molecular staining results in observation of previously invisible disease marker-positive cell populations in human glioma specimens, with potential implications for tumor aggressiveness. dExPath results in improved fluorescence signals even as it eliminates lipofuscin-associated autofluorescence. Thus, this form of expansion-mediated protein decrowding may, through improved epitope access for antibodies, render immunohistochemistry more powerful in clinical science and diagnosis.
NAD metabolism modulates inflammation and mitochondria function in diabetic kidney disease
Authors: Myakala Komuraiah , Wang Xiaoxin X , Shults Nataliia V. , Jones Bryce A. , Yang Xiaoping , Rosenberg Avi Z , Ginley Brandon , Sarder Pinaki , Brodsky Leonid , Jang Yura , Na Chan Hyun , Qi Yue , Zhang Xu , Guha Udayan , Wu Ci , Bansal Shivani , Ma Junfeng , Cheema Amrita , Albanese Chris , Hirschey Matthew D , Yoshida Teruhiko , Kopp Jeffrey B. , Panov Julia , Levi Moshe
Published: December 2021

Diabetes mellitus is the leading cause of cardiovascular and renal disease in the United States. In spite of the beneficial interventions available for patients with diabetes, there remains a need for additional therapeutic targets and therapies in diabetic kidney disease (DKD). Inflammation and oxidative stress are increasingly recognized as important causes of renal diseases. Inflammation is closely associated with mitochondrial damage. The molecular connection between inflammation and mitochondrial metabolism remains to be elucidated. Recently, nicotinamide adenine nucleotide (NAD+) metabolism has been found to regulate immune function and inflammation. In the present studies we tested the hypothesis that enhancing NAD metabolism could prevent inflammation in and progression of DKD. We found that treatment ofdb/dbmice with type 2 diabetes with nicotinamide riboside (NR) prevented several manifestations of kidney dysfunction (i.e., albuminuria, increased urinary kidney injury marker-1 (KIM1) excretion and pathologic changes). These effects were associated with decreased inflammation, at least in part via inhibiting the activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathway. An antagonist of the serum stimulator of interferon genes (STING) and whole-body STING deletion in diabetic mice showed similar renoprotection. Further analysis found that NR increased SIRT3 activity and improved mitochondrial function, which led to decreased mitochondrial DNA damage, a trigger for mitochondrial DNA leakage which activates the cGAS-STING pathway. Overall, these data show that NR supplementation boosted NAD metabolism to augment mitochondrial function, reducing inflammation and thereby preventing progression of diabetic kidney disease.
Mathematical expressions describing enzyme velocity and inhibition at high enzyme concentration
Authors: Hernandez Agustin
Published: December 2021

Enzyme behaviour is typically characterised in the laboratory using very diluted solutions of enzyme. However, in vivo processes usually occur at [ST] ≈ [ET] ≈ Km. Furthermore, the study of enzyme action usually involves analysis and characterisation of inhibitors and their mechanisms. However, to date, there have been no reports proposing mathematical expressions that can be used to describe enzyme activity at high enzyme concentration apart from the simplest single substrate, irreversible case. Using a continued fraction approach, equations can be easily derived to apply to the most common cases in monosubstrate reactions, such as irreversible or reversible reactions and small molecule (inhibitor or activator) kinetic interactions. These expressions are simple and can be understood as an extension of the classical Michaelis-Menten equations. A first analysis of these expressions permits to deduce some differences at high vs low enzyme concentration, such as the greater effectiveness of allosteric inhibitors compared to catalytic ones. Also, they can be used to understand catalyst saturation in a reaction. Although they can be linearised following classical approaches, these equations also show some differences that need to be taken into account. The most important one may be the different meaning of line intersection points in Dixon plots. All in all, these expressions may be useful tools for the translation in vivo of in vitro experimental data or for modelling in vivo and biotechnological processes.
Quantitative genetic analysis of interactions in the pepper-Phytophthora capsici pathosystem
Authors: Vogel Gregory , Giles Garrett , Robbins Kelly R. , Gore Michael A. , Smart Christine D.
Published: December 2021

The development of pepper cultivars with durable resistance to the oomycete Phytophthora capsici has been challenging due to differential interactions between the species that allow certain pathogen isolates to cause disease on otherwise resistant host genotypes. Currently, little is known about the pathogen genes that are involved in these interactions. To investigate the genetic basis of P. capsici virulence on individual pepper genotypes, we inoculated sixteen pepper accessions – representing commercial varieties, sources of resistance, and host differentials – with 117 isolates of P. capsici, for a total of 1,864 host-pathogen combinations. Analysis of disease outcomes revealed a significant effect of inter-species genotype-by-genotype interactions, although these interactions were quantitative rather than qualitative in scale. Isolates were classified into five pathogen subpopulations, as determined by their genotypes at over 60,000 single-nucleotide polymorphisms (SNPs). While absolute virulence levels on certain pepper accessions significantly differed between subpopulations, a multivariate phenotype reflecting relative virulence levels on certain pepper genotypes compared to others showed the strongest association with pathogen subpopulation. A genome-wide association study (GWAS) identified four pathogen loci significantly associated with virulence, two of which colocalized with putative RXLR effector genes and another with a polygalacturonase gene cluster. All four loci appeared to represent broad-spectrum virulence genes, as significant SNPs demonstrated consistent effects regardless of the host genotype tested. Host genotype-specific virulence variants in P. capsici may be difficult to map via GWAS, perhaps controlled by many genes of small effect or by multiple alleles that have arisen independently at the same loci.
Interoceptive sensitivity modulates heart rate and insula activity when listening to music
Authors: Maekawa Toru , Sasaoka Takafumi , Inui Toshio , Yamawaki Shigeto
Published: December 2021

Interoception plays an important role in emotion processing, but the relationship between the physiological responses associated with emotional experience and interoception is unclear. In this study, we measured interoceptive sensitivity using the heartbeat discrimination task and investigated the effects of individual differences in interoceptive sensitivity on changes in heart rate and insula activity in response to music-induced emotions. We found that the heart rate increased when listening to the music pieces rated as emotionally high-touching in the high interoceptive sensitivity group only. Compared to the emotionally low-touching music, listening to the emotionally high-touching music was associated with higher insula activity. Furthermore, relative to individuals with low interoceptive sensitivity, the region of interest analysis of the insula subregions for individuals with high interoceptive sensitivity revealed significant activity in the bilateral dorsal granular insula, the right ventral dysgranular insula, and the right granular and dorsal dysgranular insula while listening to the high-touching music pieces. Our results suggest that individuals with high interoceptive sensitivity use their physical condition to assess their emotional level when listening to music. Furthermore, the insula activity may reflect the use of interoception to estimate emotions.
Tracing the genetics of neurological disease to the mutation-directed addition of single hydrogen bonds
Authors: Zhou Xiaoming , Tashiro Kyuto , Sumrow Lily , Sutherland Lillian , Liszczak Glen , McKnight Steven L.
Published: December 2021

Mutations causative of neurological and neurodegenerative disease can occur in coding regions that specify protein domains of low sequence complexity. These autosomal dominant mutations can be idiosyncratic in their recurrent appearance at the same amino acid. Here we report studies of recurrent mutations in proline residues located within low complexity (LC) domains associated with the neurofilament light chain protein, the microtubule-associated tau protein, and the heterogeneous nuclear RNPA2 protein. All such mutations manifest their effects by directing formation of variant proteins endowed with the addition of a single, main chain hydrogen bond specified by the variant amino acid replacing proline. Here we show that methylation of the peptide backbone nitrogen atom associated with these variant amino acids eliminates the aberrant hydrogen bond and restores normal protein function.
Relationships between pond water and tilapia skin microbiomes in aquaculture ponds in Malawi
Authors: McMurtrie Jamie , Alathari Shayma , Chaput Dominique L. , Bass David , Ghambi Camerson , Nagoli Joseph , Delamare-Deboutteville Jérôme , Mohan Chadag Vishnumurthy , Cable Joanne , Temperton Ben , Tyler Charles R.
Published: December 2021

Intensification of fish farming practices is being driven by the demand for increased food production to support a rapidly growing global human population, particularly in lower-middle income countries. Intensification of production, however, increases the risk of disease outbreaks and thus the likelihood for crop losses. The microbial communities that colonise the skin mucosal surface of fish are poorly understood, but are important in maintaining fish health and resistance against disease. This skin microbial community is susceptible to disruption through stressors associated with transport, handling and the environment of intensive practices, and this risks the propagation of disease-causing pathogens. In this study, we characterised the microbial assemblages found on tilapia skin — the most widely farmed finfish globally — and in the surrounding water of seven earthen aquaculture ponds from two pond systems in distinct geographic regions in Malawi. Metabarcoding approaches were used to sequence the prokaryotic and microeukaryotic communities. We found 92% of prokaryotic amplicon sequence variants were common to both skin and water samples. Differentially enriched and core taxa, however, differed between the skin and water samples. In tilapia skin, Cetobacterium, Paucibacter, Pseudomonas and Comamonadaceae were enriched, whereas, the cyanobacteria Cyanobium, Microcystis and/or Synechocystis, and the diatom Cyclotella, were most prevalent in pond water. Ponds that clustered together according to their water prokaryotic communities also had similar microeukaryotic communities indicating strong environmental influences on prokaryotic and microeukaryotic community structures. While strong site-specific clustering was observed in pond water, the grouping of tilapia skin prokaryotes by pond site was less distinct, suggesting fish microbiota have a greater buffering capacity against environmental influences. The characterised diversity, structure and variance of microbial communities associated with tilapia culture in Malawi provide the baseline for studies on how future intensification practices may lead to microbial dysbiosis and disease onset.

Highlights

Fish skin and pond water communities differ structurally, but share common taxa

Pond locations have a stronger influence on water versus fish skin microbiome community structure

Selected skin-associated taxa could be used to monitor dysbiotic events in aquaculture

Taxa with opportunistic pathogen potential were identified at low abundance
Imaging-Guided Bioreactor for De-Epithelialization and Long-Term Cultivation ofEx VivoRat Trachea
Authors: Mir Seyed Mohammad , Chen Jiawen , Pinezich Meghan R. , O’Neill John D. , Huang Sarah X.L. , Vunjak-Novakovic Gordana , Kim Jinho
Published: December 2021

Recent synergistic advances in organ-on-chip and tissue engineering technologies offer opportunities to createin vitro-grown tissue or organ constructs that can faithfully recapitulate theirin vivocounterparts. Suchin vitrotissue or organ constructs can be utilized in multiple applications, including rapid drug screening, high-fidelity disease modeling, and precision medicine. Here, we report an imaging-guided bioreactor that allowsin situmonitoring of the lumen ofex vivoairway tissues during controlledin vitrotissue manipulation and cultivation of isolated rat trachea. Using this platform, we demonstrated selective removal of the rat tracheal epithelium (i.e., de-epithelialization) without disrupting the underlying subepithelial cells and extracellular matrix. Through different tissue evaluation assays, such as immunofluorescent staining, DNA/protein quantification, and electron beam microscopy, we showed that the epithelium of the tracheal lumen can be effectively removed with negligible disruption in the underlying tissue layers, such as cartilage and blood vessel. Notably, using a custom-built micro-optical imaging device integrated with the bioreactor, the trachea lumen was visualized at the cellular level in real time, and removal of the endogenous epithelium and distribution of locally delivered exogenous cells were demonstratedin situ. Moreover, the de-epithelialized trachea supported on the bioreactor allowed attachment and growth of exogenous cells seeded topically on its denuded tissue surface. Collectively, the results suggest that our imaging-enabled rat trachea bioreactor and selective cell replacement method can facilitate creating of bioengineeredin vitroairway tissue that can be used in different biomedical applications.
THO and TRAMP complexes prevent transcription-replication conflicts, DNA breaks, and CAG repeat contractions
Authors: Brown Rebecca E. , Su Xiaofeng A. , Fair Stacey , Wu Katherine , Verra Lauren , Jong Robyn , Andrykovich Kristin , Freudenreich Catherine H.
Published: December 2021

Expansion of structure-forming CAG/CTG repetitive sequences is the cause of several neurodegenerative disorders and deletion of repeats is a potential therapeutic strategy. Transcription-associated mechanisms are known to cause CAG repeat instability. In this study, we discovered that Thp2, an RNA export factor and member of the THO complex, and Trf4, a key component of the TRAMP complex involved in nuclear RNA degradation, are necessary to prevent CAG fragility and repeat contractions in a S. cerevisiae model system. Depletion of both Thp2 and Trf4 proteins causes a highly synergistic increase in CAG repeat fragility, indicating a complementary role of the THO and TRAMP complexes in preventing genome instability. Loss of either Thp2 or Trf4 causes an increase in RNA polymerase stalling at the CAG repeats and genome-wide transcription-replication conflicts (TRCs), implicating impairment of transcription elongation as a cause of CAG fragility and instability in their absence. Analysis of the effect of RNase H1 overexpression on CAG fragility and TRCs suggests that co-transcriptional R-loops are the main cause of CAG fragility in the thp2Δ mutants. In contrast, CAG fragility and TRCs in the trf4Δ mutant can be compensated for by RPA overexpression, suggesting that excess unprocessed RNA in TRAMP4 mutants leads to reduced RPA availability and high levels of TRCs. Our results show the importance of RNA surveillance pathways in preventing RNAPII stalling, TRCs, and DNA breaks, and show that RNA export and RNA decay factors work collaboratively to maintain genome stability.
Chromatin accessibility differences between alpha, beta, and delta cells identifies common and cell type-specific enhancers
Authors: Mawla Alex M. , van der Meulen Talitha , Huising Mark O.
Published: December 2021

High throughput sequencing has enabled the interrogation of the transcriptomic landscape of glucagon-secreting alpha cells, insulin-secreting beta cells, and somatostatin-secreting delta cells. These approaches have furthered our understanding of expression patterns that define healthy or diseased islet cell types and helped explicate some of the intricacies between major islet cell crosstalk and glucose regulation. All three endocrine cell types derive from a common pancreatic progenitor, yet alpha and beta cells have partially opposing functions, and delta cells modulate and control insulin and glucagon release. While gene signatures that define and maintain cellular identity have been widely explored, the underlying epigenetic components are incompletely characterized and understood. Chromatin accessibility and remodeling is a dynamic attribute that plays a critical role to determine and maintain cellular identity. Here, we compare and contrast the chromatin landscape between mouse alpha, beta, and delta cells using ATAC-Seq to evaluate the significant differences in chromatin accessibility. The similarities and differences in chromatin accessibility between these related islet endocrine cells help define their fate in support of their distinct functional roles. We identify patterns that suggest that both alpha and delta cells are poised, but repressed, from becoming beta-like. We also identify patterns in differentially enriched chromatin that have transcription factor motifs preferentially associated with different regions of the genome. Finally, we identify and visualize both novel and previously discovered common endocrine- and cell specific- enhancer regions across differentially enriched chromatin.
Disentangling hand and tool processing: distal effects of neuromodulation
Authors: Amaral L. , Donato R. , Valério D. , Caparelli-Dáquer E. , Almeida J. , Bergström F.
Published: December 2021

The neural processing within a brain region that responds to more than one object category can be separated by looking at the horizontal modulations established by that region, which suggests that local representations can be affected by connections to distal areas, in a category-specific way. Here we first wanted to test whether by applying transcranial direct current stimulation (tDCS) to a region thatre sponds both to hands and tools (posterior middle temporal gyrus; pMTG), while participants performed either a hand- or tool-related training task, we would be able to specifically target the trained category, and thereby dissociate the overlapping neural processing. Second, we wanted to see if these effects were limited to the target area or extended to distal but functionally connected brain areas. After each combined tDCS and training session, participants therefore viewed images of tools, hands, and animals, in an fMRI scanner. Using multivoxel pattern analysis, we found that tDCS stimulation to pMTG indeed improved the classification accuracy between tools vs. animals, but only when combined with a tool training task (not a hand training task). However, surprisingly, tDCS stimulation to pMTG also improved the classification accuracy between hands vs. animals when combined with a tool training task (not a hand training task). Our findings suggest that overlapping but functionally-specific networks can be separated by using a category-specific training task together with tDCS - a strategy that can be applied more broadly to other cognitive domains using tDCS - and demonstrates the importance of horizontal modulations in objectcategory representations.
Short latency stretch reflexes depend on the balance of activity in agonist and antagonist muscles during ballistic elbow movements
Authors: Villamar Zoe , Ludvig Daniel , Perreault Eric J
Published: December 2021

The spinal stretch reflex is a fundamental building block of motor function, with a sensitivity that varies continuously during movement and when changing between movement and posture. Many have investigated task-dependent reflex sensitivity, but few have provided simple, quantitative analyses of the relationship between the volitional control and stretch reflex sensitivity throughout tasks that require coordinated activity of several muscles. Here we develop such an analysis and use it to test the hypothesis that modulation of reflex sensitivity during movement can be explained by the balance of activity within agonist and antagonist muscles better than by activity only in the muscle homonymous with the reflex. Subjects completed hundreds of flexion and extension movements as small, pseudo-random perturbations of elbow angle were applied to obtain estimates of stretch reflex amplitude throughout the movement. A subset of subjects performed a postural control task at muscle activities matched to those during movement. We found that reflex modulation during movement can be described by background activity in antagonist muscles about the elbow much better than by activity only in the muscle homonymous to the reflex (p<0.001). Agonist muscle activity enhanced reflex sensitivity whereas antagonist activity suppressed it. Surprisingly, the magnitude of these effects was similar, suggesting a balance of control between agonists and antagonists very different from the dominance of sensitivity to homonymous activity during posture. This balance is due to a large decrease in sensitivity to homonymous muscle activity during movement rather than substantial changes in the influence of antagonistic muscle activity.

New and Noteworthy

This study examined the sensitivity of the stretch reflexes elicited in elbow muscles to the background activity in these same muscles during movement and postural tasks. We found a heightened reciprocal control of reflex sensitivity during movement that was not present during maintenance of posture. These results help explain previous discrepancies in reflex sensitivity measured during movement and posture and provide a simple model for assessing their contributions to muscle activity in both tasks.
The accuracy of absolute differential abundance analysis from relative count data
Authors: Roche Kimberly E. , Mukherjee Sayan
Published: December 2021

Concerns have been raised about the use of relative abundance data derived from next generation sequencing as a proxy for absolute abundances. For example, in the differential abundance setting, compositional effects in relative abundance data may give rise to spurious differences (false positives) when considered from the absolute perspective. In practice however, relative abundances are often transformed by renormalization strategies intended to compensate for these effects and the scope of the practical problem remains unclear. We used simulated data to explore the consistency of differential abundance calling on renormalized relative abundances versus absolute abundances and find that, while overall consistency is high, with a median sensitivity (true positive rates) of 0.91 and specificity (1 - false positive rates) of 0.89, consistency can be much lower where there is widespread change in the abundance of features across conditions. We confirm these findings on a large number of real data sets drawn from 16S metabarcoding, expression array, bulk RNA-seq, and single-cell RNA-seq experiments, where data sets with the greatest change between experimental conditions are also those with the highest false positive rates. Finally, we evaluate the predictive utility of summary features of relative abundance data themselves. Estimates of sparsity and the prevalence of feature-level change in relative abundance data give reasonable predictions of discrepancy in differential abundance calling in simulated data and can provide useful bounds for worst-case outcomes in real data.
ARBRE: Computational resource to predict pathways towards industrially important aromatic compounds
Authors: Sveshnikova Anastasia , MohammadiPeyhani Homa , Hatzimanikatis Vassily
Published: December 2021

Synthetic biology and metabolic engineering rely on computational search tools for predictions of novel biosynthetic pathways to industrially important compounds, many of which are derived from aromatic amino acids. Pathway search tools vary in their scope of covered reactions and compounds, as well as in metrics for ranking and evaluation. In this work, we present a new computational resource called ARBRE: Aromatic compounds RetroBiosynthesis Repository and Explorer. It consists of a comprehensive biochemical reaction network centered around aromatic amino acid biosynthesis and a computational toolbox for navigating this network. ARBRE encompasses over 28’000 known and 100’000 novel reactions predicted with generalized enzymatic reactions rules and over 70’000 compounds, of which 22’000 are known to biochemical databases and 48’000 only to PubChem. Over 1,000 molecules that were solely part of the PubChem database before and were previously impossible to integrate into a biochemical network are included into the ARBRE reaction network by assigning enzymatic reactions. ARBRE can be applied for pathway search, enzyme annotation, pathway ranking, visualization, and network expansion around known biochemical pathways to predict valuable compound derivations. In line with the standards of open science, we have made the toolbox freely available to the scientific community athttp://lcsb-databases.epfl.ch/arbre/. We envision that ARBRE will provide the community with a new computational toolbox and comprehensive search tool to predict and rank pathways towards industrially important aromatic compounds.
Through-plane super-resolution with autoencoders in diffusion magnetic resonance imaging of the developing human brain
Authors: Kebiri Hamza , Canales Rodríguez Erick J. , Lajous Hélène , de Dumast Priscille , Girard Gabriel , Alemán-Gómez Yasser , Koob Mériam , Jakab András , Cuadra Meritxell Bach
Published: December 2021

Fetal brain diffusion magnetic resonance images are often acquired with a lower through-plane than in-plane resolution. This anisotropy is often overcome by classical upsampling methods such as linear or cubic interpolation. In this work, we employ an unsupervised learning algorithm using an autoencoder neural network to enhance the through-plane resolution by leveraging a large amount of data. Our framework, which can also be used for slice outliers replacement, overperformed conventional interpolations quantitatively and qualitatively on pre-term newborns of the developing Human Connectome Project. The evaluation was performed on both the original diffusion-weighted signal and on the estimated diffusion tensor maps. A byproduct of our autoencoder was its ability to act as a denoiser. The network was able to generalize to fetal data with different levels of motion and we qualitatively showed its consistency, hence supporting the relevance of pre-term datasets to improve the processing of fetal brain images.
Degradation of lactoferrin caused by droplet atomization process via two-fluid nozzle: The detrimental effect of air–water interfaces
Authors: Dao Huy M. , Sahakijpijarn Sawittree , Chrostowski Robert R. , Moon Chaeho , Mangolini Filippo , Cui Zhengrong , Williams Robert O.
Published: December 2021

Biological macromolecules, especially therapeutic proteins, are delicate and highly sensitive to degradation from stresses encountered during the manufacture of dosage forms. Thin-film freeze-drying (TFFD) and spray freeze-drying (SFD) are two processes used to convert liquid forms of protein into dry powders. In the production of inhalable dry powders that contain proteins, these potential stressors fall into three categories based on their occurrence during the primary steps of the process: (1) droplet formation (e.g., the mechanism of droplet formation, including spray atomization), (2) freezing, and (3) frozen water removal (e.g., sublimation). This study compares the droplet formation mechanism used in TFFD and SFD by investigating the effects of spraying on the stability of proteins, using lactoferrin as a model. This study considers various perspectives on the degradation (e.g., conformation) of lactoferrin after subjecting the protein solution to the atomization process using a pneumatic two-fluid nozzle (employed in SFD) or a low-shear drop application through the nozzle. The surface activity of lactoferrin was examined to explore the interfacial adsorption tendency, diffusion, and denaturation process. Subsequently, this study also investigates the secondary and tertiary structure of lactoferrin, the quantification of monomers, oligomers, and ultimately, aggregates. The spraying process affected the tertiary structure more negatively than the tightly woven secondary structure, resulting in a 1.5 nm red shift in peak position corresponding to the Tryptophan (Trp) residues. This conformational change can either (a) be reversed at low concentrations via relaxation or (b) proceed to form irreversible aggregates at higher concentrations. Interestingly, when the sample was allowed to progress into micron-sized aggregates, such a dramatic change was not detected using methods such as size-exclusion chromatography, polyacrylamide gel electrophoresis, and dynamic light scattering at 173°. A more complete understanding of the heterogeneous protein sample was achieved only through a combination of 173° and 13° backward and forward scattering, a combination of derived count rate measurements, and micro-flow imaging (MFI). Finally, compared to the low-shear dripping used in the TFFD process, lactoferrin underwent a relatively fast conformational change upon exposure to the high air-water interface of the two-fluid atomization nozzle used in the SFD process as compared to the low shear dripping used in the TFFD process. The interfacial induced denaturation that occurred during spraying was governed primarily by the size of the atomized droplets, regardless of the duration of exposure to air.
Summary statistics knockoff inference empowers identification of putative causal variants in genome-wide association studies
Authors: He Zihuai , Liu Linxi , Belloy Michael E. , Le Guen Yann , Sossin Aaron , Liu Xiaoxia , Qi Xinran , Ma Shiyang , Wyss-Coray Tony , Tang Hua , Sabatti Chiara , Candès Emmanuel , Greicius Michael D. , Ionita-Laza Iuliana
Published: December 2021

Recent advances in genome sequencing and imputation technologies provide an exciting opportunity to comprehensively study the contribution of genetic variants to complex phenotypes. However, our ability to translate genetic discoveries into mechanistic insights remains limited at this point. In this paper, we propose an efficient knockoff-based method, GhostKnockoff, for genome-wide association studies (GWAS) that leads to improved power and ability to prioritize putative causal variants relative to conventional GWAS approaches. The method requires only Z-scores from conventional GWAS and hence can be easily applied to enhance existing and future studies. The method can also be applied to meta-analysis of multiple GWAS allowing for arbitrary sample overlap. We demonstrate its performance using empirical simulations and two applications: (1) analysis of 1,403 binary phenotypes from the UK Biobank data in 408,961 samples of European ancestry, and (2) a meta-analysis for Alzheimer’s disease (AD) comprising nine overlapping large-scale GWAS, whole-exome and whole-genome sequencing studies. The UK Biobank analysis demonstrates superior performance of the proposed method compared to conventional GWAS in both statistical power (2.05-fold more discoveries) and localization of putative causal variants at each locus (46% less proxy variants due to linkage disequilibrium). The AD meta-analysis identified 55 risk loci (including 31 new loci) with ~70% of the proximal genes at these loci showing suggestive signal in downstream single-cell transcriptomic analyses. Our results demonstrate that GhostKnockoff can identify putatively functional variants with weaker statistical effects that are missed by conventional association tests.
Dairy vs. beef production – expert views on welfare
Authors: Mandel Roi , Bracke Marc B.M. , Nicol Christine J. , Webster John A. , Gygax Lorenz
Published: December 2021

Consumers’ views and concerns about the welfare of farm animals may play an important role in their decision to consume dairy, meat and/or plants as their primary protein source. As animals are killed prematurely in both dairy and beef industries, it is important to quantify and compare welfare compromise in these two sectors before the point of death. Seventy world-leading bovine welfare experts based in 23 countries, were asked to evaluate the likelihood of a bovine to experience 12 states of potential welfare concern, inspired by the Welfare Quality® protocol. The evaluation focused on the most common beef and dairy production systems in the experts’ country, and was carried out separately for dairy/beef calves raised for red-meat, dairy/beef calves raised for veal, dairy/beef calves raised as replacement, and for dairy/beef cows. The results show experts rated the overall likelihood of a negative welfare state (i.e. welfare risk) to be higher in animals from dairy herds than from beef herds, for all animal categories, regardless of whether they were used to produce milk, red-meat or veal. These findings suggest that consuming food products derived from common dairy production systems (dairy or meat), may be more harmful to the welfare of animals than consuming products derived from common beef production systems (i.e. from animals solely raised for their meat). Raising awareness about the linkage between dairy and meat production, and the toll of milk production on the welfare state of animals in the dairy industry, may encourage a more sustainable and responsible food consumption.
A naturally DNase-free CRISPR-Cas12c enzyme silences gene expression
Authors: Huang Carolyn J. , Adler Benjamin A. , Doudna Jennifer A.
Published: December 2021

Used widely for genome editing in human cells, plants and animals, CRISPR-Cas enzymes including Cas9 and Cas12 provide RNA-guided immunity to microbes by targeting foreign DNA sequences for cleavage. We show here that the native activity of CRISPR-Cas12c protects bacteria from phage infection by binding to DNA targets without cleaving them, revealing that antiviral interference can be accomplished without chemical attack on the invader or general metabolic disruption in the host. Biochemical experiments demonstrate that Cas12c is a site-specific ribonuclease capable of generating mature CRISPR RNAs (crRNAs) from precursor transcripts. Furthermore, we find that crRNA maturation is essential for Cas12c-mediated DNA targeting. Surprisingly, however, these crRNAs direct double-stranded DNA binding by Cas12c using a mechanism that precludes DNA cutting. Cas12c’s RNA-guided DNA binding activity enables robust transcriptional repression of fluorescent reporter proteins in cells. Furthermore, this naturally DNase-free Cas12c enzyme can protect bacteria from lytic bacteriophage infection when targeting an essential phage gene. Together these results show that Cas12c employs targeted DNA binding to provide anti-viral immunity in bacteria, providing a native DNase-free pathway for transient antiviral immunity.
Processing body dynamics drive non-genetic MEK inhibitors tolerance by fine-tuning KRAS and NRAS translation
Authors: Vidal-Cruchez Olivia , Nicolini Victoria J , Rete Tifenn , Rezzonico Roger , Lacoux Caroline , Fassy Julien , Jacquet Karine , Domdom Marie-Angela , Ventujol Chloé , Juhel Thierry , Roméo Barnabé , Roux Jérémie , Hubstenberger Arnaud , Mari Bernard , Mograbi Baharia , Hofman Paul , Brest Patrick
Published: December 2021

Overactivation of the Mitogen-activated protein kinase (MAPK) pathway is a critical driver of many human cancers. However, therapies targeting this pathway have proven effective in only a few cancers, as cancers inevitably develop resistance. Puzzling observations suggest that MAPK targeting fails in tumors due to early compensatory RAS overexpression, albeit by unexplained mechanisms. We identified a novel mechanism of drug tolerance to MEK inhibitors (MEKi) that involves Processing Bodies (PBs), a membraneless organelle (MLO). MEKi promoted translation of the oncogenes KRAS and NRAS, which in turn triggered BRAF phosphorylation. This overexpression, which occurred in the absence of neotranscription, depended on PB dissolution as the source of the RAS mRNA. Moreover, in response to MEKi removal, the process was dynamic as PBs rapidly reformed and reduced MAPK signaling. These results highlight a dynamic spatiotemporal negative feedback loop of MAPK signaling via RAS mRNA sequestration. Furthermore, we observed a phenotype with a low number of PBs along with strong KRAS and NRAS induction capacities. Overall, we describe a new intricate mechanism involving PBs in the translational regulation of essential cellular signaling pathways like MAPKs, paving the way for future therapies altering MLO and thereby improving targeted cancer therapies.
Exophers are components of mammalian cell neurobiology in health and disease
Authors: Siddique Ibrar , Di Jing , Williams Christopher K. , Markovic Daniela , Vinters Harry V. , Bitan Gal
Published: December 2021

Maintenance of cellular homeostasis is critically important for the survival of cells and organisms. Degradation and recycling of biomolecules and whole organelles is an essential mechanism for maintaining cellular homeostasis. The main systems responsible for these processes are the ubiquitin-proteasome system and autophagy-lysosome pathway. Another mechanism was reported in c. elegans—formation of large, membrane-enclosed projections called “exophers,” into which cells direct debris and toxic protein aggregates1. Exophers were shown to act as large, temporary disposal compartments that disconnected from the cells within several hours. Here, we report the discovery of exophers in the mammalian brain, including the brains of humans and mice. Similar to those described in nematodes, the mammalian exophers appear to emanate from the cell body, initially connected by a nanotube, and eventually disconnect. Rare, innate exophers were found in healthy human brain and primary neurons from wild-type mice, presumably mediating transfer of large cargo between cells. The number of exophers increased as an adaptive response under proteostatic stress, e.g., in Alzheimer’s disease brain or in primary neurons from two tauopathy mouse models, where the exophers likely facilitated expulsion of proteotoxic material. Our findings suggest that exopherogenesis is a rare, innate house-keeping process that is elevated adaptively in response to proteostatic pressure and is a conserved mechanism from nematodes to humans.
SPECIFIC DETECTION OF SARS-COV-2 B.1.1.529 (OMICRON) VARIANT BY FOUR RT-qPCR DIFFERENTIAL ASSAYS
Authors: Erster Oran , Beth-Din Adi , Asraf Hadar , Levy Virginia , Kabat Areej , Mannasse Batya , Azar Roberto , Shifman Ohad , Lazar Shirley , Mandelboim Michal , Fleishon Shay , Mendelson Ella , Zuckerman Neta S
Published: December 2021

In this report, we describe four RT-qPCR assays that enable rapid identification of the newly emerging SARS-COV-2 Omicron (B.1.1.529) variant of concern. The assays target Omicron characteristic mutations in the nsp6 (Orf1a), spike and nucleocapsid genes. We demonstrate that the assays are straightforward to assemble and perform, are amendable for multiplexing, and may be used as a reliable first-line tool to identify B.1.1.529 suspected samples. Importantly, this is a preliminary development report. Further validation and optimization of the assays described herein will be published hereafter.
Fawn and deer: a public institution’s biological assets valuation
Authors: Abdullah Zaimah , Shaari Hasnah , Chandren Sitraselvi , Mohd Ariff Arifatul Husna
Published: December 2021

Study level/applicability

The teaching case is designed to be used by students in higher education institutions at the undergraduate level. This case may also be relevant for staff at the bursary departments of any public universities or public organizations that have biological assets.

Case overview

This case provides a study on agricultural activity at Universiti Pengurusan Malaysia (UNIPM). The purpose of this case is to create greater awareness for case users on the accounting framework and on methods recommended for recording specific assets in agricultural activity, i.e., biological assets. This case provides users with experience in explaining the nature of an organization’s agricultural activities and accounting for biological assets as recommended in the Malaysian accounting framework. In addition, users are exposed to some current issues in accounting standards, such as ethical issues. In this case, Fakhrul, an accountant at UNIPM and a leader of the Asset Unit, was responsible for reporting the value of all UNIPM’s assets, including biological assets. He was instructed to accurately recognize, measure, and disclose the value of biological assets according to the appropriate accounting standard. Furthermore, UNIPM had been urged to replace the existing accounting standard of the Malaysian Private Entity Reporting Standard (MPERS) with the Malaysian Public Sector Accounting Standard (MPSAS). Fakhrul was considering how to account for and report biological assets according to the new MPSAS. This case is a decision making or ‘unfinished’ case which is suitable for financial accounting and reporting courses. The names of the people and the university are fictitious, but the details were based on actual events. A series of interviews were conducted with the key players to gather the data. Other useful documents such as the university’s annual report, university’s website and the deer reports were also referred.

Expected learning outcomes

The primary objective of this teaching case is to provide an opportunity for case users to understand both the accounting framework and the methods recommended for recording specific assets in agricultural activity. More specifically, the teaching objectives of this case are to achieve the following learning outcomes: to identify the relevant accounting standard for recognizing, measuring, reporting, and disclosing biological assets by public universities in Malaysia, to apply the appropriate accounting treatment in recognizing, measuring, reporting, and disclosing biological assets in accordance with the appropriate accounting standard for public universities in Malaysia and to understand the ethical issues involved in deer valuation methods.

Supplementary materials

Teaching notes are available for educators only.

Subject code

CSS 1: Accounting and finance.
A machine learning method to predict the technology adoption of blockchain in Palestinian firms
Authors: Hamdan Ihab K.A. , Sumarliah Eli , Fauziyah Fauziyah
Published: December 2021

Purpose

The study aims to deliver a decision support system for business leaders to estimate the potential for effective technological adoption of the blockchain (TAB) with a machine learning approach.

Design/methodology/approach

This study uses a Bayesian network examination to develop an extrapolative system of decision support, highlighting the influential determinants that managers can employ to predict the TAB possibilities in their companies. Data were gathered from 167 SMEs in the largest industrial sectors in Palestine.

Findings

The results reveal perceived benefit and ease of use as the most influential determinants of the TAB.

Originality/value

This research is an initial effort to examine factors influencing TAB in the perspective of SMEs in Palestine using machine learning algorithms.