bluuebunny/crossref_metadata_2025 huggingface dataset:
A Simple Method to Retract the Descending Palatine Neurovascular Bundle During Osseous Removal of Posterior Interferences in Le Fort I Osteotomy
Authors: Rodrigues Moacyr Tadeu Vicente , Mendes Bruno Coelho , Borba Alexandre Meireles , Nóia Claudio Ferreira
Published: February 2022

For accurate repositioning of the maxilla in Le Fort I osteotomy, bone removal around the descending palatine neurovascular bundle and maxillary tuberosity is frequently required. Such task can be challenging due to the high vascularity of the region, which is the most common site of hemorrhage during removal of bony interferences. Although a rare occurrence, ligation of the descending palatine artery in cases of intraoperative vascular damage can be related to the development of aseptic necrosis. This article reports a simple technique for retraction and protection of the descending palatine neurovascular bundle during bony removal related to a posterior maxillary impaction, which can be easily reproduced in orthognathic selected cases.
Recombinant human erythropoietin protects long-term cultured ageing primary nerve cells by upregulating the PI3K/Akt pathway
Authors: Wang Huqing , Chen Ming , Gao Zhen , Gong Yu , Yu Xiaorui , Wu Haiqin
Published: February 2022

Objective

Previous studies have found that recombinant human erythropoietin (rhEPO) protects long-term cultured ageing primary nerve cells by enhancing the endogenous antioxidant capacity of cells; however, its signalling pathways are not clear. This study aimed to explore the relationship between the rhEPO and PI3K/Akt pathways in the protection of senescent nerve cells at the cellular level.

Methods

Primary nerve cells were cultured for 22 days to mimic the natural ageing process of nerve cells. rhEPO and LY294002 were administered as an intervention on the 11th day of culture. Western blot, immunochemistry, 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide, immunofluorescence double-labelling staining, Annexin V-FITC/PI double-labelling flow cytometry, and SA-β-gal staining experiments were used to observe the expression levels of erythropoietin receptor (EPOR) and phosphorylated Akt (p-Akt) protein and the related indices of nerve cell senescence.

Results

Western blot experiments showed that in ageing long-term cultured primary neurons, the EPOR and p-Akt decreased and rhEPO upregulated the expression levels of EPOR and p-Akt protein. The rest showed that the PI3K/Akt pathway blockade reduced the antioxidation capacity, cell viability, cell morphology, and ratio of apoptotic cells and senescent cells of rhEPO on ageing long-term cultured primary nerve cells.

Conclusions

This study explored the relationship between the rhEPO and PI3K/Akt pathways in the protection of ageing nerve cells at the cellular level and found that rhEPO protects long-term cultured ageing primary nerve cells by upregulating the PI3K/Akt pathway. These findings provide a theoretical basis and experimental evidence for the antiaeging mechanism of EPO in the nervous system.
The role of a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type receptor modulators in object recognition memory reconsolidation
Authors: Man Xin-Yi , Chang Zao-Shang , Mo Yan-Xin , Liang Kai , Wang Le , Xiao Zhi-Yong
Published: February 2022

Objective

Numerous studies suggest that the a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type (AMPA) receptor appears to play a central role in mediating brain functions, such as learning and memory. Trafficking of this receptor is related to different long-term memory processes. This study explores the role of two AMPA receptor (AMPAR) modulators in object recognition memory (ORM) reconsolidation.

Methods

First, the effects of immediate administration of each drug after memory reactivation were investigated and compared. Then, this drug’s efficient time window and its effects without memory reactivation were investigated.

Results

Immediate CX546 administration after reactivation did not affect ORM reconsolidation. In contrast, administration of 10-mg/kg NBQX significantly impaired ORM reconsolidation within a 6-h time window. Importantly, the observed effects were not attributed to the exploratory behavior or locomotor activity of mice.

Conclusion

These findings provide new evidence that the AMPA receptor plays an important role in the reconsolidation phase of ORM.
Language specificity in the processing of affirmative and negative sentences
Authors: Huang Yingying , Dong Jie , He Yan , Hei Yuqin , Duan Xu , Zhang Wenjia , Yan Hao
Published: February 2022

Objective

It is agreed that understanding a negative sentence elicits additional neural responses in reversing the truth of an embedded affirmative proposition. However, this argument is challenged by previous neuroimaging studies when distinct languages are used. Therefore, we intended to explore the language specificity of affirmative and negative sentence processing in this study.

Methods

We recruited a group of Chinese-English bilinguals to conduct a grammar judgment task of affirmative and negative sentences during functional magnetic resonance imaging scanning. And we kept syntactic complexity/sentence length matched in both affirmative and negative sentences.

Results

We found that negative sentences elicited more activation in the perisylvian region, which supported the ‘truth reversing hypothesis’ and argued the reversing process was implemented by the dorsal anterior cingulate cortex. The significant language-by-sentence interaction effect in the inferior prefrontal cortex and rostral prefrontal cortex showed that sentential negation was influenced by distinctive language expression.

Conclusion

These results demonstrated the ‘truth reversing hypothesis’. Further analysis revealed the effect of language expression on the neural mechanism of sentential negation.
Mate Competition Drives Aggressive Behaviour in Female Drosophila
Authors: Gaspar Miguel , Dias Sophie , Vasconcelos Maria Luísa
Published: February 2022

Aggression is an adaptive set of behaviours that allows animals to compete against one another in an environment of limited resources. In Drosophila such aggressive behaviour has been extensively studied in males. Despite recent work highlighting territorial defence in females, female aggression in Drosophila is still poorly understood. Indeed, whether females compete for mating partners, as males do, has remained unknown so far. In the present work, we report that Drosophila melanogaster females reliably display aggression towards mating pairs. This aggressive behaviour is positively associated with the female’s mating drive and relies heavily on olfaction. Furthermore, we found that food odour in combination with OR47b-dependent fly odour sensing are required for proper expression of aggressive behaviour. Taken together, we describe a social context linked to reproduction in which Drosophila females aspiring to mate produce consistent and stereotyped displays of aggression. These findings open the door for further inquiries into the neural mechanisms that govern this behaviour.
Direct Modulation Index: a measure of phase amplitude coupling for neurophysiology data
Authors: Scherer Maximilian , Wang Tianlu , Guggenberger Robert , Milosevic Luka , Gharabaghi Alireza
Published: February 2022

Neural communication across different spatial and temporal scales is a topic of great interest in clinical and basic science. Phase-amplitude coupling (PAC) has attracted particular interest due to its functional role in a wide range of cognitive and motor functions. Here, we introduce a novel measure termed the direct modulation index (dMI). Based on the classical modulation index, dMI provides an estimate of PAC that is bound to an absolute interval between 0 and +1, resistant against noise, and reliable even for small amounts of data. To highlight the properties of this newly-proposed measure, we evaluated dMI by comparing it to the classical modulation index, mean vector length, and phase-locking value using simulated data. We ascertained that dMI provides a more accurate estimate of PAC than the existing methods and that is resilient to varying noise levels and signal lengths. As such, dMI permits a reliable investigation of PAC, which may reveal insights crucial to our understanding of functional brain architecture in key contexts such as behaviour and cognition. A Python toolbox that implements dMI and other measures of PAC is freely available at https://github.com/neurophysiological-analysis/FiNN.

Highlights

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Neural coupling measures are sensitive to higher harmonics of the target oscillation.

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dMI achieves frequency-specificity by sine-fitting the phase-amplitude histogram.

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Increased robustness to noise and signal duration in comparison to other measures.

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dMI allows for reliable estimation of phase-amplitude coupling.
Clinically driven knowledge distillation for sparsifying high-dimensional multi-omics survival models
Authors: Wissel David , Rowson Daniel , Boeva Valentina
Published: February 2022

Recently, various methods have been proposed to integrate different heterogeneous high-dimensional genomic data sources to predict cancer survival, often in addition to widely available and highly predictive clinical data. Although clinical applications of survival models have high sparsity requirements, most state-of-the-art models do not naturally exhibit this sparsity, as they are based on random forests or deep learning. We propose to use𝓁1-penalized linear student models within a knowledge distillation framework to sparsify underlying multi-omics black-box teachers. We show that by excluding clinical variables from our𝓁1penalty, we can effectively guide the knowledge distillation, reaching virtually identical discriminative performance to the teachers while using on average 140 features or less across the 17 cancer datasets from The Cancer Genome Atlas (TCGA) considered in our study.
Bacterioplankton taxa compete for iron along the early spring-summer transition in the Arctic Ocean
Authors: Puente-Sánchez Fernando , Macías Luis , Campbell Karley L. , Royo-Llonch Marta , Balagué Vanessa , Sánchez Pablo , Tamames Javier , Mundy C.J. , Pedrós-Alió Carlos
Published: February 2022

Microbial assemblages under sea ice of Dease Strait, Canadian Arctic, were sequenced for metagenomes and metatranscriptomes of the small size fraction (0.2 to 3 µm). The community from early March was typical for this season, with Alpha- and Gammaproteobacteria as the dominant taxa, followed by Thaumarchaeota and Bacteroidetes. Towards summer, Bacteroidetes and particularly the genus Polaribacter, became increasingly dominant, followed by the Gammaproteobacteria. Analysis of genes responsible for microbial acquisition of iron showed an abundance of ABC transporters for divalent cations and ferrous iron. The most abundant transporters, however, were the outer membrane TonB dependent transporters of iron-siderophore complexes. The abundance of iron acquisition genes suggested this element was essential for the microbial assemblage. Interestingly, Gammaproteobacteria were responsible for most of the siderophore synthesis genes. On the contrary, Bacteroidetes did not synthesize siderophores but accounted for most of the transporters, suggesting a role as cheaters in the competition for siderophores as public goods. Likely, this cheating ability of the Bacteroidetes contributed to their dominance in summer.
The relationship between frequency content and representational dynamics in the decoding of neurophysiological data
Authors: Higgins Cameron , van Es Mats W.J. , Quinn Andrew , Vidaurre Diego , Woolrich Mark
Published: February 2022

Decoding of high temporal resolution, stimulus-evoked neurophysiological data is increasingly used to test theories about how the brain processes information. However, a fundamental relationship between the frequency spectra of the neural signal and the subsequent decoding accuracy timecourse is not widely recognised. We show that, in commonly used instantaneous signal decoding paradigms, each sinusoidal component of the evoked response is translated to double its original frequency in the subsequent decoding accuracy timecourses. We therefore recommend, where researchers use instantaneous signal decoding paradigms, that more aggressive low pass filtering is applied with a cut-off at one quarter of the sampling rate, to eliminate representational alias artefacts. However, this does not negate the accompanying interpretational challenges. We show that these can be resolved by decoding paradigms that utilise both a signal’s instantaneous magnitude and its local gradient information as features for decoding. On a publicly available MEG dataset, this results in decoding accuracy metrics that are higher, more stable over time, and free of the technical and interpretational challenges previously characterised. We anticipate that a broader awareness of these fundamental relationships will enable stronger interpretations of decoding results by linking them more clearly to the underlying signal characteristics that drive them.

Highlights

We investigate different decoding paradigms applied to epoched data and characterise the information content available to each over time.

Under commonly used instantaneous signal decoding paradigms, sinusoidal components of the evoked response are translated to double their original frequency in decoding accuracy metrics, presenting technical and interpretational challenges.

When instantaneous signal decoding is used, we recommend using low pass filters with a cut-off less than one quarter of the sampling rate to eliminate spurious representational alias artefacts.

The interpretational issues associated with instantaneous signal decoding can be resolved with alternative paradigms such as complex spectrum decoding.

We show that complex spectrum decoding results in decoding accuracy metrics that are higher, more stable over time, and free of representational aliasing.
A robust core architecture of functional brain networks supports topological resilience and cognitive performance in aging
Authors: Stanford William , Mucha Peter J. , Dayan Eran
Published: February 2022

Aging is associated with gradual changes in cognition, yet some individuals exhibit protection against aging-related cognitive decline. The topological characteristics of brain networks that support protection against cognitive decline in aging are unknown. Here, we investigated whether the robustness of brain networks, queried via the delineation of the brain’s core network structure, supports superior cognitive performance in healthy aging individuals (n=320, ages 60-90). First, we decomposed each subject’s functional brain networks using k-shell decomposition, finding that cognitive function is associated with more robust connectivity of core nodes, primarily within the frontoparietal control network (FPCN). Next, we find that the resilience of core brain network nodes, within the FPCN in particular, relates to cognition. Finally, we show that the degree of segregation in functional networks mediates relationships between network resilience and cognition. Together, these findings suggest that brain networks balance between robust core connectivity and segregation to facilitate high cognitive performance in aging.
Distal gene regulation mediated by non-coding RNAs contributes to germline risk for breast and prostate cancer
Authors: Cole Nolan , Lee Paige , Schwarz Tommer , Zhang Pan , Freedman Matthew L. , Gusev Alexander , Lindström Sara , Gandal Michael J. , Pasaniuc Bogdan , Bhattacharya Arjun
Published: February 2022

Genome-wide association studies (GWAS) have identified numerous genetic loci associated with breast and prostate cancer risk, suggesting that germline genetic dysregulation influences tumorigenesis. However, the biological function underlying many genetic associations is not well-understood. Previous efforts to annotate loci focused on protein-coding genes (pcGenes) largely ignore non-coding RNAs (ncRNAs) which account for most transcriptional output in human cells and can regulate transcription of both pcGenes and other ncRNAs. Though the biological roles of most ncRNAs are not well-defined, many ncRNAs are involved in cancer development. Here, we explore one regulatory hypothesis: ncRNAs astrans-acting mediators of gene expression regulation in non-cancerous and tumor breast and prostate tissue. Using germline genetics as a causal anchor, we categorize distal (>1 Megabase) expression quantitative trait loci (eQTLs) of pcGenes significantly mediated by local-eQTLs of ncRNAs (within 1 Megabase). We find over 300 mediating ncRNAs and show the linked pcGenes are enriched for immunoregulatory and cellular organization pathways. By integrating eQTL and cancer GWAS results through colocalization and genetically-regulated expression analyses, we detect overlapping signals in nine known breast cancer loci and one known prostate cancer locus, and multiple novel genetic associations. Our results suggest a strong transcriptional impact of ncRNAs in breast and prostate tissue with implications for cancer etiology. More broadly, our framework can be systematically applied to functional genomic features to characterize genetic variants distally regulating transcription throughtrans-mechanisms.

SIGNIFICANCE

This study identifies non-coding RNAs that potentially regulate gene expression intrans-pathways and overlap with genetic signals for breast and prostate cancer susceptibility, with implications for interpretation of cancer genome-wide association studies.
Step forward in epidemiological modeling: Introducing the indicator function to capture waves
Authors: Atangana Abdon , Araz Seda İğret
Published: February 2022

In the last century mathematical modelled have been used to depict the dynamic spread of infectious. The aim is to determine the total numbers of infectious, recovered and susceptible classes, however the classes only represent accumulative. Having these classes one will be unable to predict waves, to determine a day to day numbers of newly infected cases some additional calculations are required. Collected data from real world situations are represented as day to day newly infections, from these data help to determine numbers of waves. The current existing mathematical models cannot be used to predict waves, while having known the predicted numbers of waves one can take several measures to control the situation. To solve this problem, we questioned the fact that the rates of infection and recovery are constant and suggested an indicator function, the function is obtained using experimental data. The indicator function is used as rate and introduced into the mathematical model. We considered a simple SIR model with different types of differential operators including classical and fractional derivatives. The models were solved numerically using well-known numerical schemes. The numerical solutions were plotted for different theoretical parameters, the obtained results depict real-world behaviours. To test the efficiency of this new approach, we collected data from South Afrıca and compared with experimental data. Not only our model waves but also it fit experimental data very accurately. This new approach will open new doors of investigation toward revolution to epidemiological modelling.
Safety and immunogenicity of a live recombinant Newcastle disease virus-based COVID-19 vaccine (Patria) administered via the intramuscular or intranasal route: Interim results of a non-randomized open label phase I trial in Mexico
Authors: Ponce-de-León Samuel , Torres Martha , Soto-Ramírez Luis Enrique , José Calva Juan , Santillán-Doherty Patricio , Carranza-Salazar Dora Eugenia , Carreño Juan Manuel , Carranza Claudia , Juárez Esmeralda , Carreto-Binaghi Laura E. , Ramírez-Martínez Luis , Rosa Georgina Paz-De la , Vigueras-Moreno Rosalía , Ortiz-Stern Alejandro , López-Vidal Yolanda , Macías Alejandro E. , Torres-Flores Jesús , Rojas-Martínez Oscar , Suárez-Martínez Alejandro , Peralta-Sánchez Gustavo , Kawabata Hisaaki , González-Domínguez Irene , Martínez-Guevara José Luis , Sun Weina , Sarfati-Mizrahi David , Soto-Priante Ernesto , Chagoya-Cortés Héctor Elías , López-Macías Constantino , Castro-Peralta Felipa , Palese Peter , García-Sastre Adolfo , Krammer Florian , Lozano-Dubernard Bernardo
Published: February 2022

There is still a need for safe, efficient and low-cost coronavirus disease 2019 (COVID-19) vaccines that can stop transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here we evaluated a vaccine candidate based on a live recombinant Newcastle disease virus (NDV) that expresses a stable version of the spike protein in infected cells as well as on the surface of the viral particle (AVX/COVID-12-HEXAPRO, also known as NDV-HXP-S). This vaccine candidate can be grown in embryonated eggs at low cost similar to influenza virus vaccines and it can also be administered intranasally, potentially to induce mucosal immunity. We evaluated this vaccine candidate in prime-boost regimens via intramuscular, intranasal, or intranasal followed by intramuscular routes in an open label non-randomized non-placebo-controlled phase I clinical trial in Mexico in 91 volunteers. The primary objective of the trial was to assess vaccine safety and the secondary objective was to determine the immunogenicity of the different vaccine regimens. In the interim analysis reported here, the vaccine was found to be safe and the higher doses tested were found to be immunogenic when given intramuscularly or intranasally followed by intramuscular administration, providing the basis for further clinical development of the vaccine candidate. The study is registered under ClinicalTrials.gov identifier NCT04871737. Funding was provided by Avimex and CONACYT.
“Half the truth is often a great lie:” testing for tick-borne diseases and implications for surveillance
Authors: Marusiak Amanda Brown , Hollingsworth Brandon D. , Abernathy Haley , Alejo Aidin , Arahirwa Victor , Mansour Odai , Giandomenico Dana , Schmitz John , Williams Carl , Barbarin Alexis , Boyce Ross M.
Published: February 2022

Importance

Tick-borne diseases (TBD) including Spotted Fever Group Rickettsiosis (SFGR), ehrlichiosis, and increasingly Lyme disease represent a substantial public health concern throughout much of the Southeastern United States. Yet, there is uncertainty about the epidemiology of these diseases due to pitfalls in existing diagnostic test methodologies.

Objective

To examine patterns of diagnostic testing and incidence of TBD in a large, academic healthcare system.

Design

Cross-sectional study of diagnostic test results from UNC Health for the period January 1st, 2017 to November 30th, 2020.

Setting

Large, academic healthcare system in central North Carolina including inpatient and outpatient facilities.

Participants

All Individuals seeking routine care at UNC Health facilities who had testing for SFGR, ehrlichiosis or Lyme disease performed during the study period

Measurements

Rates of test positivity, testing completeness, and incidence of TBD

Results

Among the 20,528 diagnostic tests performed, we identified 47 laboratory-confirmed, incident cases of SFGR, 27 of ehrlichiosis, and 76 of Lyme, representing incidence rates of 4.7%, 7.1%, and 0.7% respectively. However, 79.3% of SFGR tests and 74.3% Ehrlichia tests lacked a paired convalescent sample. The total number of tests for Lyme disease was more than SFGR and ehrlichiosis combined, despite the relatively low incidence of disease in region. Most striking, testing for ehrlichiosis was performed in only half of patients in whom SFGR was ordered, suggesting that this disease remains underrecognized. Overall, we estimate that there were 187 incident cases of SFGR and 309 of ehrlichiosis that were not identified due to incomplete testing; a number that would drastically increase – and in the case of ehrlichiosis, nearly double – the total number of cases reported.

Conclusions and Relevance

A majority of patients suspected of having TBD did not have testing performed in accordance with established guidelines, substantially limiting our understanding of TBD epidemiology. Furthermore, there appears to be a large discrepancy between the local burden of disease and the testing that is performed. These findings underscore the need to pursue more robust, active surveillance strategies to estimate the burden of TBDs and distribution of causative pathogens.
Reduced Hippocampal-Cortical Connectivity During Memory Suppression Predicts the Ability to Forget Unwanted Memories
Authors: Yan Yuchi , Hulbert Justin C. , Zhuang Kaixiang , Liu Wei , Wei Dongtao , Qiu Jiang , Anderson Michael C. , Yang Wenjing
Published: February 2022

The ability to suppress unwelcome memories is important for productivity and well-being. Successful memory suppression is associated with hippocampal deactivations and a concomitant disruption of this region’s functionality. Much of the previous neuroimaging literature exploring such suppression-related hippocampal modulations has focused on the region’s negative coupling with the prefrontal cortex. In contrast, task-based changes in functional connectivity between the hippocampus and other brain regions have remained relatively underexplored. Here, we utilize psychophysiological interactions and seed connectome-based predictive modeling (seed-CPM) to investigate the relationship between the hippocampus and the rest of the brain as 134 participants attempted to suppress unwanted memories during the Think/No-Think task. The results show that during retrieval suppression, the right hippocampus exhibited decreased functional connectivity with visual cortical areas (bilateral intracalcarine cortex, right cuneal cortex, left lingual gyrus, right supracalcarine cortex, right occipital pole), left nucleus accumbens and the brain-stem that predicted superior forgetting of unwanted memories on later memory tests. Validation tests verified that prediction performance was not an artifact of head motion or prediction method and that the negative features remained consistent across different brain parcellations. These findings suggest that systemic memory suppression involves more than the modulation of hippocampal activity—it alters functional connectivity patterns between the hippocampus and visual cortex, leading to successful forgetting.
Resistance bioassays and allele characterisation inform analysis ofSpodoptera frugiperda(Lepidoptera: Noctuidae) introduction pathways in Asia and Australia
Authors: Tay W. T. , Rane R. V. , James W. , Gordon K. H. J. , Downes S. , Kim J. , Kuniata L. , Walsh TK T. K.
Published: February 2022

The fall armyworm (FAW)Spodoptera frugiperdais present in over 70 countries in Africa, Asia, and Oceania. Its rapid dispersal since 2016 when it was first reported in western Africa, and associated devastation to agricultural productivity, highlight the challenges posed by this pest. Currently, its management largely relies on insecticide sprays and transgenicBacillus thuringiensistoxins, therefore understanding their responses to these agents and characteristics of any resistance genes enables adaptive strategies. In Australia,S. frugiperdawas reported at the end of January 2020 in northern Queensland and by March 2020, also in northern Western Australia. As an urgent first response we undertook bioassays on two Australian populations, one each from these initial points of establishment. To assist with preliminary sensitivity assessment, two endemic noctuid pest species,Helicoverpa armigeraandSpodoptera litura, were concurrently screened to obtain larval LC50 estimates against various insecticides. We characterised known resistance alleles from the VGSC, ACE-1, RyR, and ABCC2 genes to compare with published allele frequencies and bioassay responses from native and invasiveS. frugiperdapopulations. An approximately 10x LC50 difference for indoxacarb was detected between Australian populations, which was approximately 28x higher than that reported from an Indian population. Characterisation of ACE-1 and VGSC alleles provided further evidence of multiple introductions in Asia, and multiple pathways involving genetically distinct individuals into Australia. The preliminary bioassay results and resistance allele patterns from invasiveS. frugiperdapopulations suggest multiple introductions have contributed to the pest’s spread and challenge the axiom of its rapid ‘west-to-east’ spread.
Immunomodulatory actions of a kynurenine-derived endogenous electrophile
Authors: Carreño Mara , Pires Maria F. , Woodcock Steven R. , Brzoska Tomasz , Ghosh Samit , Salvatore Sonia R. , Dunn Matthew , Connors Nora , Yuan Shuai , Straub Adam C. , Wendell Stacy G. , Kato Gregory J. , Freeman Bruce A. , Ofori-Acquah Solomon , Sundd Prithu , Schopfer Francisco J. , Vitturi Dario A.
Published: February 2022

The inflammatory upregulation of kynurenine metabolism induces immunomodulatory responses via incompletely understood mechanisms. We report that increases in cellular and systemic kynurenine levels yield the electrophilic derivative kynurenine-carboxyketoalkene (Kyn-CKA), as evidenced by the accumulation of thiol-conjugates and saturated metabolites. Under physiological conditions, Kyn-CKA induces Nrf2-regulated genes and inhibits NF-κB and NLRP3-dependent pro-inflammatory signaling. Sickle Cell Disease (SCD) is a hereditary hemolytic condition characterized by basal inflammation and recurrent vaso-occlusive crises. Both a transgenic SCD murine model and SCD patients exhibit increased kynurenine synthesis and elevated Kyn-CKA metabolite levels. Plasma hemin and kynurenine concentrations are positively correlated, indicating that Kyn-CKA synthesis in SCD is upregulated during pathogenic vascular stress. Remarkably, exogenous administration of Kyn-CKA abrogated pulmonary microvasculature occlusion in SCD mice, an important factor in the development of lung injury. These findings demonstrate that the upregulation of kynurenine synthesis and its metabolism to Kyn-CKA is an adaptive response that attenuates inflammation and protects tissues.

One-Sentence Summary

Kyn-CKA is a kynurenine-derived signaling mediator that transduces its immunomodulatory protective actions and attenuates vaso-occlusion in sickle cell disease.
DNA barcoding of fungal specimens using long-read high-throughput sequencing
Authors: Runnel Kadri , Abarenkov Kessy , Copoț Ovidiu , Mikryukov Vladimir , Kõljalg Urmas , Saar Irja , Tedersoo Leho
Published: February 2022

Molecular methods are increasingly used to identify species that lack conspicuous macro- or micromorphological characters. Taxonomic and ecological research teams barcode large numbers of collected voucher specimens annually. In this study we assessed the efficiency of long-read high throughput sequencing (HTS) as opposed to the traditionally used Sanger method for taxonomic identification of multiple vouchered fungal specimens, and providing reference information about intra-individual allele polymorphism. We developed a workflow based on a test-set of 423 fungal specimens (representing 205 species), PacBio HTS method, and ribosomal rRNA operon internal transcribed spacer (ITS) and 28S rRNA gene (LSU) markers. PacBio HTS had a higher success rate than Sanger sequencing at a comparable cost. Species identification based on PacBio reads was usually straightforward, because the dominant operational taxonomic unit (OTU) typically represented the targeted organism. Unlike the Sanger method, PacBio HTS enabled detecting widespread allele polymorphism within the ITS marker in the studied specimens. We conclude that multiplex DNA barcoding of the fungal ITS and LSU markers using a PacBio HTS is a useful tool for taxonomic identification of large amounts of collected voucher specimens at competitive price. Furthermore, PacBio HTS accurately recovers various alleles, which can provide crucial information for species delimitation and population-level studies.
Chimeric Inheritance and Crown-Group Acquisitions of Carbon Fixation Genes within Chlorobiales
Authors: Paoletti Madeline M. , Fournier Gregory P.
Published: February 2022

The geological record of microbial metabolisms and ecologies primarily consists of stable isotope fractionations and the diagenetic products of biogenic lipids. Carotenoid lipid biomarkers are particularly useful proxies for reconstructing this record, providing information on microbial phototroph primary productivity, redox couples, and oxygenation. The biomarkers okenane, chlorobactane, and isorenieratene are generally considered to be evidence of anoxygenic phototrophs, and provide a record that extends to ∼1.64 Ga. The utility of the carotenoid biomarker record may be enhanced by examining the carbon isotopic ratios in these products, which are diagnostic for specific pathways of biological carbon fixation found today within different microbial groups. However, this joint inference assumes that microbes have conserved these pathways across the duration of the preserved biomarker record. Testing this hypothesis, we performed phylogenetic analyses of the enzymes constituting the reductive tricarboxylic acid (rTCA) cycle in Chlorobiales, the group of anoxygenic phototrophic bacteria usually implicated in the deposition of chlorobactane and isorenieretane. We find phylogenetically incongruent patterns of inheritance across all enzymes, indicative of horizontal gene transfers to both stem and crown Chlorobiales from multiple potential donor lineages. This indicates that a complete rTCA cycle was independently acquired at least twice within Chlorobiales and was not present in the last common ancestor. When combined with recent molecular clock analyses, these results predict that the Mesoproterzoic lipid biomarker record diagnostic for Chlorobiales should not preserve isotopic fractionations indicative of a full rTCA cycle. Furthermore, we conclude that coupling isotopic and biomarker records is insufficient for reliably reconstructing microbial paleoecologies in the absence of a complementary and consistent phylogenomic narrative.
A simulation study of the ecological speciation conditions in the Galician marine snailLittorina saxatilis
Authors: Fernández-Meirama M. , Rolán-Alvarez E. , Carvajal-Rodríguez A.
Published: February 2022

In the last years the interest on evolutionary divergence at small spatial scales has increased and so did the study of speciation caused by ecologically-based divergent natural selection. The evolutionary interplay between gene flow and local adaptation can lead to low-dispersal locally adapted specialists. When this occurs the evolutionary interplay between gene flow and local adaptation could eventually lead to speciation.

TheL. saxatilissystem consists of two ecotypes displaying a microhabitat-associated intraspecific dimorphism along the wave-exposed rocky shores of Galicia. In spite of being a well-known system, the dynamics of the ecotype formation remains unclear and cannot be studied from empirical evidence alone. In this study, individual-based simulations were used to incorporate relevant ecological, spatial and genetic information, to check different evolutionary scenarios that could evolve non-random mating preferences and finally may facilitate speciation.

As main results, we observed the evolution of intermediate values of choice which matches estimates from empirical data ofL. saxatilisin Galician shores and coincides with previous theoretical outcomes. Also, the use of the mating correlation as a proxy for assortative mating led to spuriously inferring greater reproductive isolation in the middle habitat than in the others, which does not happen when directly considering the choice values from the simulations. We also corroborate the well-known fact that the occurrence of speciation is influenced by the strength of selection. Taken together, this means, also according to otherL. saxatilissystems, that speciation is not an immediate consequence of local divergent selection and mating preferences, but a fine tuning among several factors including the ecological conditions in the shore levels, the selection strength, the mate choice stringency and cost to choosiness. TheL. saxatilissystem could correspond to a case of incomplete reproductive isolation, where choice intensity is intermediate and local adaptation within the habitat is strong. These results support previous interpretations of theL. saxatilismodel system and indicate that further empirical studies would be interesting to test whether the mate choice mechanism functions as a similarity-like mechanism as has been shown in other littorinids.
The addition of FAIMS Increases Targeted Proteomics Sensitivity from FFPE Tumor Biopsies
Authors: Sweet Steve , Chain David , Yu Wen , Martin Philip , Rebelatto Marlon , Chambers Andrew , Cecchi Fabiola , Kim Yeoun Jin
Published: February 2022

Mass spectrometry-based targeted proteomics allows objective protein quantitation of clinical biomarkers from a single section of formalin-fixed, paraffin-embedded (FFPE) tumor tissue biopsies. We combined high-field asymmetric waveform ion mobility spectrometry (FAIMS) and parallel reaction monitoring (PRM) to increase assay sensitivity. The modular nature of the FAIMS source allowed direct comparison of the performance of FAIMS-PRM to PRM. Limits of quantitation were determined by spiking synthetic peptides into a human spleen matrix. In addition, 20 clinical samples were analyzed using FAIMS-PRM and the quantitation of HER2 was compared with that obtained with the Ventana immunohistochemistry assay. FAIMS-PRM improved the overall signal-to-noise ratio over that from PRM and increased assay sensitivity in FFPE tissue analysis for four (HER2, EGFR, cMET, and KRAS) of five proteins of clinical interest. FAIMS-PRM enabled sensitive quantitation of basal HER2 expression in breast cancer samples classified as HER2 negative by immunohistochemistry. Furthermore, we determined the degree of FAIMS-dependent background reduction and showed that this correlated with an improved lower limit of quantitation with FAIMS. FAIMS-PRM is anticipated to benefit clinical trials in which multiple biomarker questions must be addressed and the availability of tumor biopsy samples is limited.
Growing Phylogenetic Trees Using Hierarchical Clustering
Authors: Eberhard Onno
Published: February 2022

We compare mitochondrial DNA of different species to build a phylogenetic tree. The main challenge is that the calculation of the Levenshtein distance is very slow for large sequences. We introduce an approximate scheme which uses Levenshtein for lower-level details and a fast distance based on sequence length for high-level attributes. The tree is built using average linkage hierarchical clustering.
Task-dependent and automatic tracking of hierarchical linguistic structure
Authors: Oever Sanne Ten , Carta Sara , Kaufeld Greta , Martin Andrea E.
Published: February 2022

Linguistic phrases are tracked in sentences even though there is no clear acoustic phrasal marker in the physical signal. This phenomenon suggests an automatic tracking of abstract linguistic structure that is endogenously generated by the brain. However, all studies investigating linguistic tracking compare conditions where either relevant information at linguistic timescales is available, or where this information is absent altogether (e.g., sentences versus word lists during passive listening). It is therefore unclear whether tracking at these phrasal timescales is related to the content of language, or rather, is a consequence of attending to the timescales that happen to match behaviourally-relevant information. To investigate this question, we presented participants with sentences and word lists while recording their brain activity with MEG. Participants performed passive, syllable, word, and word-combination tasks corresponding to attending to rates they would naturally attend to, syllable-rates, word-rates, and phrasal-rates, respectively. We replicated overall findings of stronger phrasal-rate tracking measured with mutual information (MI) for sentences compared to word lists across the classical language network. However, in the inferior frontal gyrus (IFG) we found a task-effect suggesting stronger phrasal-rate tracking during the word-combination task independent of the presence of linguistic structure, as well as stronger delta-band connectivity during this task. These results suggest that extracting linguistic information at phrasal-rates occurs automatically with or without the presence of an additional task, but also that that IFG might be important for temporal integration across various perceptual domains.
Functional, transcriptional, and microbial shifts associated with healthy pulmonary aging: insights from rhesus macaques
Authors: Rhoades Nicholas S. , Davies Michael , Lewis Sloan A. , Cinco Isaac R. , Kohama Steven G. , Bermudez Luiz E. , Winthrop Kevin L. , Fuss Cristina , Mattison Julie A. , Spindel Eliot R. , Messaoudi Ilhem
Published: February 2022

Older individuals are at increased risk of developing severe respiratory infections due to age-related changes in the immunological, microbial, and functional landscape of the lung. However, our understanding of the impact of age on the respiratory tract remains limited as samples from healthy humans are challenging to obtain and confounding variables such as smoking and environmental pollutant exposure make it difficult to assess the true impact of aging. On the other hand, studies in rodent models are biased by their specific pathogen free status. In this study, we utilize a rhesus macaque model of healthy aging to examine the functional, immunological, and microbial consequences of aging in the lung. Pulmonary function testing in this large (n=34 adult, n=49 aged) cross-sectional study established age and sex differences similar to humans supporting the translational accuracy of this model. Additionally, an increased abundance of myeloid cells (alveolar and infiltrating macrophages) and a concomitant decrease in T-cells were also observed in aged animals. Single cell RNA sequencing indicated a transcriptional shift in the pulmonary CD8+ T-cell population from GRZMB expressing cells to IFN expressing cells, while frequency of IL-1B expressing alveolar macrophages was significantly reduced. Interestingly, the lung microbiome of many animals was dominated by a single microbe, Tropheryma spp., the prevalence of which decreased with age. These data provide a comprehensive picture of the functional, microbial and immunological changes of the lung in healthy macaque aging and provide insight into the increased prevalence and severity of respiratory disease in the elderly.
Inhibitory NPY neurons provide a large and heterotopic commissural projection in the inferior colliculus
Authors: Anair Justin D. , Silveira Marina A. , Mirjalili Pooyan , Beebe Nichole L. , Schofield Brett R. , Roberts Michael T.
Published: February 2022

Located in the midbrain, the inferior colliculus (IC) plays an essential role in many auditory computations, including speech processing and sound localization. The right and left side of the IC are interconnected by a dense fiber tract, the commissure of the IC (CoIC), that provides each IC with one its largest sources of input (i.e., the contralateral IC). Despite its prominence, the CoIC remains poorly understood. Previous studies using anterograde and retrograde tract-tracing showed that IC commissural projections are predominately homotopic and tonotopic, targeting mirror-image locations in the same frequency region in the contralateral IC. However, it is unknown whether specific classes of neurons, particularly inhibitory neurons which constitute ∼10-40% of the commissural projection, follow this pattern. We therefore examined the commissural projections of Neuropeptide Y (NPY) neurons, the first molecularly identifiable class of GABAergic neurons in the IC. Using retrograde tracing with Retrobeads in NPY-hrGFP mice of both sexes, we found that NPY neurons comprise ∼11% of the commissural projection. Moreover, focal injections of Retrobeads showed that NPY neurons in the central nucleus of the IC exhibit a more divergent and heterotopic commissural projection pattern than non-NPY neurons. Thus, commissural NPY neurons are positioned to provide cross-frequency, lateral inhibition to the contralateral IC. Through this circuit, sounds that drive activity in limited frequency bands on one side of the IC might suppress activity across a larger number of frequency bands in the contralateral IC.
Testicular Dysgenesis Syndrome-like morphology and gene expression, and activation of Hypoxia Inducible Factor 1 Alpha in juvenile lamb testes following developmental exposure to low-level environmental chemical mixture
Authors: Elcombe Chris S. , Monteiro Ana , Elcombe Matthew R. , Ghasemzadeh-Hasankolaei Mohammad , Evans Neil P. , Bellingham Michelle
Published: February 2022

Current declines in male reproductive health may, in part, be driven by anthropogenic environmental chemical exposure. Using the biosolid treated pasture (BTP) sheep model, this study examined the effects of gestational exposure to a translationally relevant mixture of environmental chemicals. At 8 weeks of age, ram lambs gestationally exposed to BTP were lighter than control, and their testes contained fewer germ cells and had a greater proportion of Sertoli-cell-only seminiferous tubules. Effects of biosolid exposure on the testicular transcriptome correlated with human testicular dysgenesis syndrome (TDS) patient data. Common differentially expressed genes indicated changes in apoptotic and mTOR signalling, which concurs with previous gene expression data from neonatal BTP lambs. Gene expression data and immunohistochemistry indicates increased HIF1α activation and nuclear localisation in BTP exposed animals, known to disrupt testosterone synthesis. Together, these results provide a potential mechanism for the pathogenesis of this phenotype, and TDS in humans.
Multinuclear MRI reveals early efficacy of stem cell therapy in stroke
Authors: Helsper Shannon , Yuan Xuegang , Bagdasarian F. Andrew , Athey Jacob , Li Yan , Borlongan Cesario V. , Grant Samuel C.
Published: February 2022

Compromised adult human mesenchymal stem cells (hMSC) can impair cell therapy efficacy and further reverse ischemic recovery. However,in vitroassays require extended passage to characterize cells, limiting rapid assessment for therapeutic potency. Multinuclear magnetic resonance imaging and spectroscopy (MRI/S) provides near real-time feedback on disease progression and tissue recovery. Applied to ischemic stroke,23Na MRI evaluates treatment efficacy within 24 h after middle cerebral artery occlusion, showing recovery of sodium homeostasis and lesion reduction in specimens treated with hMSC while1H MRS identifies reduction in lactate levels. This combined metric was confirmed by evaluating treatment groups receiving healthy or compromised hMSC versus control (sham saline injection) over 21 d. Behavioral tests to assess functional recovery and cell analysis for immunomodulatory and macrophage activity to detect hMSC potency confirm MR findings. Clinically, these MR metrics may prove critical to early evaluations of therapeutic efficacy and overall stroke recovery.