bluuebunny/crossref_metadata_2025 huggingface dataset:
When shared pain is not half the pain: enhanced central nervous system processing and verbal reports of pain in the presence of a solicitous spouse
Authors: Nees Frauke , Ditzen Beate , Flor Herta
Published: December 2021

The experience of pain and pain behaviors is not only determined by physiological but also psychosocial factors. In this context, the learning history of the individual and specifically operant reinforcement related to spouse responses might play an important role. We investigated the effect of a solicitous and habitually pain-reinforcing spouse for the processing of pain in patients with chronic pain. Using multichannel electroencephalography, pain behaviors, and self-reports of pain, we examined 20 patients with chronic back pain (10 with solicitous and 10 with nonsolicitous spouses) and 10 matched healthy controls. The participants received a series of painful and nonpainful electrical stimuli applied to the site of pain (back) and a control area (finger) in the presence vs absence of the spouse. The global field power of the electroencephalogram with a focus in the frontal region was enhanced in patients with chronic back pain who had a solicitous spouse compared to those with a nonsolicitous spouse and the healthy controls. This was specific for the painful stimulation at the back and occurred only in the presence but not the absence of the spouse. Pain ratings of intensity and unpleasantness were also higher in the patients with solicitous spouses when the spouse was present during painful stimulation. These data suggest that significant other responses indicative of operant reinforcement may have a direct effect on the cerebral processing of pain and related pain perception.
Longitudinal resting-state electroencephalography in patients with chronic pain undergoing interdisciplinary multimodal pain therapy
Authors: Heitmann Henrik , Gil Ávila Cristina , Nickel Moritz M. , Ta Dinh Son , May Elisabeth S. , Tiemann Laura , Hohn Vanessa D. , Tölle Thomas R. , Ploner Markus
Published: December 2021

Chronic pain is a major healthcare issue posing a large burden on individuals and society. Converging lines of evidence indicate that chronic pain is associated with substantial changes of brain structure and function. However, it remains unclear which neuronal measures relate to changes of clinical parameters over time and could thus monitor chronic pain and treatment responses. We therefore performed a longitudinal study in which we assessed clinical characteristics and resting-state electroencephalography data of 41 patients with chronic pain before and 6 months after interdisciplinary multimodal pain therapy. We specifically assessed electroencephalography measures that have previously been shown to differ between patients with chronic pain and healthy people. These included the dominant peak frequency; the amplitudes of neuronal oscillations at theta, alpha, beta, and gamma frequencies; as well as graph theory-based measures of brain network organization. The results show that pain intensity, pain-related disability, and depression were significantly improved after interdisciplinary multimodal pain therapy. Bayesian hypothesis testing indicated that these clinical changes were not related to changes of the dominant peak frequency or amplitudes of oscillations at any frequency band. Clinical changes were, however, associated with an increase in global network efficiency at theta frequencies. Thus, changes in chronic pain might be reflected by global network changes in the theta band. These longitudinal insights further the understanding of the brain mechanisms of chronic pain. Beyond, they might help to identify biomarkers for the monitoring of chronic pain.
Genome-wide association study of pain sensitivity assessed by questionnaire and the cold pressor test
Authors: Fontanillas Pierre , Kless Achim ,   23andMe Research Team, Bothmer John , Tung Joyce Y.
Published: December 2021

We deployed an online pain sensitivity questionnaire (PSQ) and an at-home version of the cold pressor test (CPT) in a large genotyped cohort. We performed genome-wide association studies on the PSQ score (25,321 participants) and CPT duration (6853). We identified one new genome-wide significant locus associated with the PSQ score, which was located in the TSSC1 (also known as EIPR1) gene (rs58194899, OR = 0.950 [0.933-0.967], P-value = 1.9 × 10−8). Although high pain sensitivity measured by both PSQ and CPT was associated with individual history of chronic and acute pains, genetic correlation analyses surprisingly suggested an opposite direction: PSQ score was inversely genetically correlated with neck and shoulder pain (r
g = −0.71), rheumatoid arthritis (−0.68), and osteoarthritis (−0.38), and with known risk factors, such as the length of working week (−0.65), smoking (−0.36), or extreme BMI (−0.23). Gene-based analysis followed by pathway analysis showed that genome-wide association studies results were enriched for genes expressed in the brain and involved in neuronal development and glutamatergic synapse signaling pathways. Finally, we confirmed that females with red hair were more sensitive to pain and found that genetic variation in the MC1R gene was associated with an increase in self-perceived pain sensitivity as assessed by the PSQ.
Validation of the Human Papillomavirus Impact Profile in Lebanese Women With Human Papillomavirus or Associated Lesions
Authors: Atallah David , El Feghaly Charbel , El Feghaly Murielle , Arab Wissam , Khaddage Abir , Akiki Mira , El Kassis Nadine , Abboud Sara , Chahine Georges , Moubarak Malak
Published: December 2021

Objectives

Human papillomavirus (HPV) is responsible for a multitude of lesions with high psychosocial burden. The “HPV Impact Profile” (HIP) questionnaire is one of the first and most specific tools evaluating the emotional impact of HPV. This study aimed to translate this questionnaire into Arabic and to validate it, in a sample of Lebanese female patients.

Materials and Methods

The HIP questionnaire was translated to Arabic. It was then administered to 118 Lebanese women infected with HPV or screened for HPV-associated lesions, in parallel with the Hospital Anxiety and Depression Scale questionnaire. The psychometric properties of the questionnaire were studied in our sample population.

Results

The internal consistency of the HIP questionnaire was weak as Cronbach α coefficients of most of the domains were low. The study of the composite matrix resulted in the improvement of the internal consistency after the elimination of some items. Moreover, the “adapted domains” were created by reverse-scoring items with positive implications.

The composite reliability and the average variance extracted of all the domains were analyzed. Analysis of discriminate validity through heterotrait-monotrait ratio of correlation ratio analyses of corresponding Hospital Anxiety and Depression Scale domains was also performed along with reliability analysis. There results were satisfying for the adapted domains.

Conclusions

The adapted domains of the 27 items questionnaire with reverse scoring of 8 items presented with good psychometric properties, allowing their use in clinical trials and in clinical practice.
Case Series: Different Presentations of Iris Melanoma—Potential Masquerade of Benign and Malignant
Authors: Allen Natalie , Misra Stuti L. , McGhee Charles N. J. , Crawford Alexandra Z.
Published: December 2021

SIGNIFICANCE

Iris melanoma and iris nevi can be challenging to distinguish clinically. This case series provides unique insight into the rare condition and variable clinical presentations of iris melanoma.

PURPOSE

This study aimed to highlight the varying clinical presentations of iris melanoma and to demonstrate the overlapping features of melanoma and nevi.

CASE REPORTS

This case series includes five patients of varying age and sex who presented to clinic with pigmented iris lesions. These five patients have differing timeline to presentation and very different clinical presentations of their lesions. Clinical evaluation was based around the established “ABDCEF” guide for the assessment of malignant risk in iris lesions. The presentation of each lesion is discussed in relation to this guide and the experienced clinician's clinical suspicion of malignancy. When comparing the clinical suspicion with histological analysis, after biopsy, the result may be unexpected. Notably, initially benign nevi may transform into melanoma over time. These five cases were managed on an individual basis because the management and prognosis of iris melanomas vary significantly. Importantly, iris melanotic lesions have variable metastatic risk based on cytology and genetic predisposition. Informed consent was obtained from all the patients, institutional approval was obtained, and no identifiable health information is included in this case series.

CONCLUSIONS

When presented with a pigmented iris lesion, clinicians must be vigilant with regular monitoring and have a low threshold for biopsy in pigmented lesions of high clinical suspicion.
Leadership and Advanced Degrees
Authors: Pyfer Bryan J. , Hernandez Jorge A. , Glener Adam D. , Cason Roger W. , Levinson Howard , Phillips Brett T.
Published: December 2021

Background

There are increasingly prevalent formal educational programs for physicians who seek to be better trained to advance their fields. Although higher education and advanced degrees are not necessarily linked to leadership, we hypothesize that leaders in plastic surgery commonly have dual degrees. We sought to evaluate the prevalence of and association between additional advanced degrees in academic plastic surgery and plastic surgery leadership.

Methods

Plastic surgery faculty from 96 academic training programs and all executive committee and board of directors' members from national, regional, and local plastic surgery societies were evaluated. Surgeons' institutional online profile pages, personal web pages, societal websites, and LinkedIn profiles were all evaluated for current/past leadership roles, as well as for advanced degree. Odds ratios (ORs) were used to determine if the presence of extra degrees increased their likelihood of leadership roles.

Results

A total of 1036 plastic surgeons were evaluated. Sixteen percent of academic faculty have a dual degree. Furthermore, 25.5% of plastic surgeons holding formal academic leadership roles have a dual degree (OR, 2.15; P = 0.043), as do 34.4% of those serving on the executive committee or board of directors in national plastic surgery societies (OR, 2.23; P = 0.026) and 29.2% of those serving in local/regional societal leadership roles (OR, 1.96; P = 0.043). Among all dual degrees, Masters in Business Administration has the highest association with leadership roles (OR, 3.45; P = 0.002).

Conclusions

Academic plastic surgeons with dual degrees are approximately twice as likely to hold a formal academic or societal leadership role. Additional studies are needed to determine if causative relationships exist.
Evaluation of the Efficacy of Biodegradable Plates in Maxillofacial Fractures
Authors: Hassan Thair Abdel Lateef , Razzaq Russell Mukdad A.
Published: December 2021

Background:

Maxillofacial fractures require stable fixation for uneventful bony healing and optimal remodeling. Conventional titanium plates considered the gold standard of rigid internal fixation for many years, however due to the inherent drawbacks associated with metal devices biodegradable plates have been developed.

Aim of the Study:

To evaluate the efficacy of biodegradable plates as a treatment modality of rigid internal fixation for facial fractures and to assess the perioperative complications experienced with their utilization.

Patients and Methods:

This prospective clinical study included 10 Iraqi patients, met the eligibility criteria and subjected to open reduction and internal fixation with biodegradable plates system. The data were analyzed according to the age, gender, etiology of the fracture, fracture site, surgical approach, plate application time, fracture reduction, screw holes ossification, and patient's satisfaction. The patients were radiographically followed up with either computed tomography or CBCT at 3, 24, and 48 weeks with regular follow up intervals. The statistical analysis was performed using percentages, the mean ± standard deviation, Shapiro-Wilk test and Mann-Whitney U test.

Results:

The age of patients ranged from 9 to 65 years with an average of 26.1 years and a standard deviation of ± 12.9. Regarding gender, males showed a higher percentage than female (80% versus 20%), respectively. There was a significant difference between the mean time of plate application in midface and mandible (53 versus 32.9 minutes), respectively. All cases end up with complete screw holes ossification.

Conclusions:

This study demonstrated that biodegradable plating system was a sensitive procedure and greatly depended upon surgeon's experience and improvement of the learning curve.
Systematic review of mesodiverticular band: a rare cause of small bowel strangulation and hemoperitoneum in adults
Authors: Bamarni Sahand , HungFong SuySen , Mino Jeffrey , Misra Subhasis
Published: December 2021

Introduction:

Mesodiverticular band (MDB) is a rare congenital intestinal malformation. It originates from the embryonic remnant of the vitelline artery and is usually associated with Meckel’s diverticulum (MD). Persistent MDB may cause small bowel obstruction by trapping a loop of bowel, hemoperitoneum due to aneurysmal or traumatic rupture of MDB. The purpose of this article is to review the literature of MDB and identify the patterns of presentation, complications, and management options.

Methods:

We searched PubMed for articles containing terms: “Mesodiverticular band,” “Vitelline band,” and “Vitelline artery remnant.” Abstracts were reviewed in detail and we included all the case reports available in full-text and in English language. We excluded all case reports of patients younger than 18 years of age.

Results:

Only 20 case reports were included. Only adult patients were included. The male to female ratio was 3:1. The most common presentation was small bowel obstruction followed by hemoperitoneum. The majority required exploratory laparotomy with more than half requiring small bowel resection. One death report secondary to undiagnosed internal hernia.

Conclusion:

MDB with MD is a rare cause of intestinal obstruction or hemoperitoneum in adults. It remains a diagnostic dilemma as it is usually diagnosed intraoperatively.
Genome-wide analysis of fitness-factors in uropathogenic Escherichia coli during growth in laboratory media and during urinary tract infections
Authors: García Vanesa , Grønnemose Rasmus B. , Torres-Puig Sergi , Kudirkiene Egle , Piantelli Mateo , Ahmed Shahana , Andersen Thomas E. , Møller-Jensen Jakob , Olsen John E. , Herrero-Fresno Ana
Published: December 2021

Uropathogenic

Escherichia coli

(UPEC) UTI89 is a well-characterized strain, which has mainly been used to study UPEC virulence during urinary tract infection (UTI). However, little is known on UTI89 key fitness-factors during growth in lab media and during UTI. Here, we used a transposon-insertion-sequencing approach (TraDIS) to reveal the UTI89 essential-genes for in vitro growth and fitness-gene-sets for growth in Luria broth (LB) and EZ-MOPS medium without glucose, as well as for human bacteriuria and mouse cystitis. A total of 293 essential genes for growth were identified and the set of fitness-genes was shown to differ depending on the growth media. A modified, previously validated UTI murine model, with administration of glucose prior to infection was applied. Selected fitness-genes for growth in urine and mouse-bladder colonization were validated using deletion-mutants. Novel fitness-genes, such as tusA, corA and rfaG; involved in sulphur-acquisition, magnesium-uptake, and LPS-biosynthesis, were proved to be important during UTI. Moreover, rfaG was confirmed as relevant in both niches, and therefore it may represent a target for novel UTI-treatment/prevention strategies.
Significant variability exists in the cytotoxicity of global methicillin-resistant Staphylococcus aureus lineages
Authors: Laabei Maisem , Peacock Sharon J. , Blane Beth , Baines Sarah L. , Howden Benjamin P. , Stinear Timothy P. , Massey Ruth C.
Published: December 2021

Staphylococcus aureus

is a major human pathogen where the emergence of antibiotic resistant lineages, such as methicillin-resistant

S. aureus

(MRSA), is a major health concern. While some MRSA lineages are restricted to the healthcare setting, the epidemiology of MRSA is changing globally, with the rise of specific lineages causing disease in healthy people in the community. In the past two decades, community-associated MRSA (CA-MRSA) has emerged as a clinically important and virulent pathogen associated with serious skin and soft-tissue infections (SSTI). These infections are primarily cytotoxin driven, leading to the suggestion that hypervirulent lineages/multi-locus sequence types (STs) exist. To examine this, we compared the cytotoxicity of 475 MRSA isolates representing five major MRSA STs (ST22, ST93, ST8, ST239 and ST36) by employing a monocyte-macrophage THP-1 cell line as a surrogate for measuring gross cytotoxicity. We demonstrate that while certain MRSA STs contain highly toxic isolates, there is such variability within lineages to suggest that this aspect of virulence should not be inferred from the genotype of any given isolate. Furthermore, by interrogating the accessory gene regulator (Agr) sequences in this collection we identified several Agr mutations that were associated with reduced cytotoxicity. Interestingly, the majority of isolates that were attenuated in cytotoxin production contained no mutations in the agr locus, indicating a role of other undefined genes in

S. aureus

toxin regulation.
Detection of antimicrobial resistance, pathogenicity, and virulence potentials of non-typhoidal Salmonella isolates at the Yaounde abattoir using whole genome sequencing technique
Authors: Matchawe Chelea , Machuka Eunice M. , Kyalo Martina , Bonny Patrice , Gerard Nkeunen , Njaci Isaac , Esemu Seraphine Nkie , Githae Dedan , Juma John , Bawe Mohamadou , Nsawir Bonglaisin J. , Piasentier Edi , Ndip Lucy M. , Pelle Roger
Published: December 2021

One of the crucial public health problems today is emerging and re-emerging of multidrug-resistant bacterial pathogens coupled with a decline in the development of new antimicrobials. Non-typhoidal Salmonella is classified among the multidrug-resistant bacterial pathogens of international concern. To predict their multidrug resistance potentials, 19 assembled genomes (partial genomes) of 23 non-typhoidal Salmonella isolated at the Yaounde abattoir between December 2014 and November 2015 from live cattle (n=1), beef carcass (n=19), butchers’ hands (n=1) and the beef processing environments (n=2) were explored using whole-genome sequencing. Phenotypically, while approximately 22% (n=5) of Salmonella isolates showed moderate resistance to streptomycin, 13.04 % (n=3) were multidrug-resistant. Genotypically, all the Salmonella isolates possessed high multidrug resistance potentials against several classes of antibiotics (third-generation cephalosporin and fluoroquinolone), which are assigned highest priority drugs by the World Health Organization. Moreover, more than 31% of the isolates exhibited resistance potentials to polymyxin, considered as the last resort drug with both clinical and veterinary relevance. Additionally, close to 80% of non-typhoidal Salmonella isolates in this study harboured ‘‘silent resistant genes’’ and thus constituted potential reservoirs of antibiotic resistance to other foodborne bacteria. Plasmids also appear to play a critical role in the horizontal transfer of antibiotic resistance genes of some isolates. The isolates showed a high degree of pathogenicity and possessed key effector proteins to establish infection in their hosts, including humans. The overall results demand prudent use of antibiotics and constant monitoring of antimicrobial resistance of non-typhoidal Salmonella in the Cameroonian abattoirs.

Author summary

Non-typhoidal Salmonella has been classified among the multidrug resistant bacterial pathogens of international concern. A growing resistance to a broad range of antibacterial compounds in animals and clinical settings has been reported in Non-Typhoidal Salmonella. Current knowledge of their antibiotic resistance profile is essential to inform policy decisions for the choice of appropriate management of invasive salmonellosis. The significance of our research consists in predicting the multidrug resistance, pathogenicity and virulence potentials of Salmonella organisms using whole genome sequencing. This unveils the need for the development of a diagnostic model that takes into account the genotype–phenotype antibacterial resistance profile of Salmonella, which is of both clinical and veterinary relevance.
Slice-direction geometric distortion evaluation and correction with reversed slice-select gradient acquisitions
Authors: Blazejewska Anna I. , Witzel Thomas , Andersson Jesper L.R. , Wald Lawrence L. , Polimeni Jonathan R.
Published: December 2021

Accurate spatial alignment of MRI data acquired across multiple contrasts in the same subject is often crucial for data analysis and interpretation, but can be challenging in the presence of geometric distortions that differ between acquisitions. It is well known that single-shot echo-planar imaging (EPI) acquisitions suffer from distortion in the phase-encoding direction due to B0 field inhomogeneities arising from tissue magnetic susceptibility differences and other sources, however there can be distortion in other encoding directions as well in the presence of strong field homogeneities. High-resolution ultrahigh-field MRI typically uses low bandwidth in the slice-encoding direction to acquire thin slices and, when combined with the pronounced B0 inhomogeneities, is prone to an additional geometric distortion in the slice direction as well. Here we demonstrate a presence of this slice distortion in high-resolution 7T EPI acquired with a novel pulse sequence allowing for the reversal of the slice-encoding gradient polarity that enables the acquisition of pairs of images with equal magnitudes of distortion in the slice direction but with opposing polarities. We also show that the slice-direction distortion can be corrected using gradient reversal-based method applying the same software used for conventional corrections of phase-encoding direction distortion.
Deep metabolic profiling assessment of tissue extraction protocols for three model organisms
Authors: Gegner Hagen M. , Mechtel Nils , Heidenreich Elena , Wirth Angela , Cortizo Fabiola Garcia , Bennewitz Katrin , Fleming Thomas , Andresen Carolin , Freichel Marc , Teleman Aurelio , Kroll Jens , Hell Rüdiger , Poschet Gernot
Published: December 2021

Metabolic profiling harbors the potential to better understand various disease entities such as cancer, diabetes, Alzheimer’s, Parkinson’s disease or COVID-19. Deciphering these intricate pathways in human studies requires large sample sizes as a means of reducing variability. While such broad human studies have discovered new associations between a given disease and certain affected metabolites, i.e. biomarkers, they often provide limited functional insights. To design more standardized experiments, reduce variability in the measurements and better resolve the functional component of such dynamic metabolic profiles, model organisms are frequently used. Standardized rearing conditions and uniform sampling strategies are prerequisites towards a successful metabolomic study. However, further aspects such as the choice of extraction protocol and analytical technique can influence the outcome drastically. Here, we employed a highly standardized metabolic profiling assay analyzing 630 metabolites across three commonly used model organisms (Drosophila, mouse and Zebrafish) to find the optimal extraction protocols for various matrices. Focusing on parameters such as metabolite coverage, metabolite yield and variance between replicates we compared seven extraction protocols. We found that the application of a combination of 75% ethanol and methyl tertiary-butyl ether (MTBE), while not producing the broadest coverage and highest yields, was the most reproducible extraction protocol. We were able to determine up to 530 metabolites in mouse kidney samples, 509 in mouse liver, 422 in Zebrafish and 388 in Drosophila and discovered a core overlap of 261 metabolites in these four matrices. To enable other scientists to search for the most suitable extraction protocol in their experimental context and interact with this comprehensive data, we have integrated our data set in the open-source shiny app “MetaboExtract”. This will enable scientists to search for their metabolite or metabolite class of interest, compare it across the different tested extraction protocols and sample types as well as find reference concentrations.
Changes of small non-coding RNAs by severe acute respiratory syndrome coronavirus 2 infection
Authors: Wu Wenzhe , Choi Eun-Jin , Wang Binbin , Zhang Ke , Adam Awadalkareem , Huang Gengming , Tunkle Leo , Huang Philip , Goru Rohit , Imirowicz Isabella , Henry Leanne , Lee Inhan , Dong Jianli , Wang Tian , Bao Xiaoyong
Published: December 2021

The ongoing pandemic of coronavirus disease 2019 (COVID-19), which results from the rapid spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a significant global public health threat, with molecular mechanisms underlying its pathogenesis largely unknown. Small non-coding RNAs (sncRNAs) are known to play important roles in almost all biological processes. In the context of viral infections, sncRNAs have been shown to regulate the host responses, viral replication, and host-virus interaction. Compared with other subfamilies of sncRNAs, including microRNAs (miRNAs) and Piwi-interacting RNAs (piRNAs), tRNA-derived RNA fragments (tRFs) are relatively new and emerge as a significant regulator of host-virus interactions. Using T4 PNK-RNA-seq, a modified next-generation sequencing (NGS), we recently found that nasopharyngeal swabs (NPS) samples from SARS-CoV-2 positive and negative subjects show a significant difference in sncRNA profiles. There are about 166 SARS-CoV-2-impacted sncRNAs. Among them, tRFs are the most significantly affected and almost all impacted tRFs are derived from the 5’-end of tRNAs (tRF5). Using a modified qRT-PCR, which was recently developed to specifically quantify tRF5s by isolating the tRF signals from its corresponding parent tRNA signals, we validated that tRF5s derived from tRNA GluCTC (tRF5-GluCTC), LysCTT (tRF5-LysCTT), ValCAC (tRF5-ValCAC), CysGCA (tRF5-CysGCA) and GlnCTG (tRF5-GlnCTG) are enhanced in NPS samples of SARS-CoV2 patients and SARS-CoV2-infected airway epithelial cells. In addition to host-derived ncRNAs, we also identified several sncRNAs derived from the virus (svRNAs), among which a svRNA derived from CoV2 genomic site 346 to 382 (sv-CoV2-346) has the highest expression. The induction of both tRFs and sv-CoV2-346 has not been reported previously, as the lack of the 3’-OH ends of these sncRNAs prevents them to be detected by routine NGS. In summary, our studies demonstrated the involvement of tRFs in COVID-19 and revealed new CoV2 svRNAs.
The future of artificial intelligence in digital pathology - results of a survey across stakeholder groups
Authors: Heinz Céline N. , Echle Amelie , Foersch Sebastian , Bychkov Andrey , Kather Jakob Nikolas
Published: December 2021

Artificial intelligence (AI) provides a powerful tool to extract information from digitized histopathology whole slide images. In the last five years, academic and commercial actors have developed new technical solutions for a diverse set of tasks, including tissue segmentation, cell detection, mutation prediction, prognostication and prediction of treatment response. In the light of limited overall resources, it is presently unclear for researchers, practitioners and policymakers which of these topics are stable enough for clinical use in the near future and which topics are still experimental, but worth investing time and effort into. To identify potentially promising applications of AI in pathology, we performed an anonymous online survey of 75 computational pathology domain experts from academia and industry. Participants enrolled in 2021 were queried about their subjective opinion on promising and appealing sub-fields of computational pathology with a focus on solid tumors. The results of this survey indicate that the prediction of treatment response directly from routine pathology slides is regarded as the most promising future application. This item was ranked highest in the overall analysis and in sub-groups by age and professional background. Furthermore, prediction of genetic alterations, gene expression and survival directly from routine pathology images scored consistently high across subgroups. Together, these data demonstrate a possible direction for the development of computational pathology systems in clinical, academic and industrial research in the near future.
Effects of footshock stress on social behavior and neuronal activation in the medial prefrontal cortex and amygdala of male and female mice
Authors: Dorofeikova Mariia , Borkar Chandrashekhar D , Weissmuller Katherine , Smith-Osborne Lydia , Basavanhalli Samhita , Bean Erin , Smith Avery , Duong Anh , Resendez Alexis , Fadok Jonathan P
Published: December 2021

Social behavior is complex and fundamental, and its deficits are common pathological features for several psychiatric disorders including anxiety, depression, and posttraumatic stress disorder. Acute stress may have a negative impact on social behavior, and these effects can vary based on sex. The aim of this study was to explore the effect of two days of footshock stress on the sociability of male and female C57Bl/6J mice measured using a standard social interaction test. Animals were divided into two main groups of footshock exposure or context exposure control. Each group had mice that were treated with either the benzodiazepine alprazolam, or vehicle. In all groups, neuronal activation during social interaction was assessed using immunohistochemistry against the immediate early gene product cFos. Although footshock stress did not significantly alter sociability or latency to approach a social interaction counterpart, it did increase defensive tail-rattling behavior specifically in males. This stress-induced increase in tail-rattling was alleviated by alprazolam, yet alprazolam had no effect on female tail-rattling behavior in the stress group. Alprazolam lowered cFos expression in the medial prefrontal cortex, and social interaction induced sex-dependent differences in cFos activation in the ventromedial intercalated cell clusters. Overall, our results suggest that acute footshock stress induces sex-dependent alterations in defensiveness and patterns of cFos activation during social interaction tests.
Modeling the dynamics of within-host viral infection and evolution predicts quasispecies distributions and phase boundaries separating distinct classes of infections
Authors: Lewis Greyson R. , Marshall Wallace F. , Jones Barbara A.
Published: December 2021

We use computational modeling to study within-host viral infection and evolution. In our model, viruses exhibit variable binding to cells, with better infection and replication countered by a stronger immune response and a high rate of mutation. By varying host conditions (permissivity to viral entry T and immune clearance intensity A) for large numbers of cells and viruses, we study the dynamics of how viral populations evolve from initial infection to steady state and obtain a phase diagram of the range of cell and viral responses. We find three distinct replicative strategies corresponding to three physiological classes of viral infections: acute, chronic, and opportunistic. We show similarities between our findings and the behavior of real viral infections such as common flu, hepatitis, and SARS-CoV-2019. The phases associated with the three strategies are separated by a phase transition of primarily first order, in addition to a crossover region. Our simulations also reveal a wide range of physical phenomena, including metastable states, periodicity, and glassy dynamics. Lastly, our results suggest that the resolution of acute viral disease in patients whose immunity cannot be boosted can only be achieved by significant inhibition of viral infection and replication.

Author summary

Virus, in particular RNA viruses, often produce offspring with slightly altered genetic composition. This process occurs both across host populations and within a single host over time. Here, we study the interactions of viruses with cells inside a host over time. In our model, the viruses encounter host cell defenses characterized by two parameters: permissivity to viral entry T and immune response A). The viruses then mutate upon reproduction, eventually resulting in a distribution of related viral types termed a quasi-species distribution. Across varying host conditions (T, A), three distinct viral quasi-species types emerge over time, corresponding to three classes of viral infections: acute, chronic and opportunistic. We interpret these results in terms of real viral types such as common flu, hepatitis, and also SARS-CoV-2019. Analysis of viral of viral mutant populations over a wide range of permissivity and immunity, for large numbers of cells and viruses, reveals phase transitions that separate the three classes of viruses, both in the infection-cycle dynamics and at steady state. We believe that such a multiscale approach for the study of within-host viral infections, spanning individual proteins to collections of cells, can provide insight into developing more effective therapies for viral disease.
REPTOR/CREBRF encode key regulators of muscle energy metabolism
Authors: Saavedra Pedro , Dumesic Phillip A. , Hu Yanhui , Jouandin Patrick , Binari Richard , Wilensky Sarah E. , Filine Elizabeth , Rodiger Jonathan , Wang Haiyun , Spiegelman Bruce M. , Perrimon Norbert
Published: December 2021

Metabolic flexibility of muscle tissue describes the capacity to use glucose or lipids as energy substrates and its disruption is associated with metabolic dysfunction. Cancer-induced cachexia is a metabolic syndrome linked with muscle wasting, changes in muscle energy metabolism and lower life expectancy in cancer patients. The molecular mechanisms driving metabolic changes in muscle, however, are poorly characterized. Here, using a Drosophila model of systemic metabolic dysfunction triggered by yorkie-induced gut tumors, we identify the transcription factor REPTOR as a key regulator of energy metabolism in muscle. We show that REPTOR is upregulated in muscles of adult flies with gut yorkie-tumors, where it is necessary to modulate glucose metabolism. REPTOR expression in muscles is induced by ImpL2, a tumor-derived insulin binding protein that reduces systemic insulin signaling, or by nutritional restriction. Further, in vitro and in vivo studies indicate that high activity of REPTOR is sufficient to increase glucose content, transcriptionally repress phosphofructokinase and increase mitochondrial respiration. Consistent with the fly studies, higher levels of CREBRF, the mammalian ortholog of REPTOR, reduce glycolysis in mouse myotubes while promoting an oxidative phenotype. Altogether, our results implicate REPTOR/CREBRF as key regulators of muscle metabolism and metabolic flexibility that share a conserved function as repressors of glycolysis and promoters of oxidative phosphorylation.
Electrobehavioral phenotype and seizure pharmacosensitivity in a novel mouse model of patient-derived SLC6A1 S295L mutation-associated neurodevelopmental epilepsy
Authors: Lindquist Britta E. , Voskobiynyk Yuliya , Paz Jeanne T.
Published: December 2021

Solute carrier family 6 member 1 (SLC6A1) gene encodes GAT-1, a GABA transporter expressed on glia and presynaptic terminals of inhibitory neurons. Mutations in SLC6A1 are associated with myoclonic atonic epilepsy, absence epilepsy, autism, and intellectual disability. However, the mechanisms leading to these defects are unknown. Here, we used a novel mouse model harboring a point mutation (S295L) recently identified in the human SLC6A1 gene that results in impaired membrane trafficking of the GAT-1 protein. We performed chronic wireless telemetry recordings of heterozygous (GAT-1S295L/+) mice, and of mice lacking one or both copies of the gene (GAT-1+/− and GAT-1−/−). We assessed their behaviors and pharmacosensitivity, and investigated the relationship between seizure burden and behavioral performance. GAT-1S295L/+ mice exhibited frequent spikewave discharges (SWDs) associated with behavioral arrest, and there was a dose-effect relationship between GAT-1 gene copy number and the severity of electrocorticogram (ECoG) abnormalities. Seizure burden was inversely correlated with behavioral performance. Forelimb grip strength was reduced in female mice. Acute administration of GAT-1 antagonist NO-711 induced SWDs in wildtype mice, exacerbated the phenotype in GAT-1S295L/+ and GAT-1+/− mice, and had no effect on GAT-1−/− mice lacking the drug target. By contrast, ethosuximide normalized the ECoG in GAT-1S295L/+ and GAT-1+/− mice. In conclusion, GAT-1S295L/+ mice show haploinsufficiency with evidence of GAT-1 hypofunction. This mouse model reconstitutes major aspects of human disease and thus provides a useful preclinical model for drug screening and gene therapy.

Significance Statement

The SLC6A1 gene encodes for GAT-1, a major GABA transporter. Mutations in SLC6A1 lead to a spectrum of neurodevelopmental disorders and epilepsies collectively referred to as SLC6A1-related disorders (SRD). A critical contributor to disability in SRD patients is the burden of seizures and their sequelae. There is an urgent need to understand the mechanisms of SRD as they will inform therapeutic interventions. Mouse models can provide critical information allowing both the assessment of candidate therapies and the design of next generations therapies. Here we used behavioral assessments and wireless electrophysiology in a new mouse model of SRD to understand the disease pathogenesis and the association between seizure burden and behavioral deficits.
Brain intrinsic connection patterns underlying tool processing in human adults are present in neonates and not in macaques
Authors: Wen Haojie , Xu Ting , Wang Xiaoying , Yu Xi , Bi Yanchao
Published: December 2021

Tool understanding and use are supported by a dedicated left-lateralized, intrinsically connected network in the human adult brain. To examine this network’s phylogenic and ontogenetic origins, we compared resting-state functional connectivity (rsFC) among regions subserving tool processing in human adults to rsFC among homologous regions in human neonates and macaque monkeys (adolescent and mature). These homologous regions formed an intrinsic network in human neonates, but not in macaques. Network topological patterns were highly similar between human adults and neonates, and significantly less so between humans and macaques. The premotor-parietal rsFC had most significant contribution to the formation of the neonate tool network. These results suggest that an intrinsic brain network potentially supporting tool processing exists in the human brain prior to individual tool use experiences, and that the premotor-parietal functional connection in particular offers a brain basis for complex tool behaviors specific to humans.
An exploratory study on the microbiome of northern and southern populations of Ixodes scapularis ticks predicts changes and unique bacterial interactions
Authors: Kumar Deepak , Downs Latoyia P. , Adegoke Abdulsalam , Machtinger Erika , Oggenfuss Kelly , Ostfeld Richard S. , Embers Monica , Karim Shahid
Published: December 2021

The black-legged tick (Ixodes scapularis) is the primary vector of Borrelia burgdorferi, the causative agent of Lyme disease in North America. However, the prevalence of Lyme borreliosis is clustered around the northern states of the United States of America. This study utilized a metagenomic sequencing approach to compare the microbial communities residing within Ix. scapularis populations from north and southern geographic locations in the USA. Using a SparCC network construction model, potential interactions between members of the microbial communities from Borrelia burgdorferi-infected tissues of unfed and blood-fed ticks were performed. A significant difference in bacterial composition and diversity among northern and southern tick populations was found between northern and southern tick populations. The network analysis predicted a potential antagonistic interaction between endosymbiont Rickettsia buchneri and Borrelia burgdorferi sensu lato. Network analysis, as expected, predicted significant positive and negative microbial interactions in ticks from these geographic regions, with the genus Rickettsia, Francisella, and Borreliella playing an essential role in the identified clusters. Interactions between Rickettsia buchneri and Borrelia burgdorferi sensu lato needs more validation and understanding. Understanding the interplay between the micro-biome and tick-borne pathogens within tick vectors may pave the way for new strategies to prevent tick-borne infections.
The genome of the Balearic shearwater (Puffinus mauretanicus), a Critically Endangered seabird: a valuable resource for evolutionary and conservation genomics
Authors: Cuevas-Caballé Cristian , Obiol Joan Ferrer , Vizueta Joel , Genovart Meritxell , Gonzalez-Solís Jacob , Riutort Marta , Rozas Julio
Published: December 2021

The Balearic shearwater (Puffinus mauretanicus) is the most threatened seabird in Europe. The fossil record suggests that human colonisation of the Balearic Islands resulted in a sharp decrease of the population size. Currently, populations continue to be decimated mainly due to predation by introduced mammals and bycatch in longline fisheries, and some studies predict their extinction by 2070. We present the first high-quality reference genome for the species which was obtained by a combination of short and long-read sequencing. Our hybrid assembly includes 4,169 scaffolds, with a scaffold N50 of 2.1 Mbp, a genome length of 1.2 Gbp, and BUSCO completeness of 96%, which is amongst the highest across sequenced avian species. This reference genome allowed us to study critical aspects relevant to the conservation status of the species, such as an evaluation of overall heterozygosity levels and the reconstruction of its historical demography. Our phylogenetic analysis using whole-genome information resolves current uncertainties in the order Procellariiformes systematics. Comparative genomics analyses uncover a set of candidate genes that may have played an important role into the adaptation to a pelagic lifestyle of Procellariiformes, including those for the enhancement of fishing capabilities, night vision and the development of natriuresis. This reference genome will be the keystone for future developments of genetic tools in conservation efforts for this Critically Endangered species.
Rapid profiling of protein complex re-organization in perturbed systems
Authors: Bludau Isabell , Nicod Charlotte , Martelli Claudia , Xue Peng , Heusel Moritz , Fossati Andrea , Uliana Federico , Frommelt Fabian , Aebersold Ruedi , Collins Ben C.
Published: December 2021

Protein complexes constitute the primary functional modules of cellular activity. To respond to perturbations, complexes undergo changes in their abundance, subunit composition or state of modification. Understanding the function of biological systems requires global strategies to capture this contextual state information on protein complexes and interaction networks. Methods based on co-fractionation paired with mass spectrometry have demonstrated the capability for deep biological insight but the scope of studies using this approach has been limited by the large measurement time per biological sample and challenges with data analysis. As such, there has been little uptake of this strategy beyond a few expert labs into the broader life science community despite rich biological information content. We present a rapid integrated experimental and computational workflow to assess the re-organization of protein complexes across multiple cellular states. It enables complex experimental designs requiring increased sample/condition numbers. The workflow combines short gradient chromatography and DIA/SWATH mass spectrometry with a data analysis toolset to quantify changes in complex organization. We applied the workflow to study the global protein complex rearrangements of THP-1 cells undergoing monocyte to macrophage differentiation and a subsequent stimulation of macrophage cells with lipopolysaccharide. We observed massive proteome organization in functions related to signaling, cell adhesion, and extracellular matrix during differentiation, and less pronounced changes in processes related to innate immune response induced by the macrophage stimulation. We therefore establish our integrated differential pipeline for rapid and state-specific profiling of protein complex organization with broad utility in complex experimental designs.
Insights into standards of care – dexamethasone and antibodies against COVID-19 in hamster models
Authors: Wyler Emanuel , Adler Julia M. , Eschke Kathrin , Alves Gustavo Teixeira , Peidli Stefan , Pott Fabian , Kazmierski Julia , Michalick Laura , Kershaw Olivia , Bushe Judith , Andreotti Sandro , Pennitz Peter , Abdelgawad Azza , Postmus Dylan , Goffinet Christine , Kreye Jakob , Reincke S Momsen , Prüss Harald , Blüthgen Nils , Gruber Achim D. , Kuebler Wolfgang M. , Witzenrath Martin , Landthaler Markus , Nouailles Geraldine , Trimpert Jakob
Published: December 2021

Rationale

In face of the ongoing SARS-CoV-2 pandemic, effective and well-understood treatment options are still scarce. While vaccines have proven instrumental in fighting SARS-CoV-2, their efficacy is challenged by vaccine hesitancy, novel variants and short-lasting immunity. Therefore, understanding and optimization of therapeutic options remains essential.

Objectives

We aimed at generating a deeper understanding on how currently used drugs, specifically dexamethasone and anti-SARS-CoV-2 antibodies, affect SARS-CoV-2 infection and host responses. Possible synergistic effects of both substances are investigated to evaluate combinatorial treatments.

Methods

By using two COVID-19 hamster models, pulmonary immune responses were analyzed to characterize effects of treatment with either dexamethasone, anti-SARS-CoV-2 spike monoclonal antibody or a combination of both. scRNA sequencing was employed to reveal transcriptional response to treatment on a single cell level.

Measurements and main results

Dexamethasone treatment resulted in similar or increased viral loads compared to controls. Anti-SARS-CoV-2 antibody treatment alone or combined with dexamethasone successfully reduced pulmonary viral burden. Dexamethasone exhibited strong anti-inflammatory effects and prevented fulminant disease in a severe COVID-19-like disease model. Combination therapy showed additive benefits with both anti-viral and anti-inflammatory potency. Bulk and single-cell transcriptomic analyses confirmed dampened inflammatory cell recruitment into lungs upon dexamethasone treatment and identified a candidate subpopulation of neutrophils specifically responsive to dexamethasone.

Conclusions

Our analyses i) confirm the anti-inflammatory properties and indicate possible modes of action for dexamethasone, ii) validate anti-viral effects of anti-SARS-CoV-2 antibody treatment, and iii) reveal synergistic effects of a combination therapy and can thus inform more effective COVID-19 therapies.