bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparing digital to analog prostate-specific membrane antigen-targeted piflufolastat 18F PET/CT in prostate cancer patients in early biochemical failure
Authors: Maliha Peter George , Nolet Benoit , Ebrahim Anwar , Abikhzer Gad , Chaussé Guillaume , Bahoric Boris , Niazi Tamim , Probst Stephan
Published: December 2022

Purpose

Prostate-specific membrane antigen (PSMA) positron emission tomography/computer tomography (PET/CT) in prostate cancer patients with biochemical failure(BCF) showslimited sensitivity when the prostate-specific antigen(PSA) <0.5 ng/mL. The development of digital PET/CT has greatly improved smaller lesion detection. This study’s goal was to compare the performance and clinical value of PSMA-targeted piflufolastat PET/CT for prostate cancer BCF with digital versus analog PET/CT.

Methods

In this retrospective study, all piflufolastat PET/CT scans in subjects with PSA ≤ 3.0 ng/mL who were referred for prostate cancer BCF were included. The performance characteristics of 171 analog PET/CT studies in 155 subjects from May 2017 to January 2020 and 106 digital PET/CT studies in 103 subjects from February 2020 to December 2020 were compared. Lesions were considered malignant if they did not match the known physiological distribution of piflufolastat and did not represent uptake in benign lesions. PSMA PET/CT studies were considered positive if at least one malignant lesion was detected and negative if none were detected.

Results

Digital piflufolastat PET/CT outperformed analog piflufolastat PET/CT in subjects with PSA < 0.5 ng/mL with a positivity rate of 69% versus 37%, respectively. In patients with PSA ≥ 0.5 ng/mL, both technologies performed similarly. There was no statistically significant difference between the number or size of piflufolastat-avid lesions detected per PET/CT study.

Conclusion

In prostate cancer patients with BCF and PSA < 0.5 ng/mL, digital piflufolastat PET/CT has a higher detection rate of malignant lesions than analog piflufolastat PET/CT.
Patient Goals in Hospice Cancer Pain Management
Authors: Ehrlich Olga , Vallerand April Hazard
Published: December 2022

Evidence-based clinical practice guidelines and hospice agency policies and procedures direct nursing assessment and interventions for the care of persons with cancer-related pain. Guidelines assert that pain should be assessed from a holistic perspective that considers physical, psychological, social, and spiritual aspects. In addition, guidelines maintain that hospice nurses should ascertain patient goals for pain management. Assessment and documentation of goals other than pain intensity goals is an area of nursing practice that has not been developed. Without inclusion of personally meaningful goals in pain assessment instruments, such goals cannot be routinely or consistently included in the hospice care plan. To address the assessment of pain and patient goals for pain management, this scenario-based article merges theoretical knowledge about pain from concept analyses with clinical guideline recommendations. Although research is needed to develop pain goal assessment tools, nurses can use this empirically based approach for asking about goals and integrating them into the plan of care.
Bacterial contamination is involved in the etiology of soft tissue filler, late-onset inflammatory adverse events
Authors: Decates Tom S. , Budding Andries E. , Velthuis Peter J. , Bachour Yara , Wolters Lisanne W. , Schelke Leonie W. , Nijsten Tamar E.C. , Niessen Frank B.
Published: December 2022

Background:

The treatment algorithm in late-onset inflammatory adverse events on soft tissue fillers depends primarily on the assumed causative factor, being either immunological or bacterial.

Methods:

We included 29 patients, of whom 13 experienced late-onset inflammatory adverse events to fillers (Inflammatory group) and 16 who did not (Reference group). We acquired biopsies from both groups with an 18 G needle. Before taking the biopsy, we acquired skin swabs in 25 of the 29 patients. We used a new and very sensitive method to detect microbiota, the IS-pro method. This is a novel broad-range PCR technique based on length and sequence variations of the 16S-23S ribosomal interspacer (IS) region. IS-pro can detect bacteria at low abundances and identify them up to species level. To exclude contamination from skin microbiota we compared the microbiota found on skin swabs with that found in the corresponding biopsies

Results:

A high level of Gram-positive bacteria was found in biopsies of soft tissue fillers, predominantly in patients from the inflammation group. This suggests that these bacteria were introduced during the primary filler injection treatment. The composition of the microbiota on the skin differed markedly from that in the filler indicating that contamination during our sampling process did not influence results.

Conclusion:

Bacteria adherent to soft tissue fillers or bacteremia probably play a causative role in adverse events. Contamination of samples in the biopsies with skin microbiota was excluded.
Ideal cardiovascular health, biomarkers, and coronary artery disease in persons with HIV
Authors: Douglas Pamela S. , McCallum Sara , Lu Michael T. , Umbleja Triin , Fitch Kathleen V. , Foldyna Borek , Zanni Markella V. , Fulda Evelynne S. , Bloomfield Gerald S. , Fichtenbaum Carl J. , Overton Edgar T. , Aberg Judith A. , Malvestutto Carlos D. , Burdo Tricia H. , Arduino Roberto C. , Ho Ken S. , Yin Michael T. , Ribaudo Heather J. , Grinspoon Steven K.
Published: December 2022

Objective:

To investigate relationships between Life's Simple 7 (LS7), an assessment of cardiovascular health (CVH), and coronary plaque among people with HIV (PWH).

Design:

Cross-sectional.

Methods:

Coronary computed tomography angiography, immune/inflammatory biomarkers, and characterization of LS7 were collected among a subset of ART-treated PWH enrolled in REPRIEVE, a primary prevention trial. Analyses adjusted for cardiovascular disease risk (ASCVD score).

Results:

Median age of the 735 participants was 51(±6) years, 16% female, and median (Q1–Q3) CVD risk was 4.5% (2.6–6.9). Forty percent had poor (≤2 ideal components), 51% had intermediate (three or four ideal components), and only 9% had ideal CVH (≥5). Coronary plaque was present in 357 (49%); 167 (23%) had one or more vulnerable plaque features, 293 (40%) had noncalcified plaque, and 242 (35%) had a coronary artery calcium score >0. All three phenotypes were increasingly more prevalent with poorer CVH and these relationships remained after adjusting for ASCVD risk. Poor CVH was associated with higher high-sensitivity C-reactive protein, oxidized low-density cholesterol, and interleukin-6. The relationship of LS7 to plaque remained after adjusting for these biomarkers.

Conclusions:

Among PWH, poor CVH as measured by LS7 was associated with coronary plaque presence, vulnerable features, and calcification. LS7 was also associated with selected biomarkers; adjustment for these and ASCVD score reduced but did not eliminate LS7's association with plaque, suggesting the possibility of additional protective mechanisms against atherogenesis and plaque remodeling. Clinical use of LS7 and further exploration of its relationships with coronary artery disease may enhance efforts to reduce cardiovascular morbidity and mortality in PWH.

Clinical Trials Registration:

NCT02344290
The Cost-effectiveness of Transplanting Hearts From Hepatitis C-infected Donors Into Uninfected Recipients
Authors: Woolley Ann E. , Gandhi Aditya R. , Jones Michelle L. , Kim Jane J. , Mallidi Hari R. , Givertz Michael M. , Baden Lindsey R. , Mehra Mandeep R. , Neilan and Anne M.
Published: December 2022

Background.

The DONATE HCV trial demonstrated the safety and efficacy of transplanting hearts from hepatitis C viremic (HCV+) donors. In this report, we examine the cost-effectiveness and impact of universal HCV+ heart donor eligibility in the United States on transplant waitlist time and life expectancy.

Methods.

We developed a microsimulation model to compare 2 waitlist strategies for heart transplant candidates in 2018: (1) status quo (SQ) and (2) SQ plus HCV+ donors (SQ + HCV). From the DONATE HCV trial and published national datasets, we modeled mean age (53 years), male sex (75%), probabilities of waitlist mortality (0.01–0.10/month) and transplant (0.03–0.21/month) stratified by medical urgency, and posttransplant mortality (0.003–0.052/month). We assumed a 23% increase in transplant volume with SQ + HCV compared with SQ. Costs (2018 United States dollar) included waitlist care ($2200–190 000/month), transplant ($213 400), 4-wk HCV treatment ($26 000), and posttransplant care ($2500–11 300/month). We projected waitlist time, quality-adjusted life-years (QALYs), lifetime costs, and incremental cost-effectiveness ratios (ICERs [$/QALY, discounted 3%/year]; threshold ≤$100 000/QALY).

Results.

Compared with SQ, SQ + HCV decreased waitlist time from 8.7 to 6.7 months, increased undiscounted life expectancy from 8.9 to 9.2 QALYs, and increased discounted lifetime costs from $671 400/person to $690 000/person. Four-week HCV treatment comprised 0.5% of lifetime costs. The ICER of SQ + HCV compared with SQ was $74 100/QALY and remained ≤$100 000/QALY with up to 30% increases in transplant and posttransplant costs.

Conclusions.

Transplanting hearts from HCV-infected donors could decrease waitlist times, increase life expectancy, and be cost-effective. These findings were robust within the context of current high HCV treatment costs.
Utility of Digital Single-operator Video Cholangioscopy for the Endoscopic Management of Biliary Complications After Liver Transplantation—A Single-center Experience
Authors: Bokemeyer Arne , Lenze Frank , Stoica Viorelia , Selcuk Sensoy Timur , Huesing-Kabar Anna , Kabar Iyad , Schmidt Hartmut , Ullerich Hansjoerg
Published: December 2022

Background.

Liver transplant recipients (LTRs) frequently develop biliary complications, and endoscopy is crucial for their subsequent management. Recently, single-operator video cholangioscopy (SOVC) with digital imaging quality was introduced. This study evaluated the utility of digital SOVC for the management of biliary complications in LTRs.

Methods.

This observational study retrospectively analyzed all LTRs undergoing digital SOVC between 2015 and 2019 at a tertiary referral center. Endpoints included the assessment of biliary strictures, performance of selective guidewire passage across biliary strictures, and diagnosis and treatment of biliary stone disease.

Results.

In total, 79 digital SOVCs performed in 50 LTRs were identified. Fifty-eight percent of the procedures were performed for biliary stricture assessment, and using visual signs or guided biopsies, SOVC excluded malignancy in all cases (100%). Of all the examinations, 29.1% (23/79) were performed solely because of a previous failure of conventional endoscopic methods to pass a guidewire across a biliary stricture. Using SOVC, guidewire passage was successfully performed in 73.9% of these examinations, enabling subsequent endoscopic therapy. Furthermore, biliary stones were found in 16.5% (13/79) of the examinations. In 38.5% of these cases, standard fluoroscopy failed to detect stones, which were only visualized using digital SOVC. Biliary stone treatment was successful in 92% (12/13) of the examinations. Complications occurred in 11.4% of all SOVCs. No procedure-associated mortalities were observed.

Conclusions.

Digital SOVC is effective and safe for the endoscopic management of biliary complications in LTRs and offers unique diagnostic and therapeutic opportunities that strongly impact the clinical course in selected cases.
Status of the SeqCode in the International Journal of Systematic and Evolutionary Microbiology
Authors: Göker Markus , Moore Edward R. B. , Oren Aharon , Trujillo Martha E.
Published: December 2022

The recent publication of an alternative nomenclatural code that targets prokaryotes, the Code of Nomenclature of Prokaryotes Described from DNA Sequence Data (SeqCode), raises questions about how to treat names ‘validly published’ under that code in the International Journal of Systematic and Evolutionary Microbiology (IJSEM). Here, it is reiterated that the IJSEM must function in accordance with the International Code of Nomenclature of Prokaryotes (ICNP). It is also reiterated that the ICNP covers all prokaryotes and that it accordingly assigns a nomenclatural status to all names of prokaryotic taxa. This implies that the ICNP also assigns a status to names that are only ‘validly published’ under the SeqCode. It follows that the IJSEM must treat such names as not validly published, since ‘validly published under the SeqCode’ is not a nomenclatural status, under the ICNP. Such names should be marked accordingly as Candidatus names or printed in quotation marks. The same measures would need to be taken by other journals which intend to adhere to the ICNP.
Frequency of quorum-sensing mutations in Pseudomonas aeruginosa strains isolated from different environments
Authors: O’Connor Kathleen , Zhao Conan Y. , Mei Madeline , Diggle Stephen P.
Published: December 2022

Pseudomonas aeruginosa

uses quorum sensing (QS) to coordinate the expression of multiple genes necessary for establishing and maintaining infection. It has previously been shown that lasR QS mutations frequently arise in cystic fibrosis (CF) lung infections, however, there has been far less emphasis on determining whether other QS system mutations arise during infection or in other environments. To test this, we utilized 852 publicly available sequenced

P. aeruginosa

genomes from the

Pseudomonas

International Consortium Database (IPCD) to study

P. aeruginosa

QS mutational signatures. To study isolates by source, we focused on a subset of 654 isolates collected from CF, wounds, and non-infection environmental isolates, where we could clearly identify their source. We also worked with a small collection of isolates in vitro to determine the impact of lasR and pqs mutations on isolate phenotypes. We found that lasR mutations are common across all environments and are not specific to infection nor a particular infection type. We also found that the pqs system proteins PqsA, PqsH, PqsL and MexT, a protein of increasing importance to the QS field, are highly variable. Conversely, RsaL, a negative transcriptional regulator of the las system, was found to be highly conserved, suggesting selective pressure to repress las system activity. Overall, our findings suggest that QS mutations in

P. aeruginosa

are common and not limited to the las system; however, LasR is unique in the frequency of putative loss-of-function mutations.
Jaccard dissimilarity in stochastic community models based on the species-independence assumption
Authors: Iritani Ryosuke , Ontiveros Vicente J. , Alonso David , Capitán José A. , Godsoe William , Tatsumi Shinichi
Published: December 2022

A fundamental problem in ecology is understanding the causes of change in species composition among sites (i.e. beta diversity). At present it is unclear how spatial heterogeneity in species occupancy across sites shapes these patterns. To address this question, we develop probabilistic models that consider two spatial or temporal sites, where presence probabilities vary both among species and between the sites. We derive analytical and approximate formulae for the expectation of pairwise beta-diversity. Using a novel graphical tool, Stochastic Incidence Plots (SIPs), which depict the presence probabilities in two sites across species labels, we develop a means to conceptualize the heterogeneity in presence probabilities: the steepness or unevenness of SIPs reflects species-level heterogeneity, while the degree of overlap between SIPs indicates site-level heterogeneity. Utilizing SIPs and a combinatorial approach in a two-species scenario, we demonstrate that beta-diversity is lower when SIPs are parallel compared to when they are anti-parallel. We also find that this prediction is testable with the well-known checkerboard pattern in incidence matrices. Finally, we applied the method to the species distribution models for five woodpecker species in Switzerland, showing that their spatial distributions will change significantly in the future. Overall, this work improves our understanding of how pairwise beta-diversity responds to occupancy heterogeneity.
Lung tumor-infiltrating Treghave divergent transcriptional profiles and function linked to checkpoint blockade response
Authors: Dykema Arbor G. , Zhang Jiajia , Zhang Boyang , Cheung Laurene S. , Zeng Zhen , Cherry Christopher M. , Li Taibo , Caushi Justina X. , Nishimoto Marni , Connor Sydney , Ji Zhicheng , Munoz Andrew J. , Hou Wenpin , Zhan Wentao , Singh Dipika , Rashid Rufiaat , Mitchell-Flack Marisa , Bom Sadhana , Tam Ada , Ionta Nick , Wang Yi , Sawosik Camille A. , Tirado Lauren E. , Tomasovic Luke M. , VanDyke Derek , Spangler Jamie B. , Anagnostou Valsamo , Yang Stephen , Spicer Jonathan , Rayes Roni , Taube Janis , Brahmer Julie R. , Forde Patrick M. , Yegnasubramanian Srinivasan , Ji Hongkai , Pardoll Drew M. , Smith Kellie N.
Published: December 2022

Regulatory T cells (Treg) are conventionally viewed to suppress endogenous and therapyinduced anti-tumor immunity; however, their role in modulating responses to immune checkpoint blockade (ICB) is unclear. In this study, we integrated single-cell RNAseq/TCRseq of >73,000 tumor-infiltrating Treg(TIL-Treg) from anti-PD-1-treated and treatment naive non-small cell lung cancers (NSCLC) with single cell analysis of tumor-associated antigen (TAA)-specific Tregderived from a murine tumor model. We identified 10 subsets of human TIL-Treg, most of which have high concordance with murine TIL-Tregsubsets. Notably, one subset selectively expresses high levels of OX40 and GITR, whose engangement by cognate ligand mediated proliferative programs and NF-kB activation, as well as multiple genes involved in Tregsuppression, in particular LAG3. Functionally, the OX40hiGITRhisubset in the most highly suppressiveex vivoand Tregexpression of OX40, GITR and LAG3, correlated with resistance to PD-1 blockade. Surprisingly, in the murine tumor model, we found that virtually all TIL-Tregexpressing T cell receptors that are specific for TAA fully develop a distinct Th1-like signature over a two-week period after entry into the tumor, down-regulating FoxP3 and up-regulating expression ofTBX21 (Tbet), IFNγ and certain pro-inflammatory granzymes. Application of a gene score from the murine TAA-specific Th1-like Tregsubset to the human single-cell dataset revealed a highly analogous subcluster that was enriched in anti-PD-1 responding tumors. These findings demonstrate that TIL-Tregpartition into multiple distinct transcriptionally-defined subsets with potentially opposing effects on ICB-induced anti-tumor immunity and suggest that TAA-specific TIL-Tregmay positively contribute to anti-tumor responses.

One-Sentence Summary

We define 10 subsets of lung cancer-infiltrating regulatory T cells, one of which is highly suppressive and enriched in anti-PD-1 non-responders and the other is Th1-like and is enriched in PD-1 responders.
Analyzing patterns of tyrosine sulfation in naive antibody repertoires
Authors: Pospelova Maria , Safonova Yana
Published: December 2022

HIV-1 infects a subset of immune cells identified by the receptor CD4 and a coreceptor, CCR5 or CXCR4. Previous studies revealed bnAbs against HIV-1 with antigen-binding sites mimicking binding sites of CCR5. Such antibodies are characterized by post-translationally sulfated tyrosines and anionic motifs in long complementarity determining regions 3 (CDR3s) of the heavy chains. Despite the great therapeutic potential of human antibodies mimicking CCR5, their immunogenetic signatures remain unknown. In this study, we analyzed human naïve heavy chain antibody repertoires and described the most common VDJ recombination scenarios generating CDR3s with sulfated tyrosines and anionic motifs. We showed ~77% of such CDR3s are generated using seven D genes from two families, IGHD3 and IGHD4. We also demonstrated that sulfated tyrosines and anionic motifs are a common feature of mammalian germline D genes.
A novel multi-epitope peptide vaccine candidate targeting Hepatitis E virus: an in-silico approach
Authors: Kumar Anoop , Sahu Utkarsha , Agnihotri Geetanjali , Dixit Anshuman , Khare Prashant
Published: December 2022

HEV is a foodborne virus transmitted through the fecal-oral route that causes viral hepatitis in humans worldwide. Ever since its discovery as a zoonotic agent, HEV was isolated from several species with an expanding range of hosts. HEV possesses several features of other RNA viruses but also has certain HEV-specific traits that make its viral-host interactions inimitable. HEV leads to severe morbidity and mortality in immunocompromised people and pregnant women across the world. The situation in underdeveloped countries is even more alarming. Even after creating a menace across the world, we still lack an effective vaccine against HEV. Till date, there is only one licensed vaccine for HEV available only in China. The development of an anti-HEV vaccine that can reduce HEV-induced morbidity and mortality is required. Live attenuated and killed vaccines against HEV are not accessible due to the lack of a tolerant cell culture system, slow viral replication kinetics and varying growth conditions. Thus, the main focus for anti-HEV vaccine development is now on the molecular approaches. In the current study, we have designed a multi-epitope vaccine against HEV through a reverse vaccinology approach(Figure 1). For the first time, we have used viral ORF3, capsid protein and polyprotein altogether for epitope prediction. These are crucial for viral replication and persistence and are major vaccine targets against HEV. The proposedin-silicovaccine construct comprises of highly immunogenic and antigenic T-cell and B-cell epitopes of HEV proteins and ORF3. The construct is capable of inducing an effective and long-lasting host immune response as evident from the simulations results. In addition, the construct is stable, non-allergic and antigenic for the host. Altogether, our findings suggest that thein-silicovaccine construct may be useful as a vaccine candidate for preventing HEV infections.
The Impact of Freeze-Thaw Cycles on the Integrity of SARS-COV-2 Viral Culture Fluids and Clinical Remnant Samples in Antigen or Nucleic Acid Testing
Authors: Hussain Hajirah Noor , Weeks Hali , Zhou Derek , Joseph Divya , Lam Brooke , Xu Haidong , Zhang Chushi , Gregg Keqin , Zhou Wenli
Published: December 2022

Preservation at ultra-low temperatures has been a gold standardfor long-term storage of many types of clinical specimens including the SARS-CoV-2 virus. The frozen specimens can be easily transported and tested later. In addition, de-identified frozen remnant samples are resources for many preclinical or clinical studies. It is therefore crucial to understand whether freeze and thaw cycles (FTCs) can adversely affect SARS-CoV-2 test performance when frozen samples are tested. Some early studies suggest that the FTCs increased the cycles threshold (Ct) of RT-PCR indicating the potential degradation of the SARS-CoV-2 nucleic acid after FTCs, while the others did not report any significant changes in the SARS-CoV-2 nucleic acids after the FTCs. Moreover, the impact of FTCs on the performance of the SARS-CoV-2 antigen test is scarcely reported.

In this study, we performed paired nucleic acid and rapid antigen testson the same samples to investigate and directly compare how FTCs affect the performance of two types of tests. Both inactivated viral culture fluid samples and clinical remnant samples were studied. Our results showed that FTCs had minimal negative effects on the performance of the rapid SARS-CoV-2 antigen test, and the test results remained largely consistent throughout the FTCs, whereas the Ct values of RT-PCR increased with the increase of the FTC numbers. In addition, our data also demonstrated that the SARS-CoV-2 is preserved better in VTM than PBS during FTCs in regard to nucleic acid testing.
Effects of mindfulness meditation and Acceptance and Commitment Therapy in patients with obstructive sleep apnea with residual excessive sleepiness: A randomized controlled pilot study
Authors: Hellrigel-Holderbaum Max , Romanczuk-Seiferth Nina , Glos Martin , Fietze Ingo
Published: December 2022

Objective

Assessing the effects of Mindfulness-Based Stress Reduction (MBSR) and Acceptance and Commitment Therapy (ACT) on symptoms of OSA, especially on the main outcome, excessive daytime sleepiness (EDS).

Methods

Parallel randomized controlled trial. 16 OSA patients with residual EDS (rEDS) were randomized and assigned to the two programs via a central computer system using REDCap. Participants completed a standardized 8-week MBSR program or a time-matched program on Acceptance and Commitment Therapy (ACT). Both programs were conducted online. Participants answered questionnaires online at baseline (pre), post-intervention (post), three months after the intervention (follow-up) and were blinded to whether their group was the treatment or control group but not to group allocation. Three participants dropped out early. Most analyses are based on the remaining 13 patients.

Results

There was a significant difference between the MBSR (n=7) and ACT group (n=6) in changes of EDS between pre and post (p=.043) and a significant reduction of EDS for patients in the ACT group at post (p=.034). This EDS reduction averaging 2.17 points on the Epworth Sleepiness Scale reached the prespecified bar for clinical significance of two points on that scale. Insomnia symptoms reduced significantly following ACT (p=.017). In MBSR, both participants and the MBSR-trainer judged movement-based exercises to be most efficacious.

Conclusion

ACT shows potential as adjunctive therapy for OSA with rEDS, although further studies are needed. It seems promising to develop therapeutic approaches for OSA with rEDS using ACT, especially if they are tailored to patients’ needs.

Trial registration

drks.de; Identifier: DRKS00026812
Fastest may not maximize gait quality: differential and individual-specific immediate effects of gait speed on biomechanical variables post-stroke
Authors: Rosenberg Michael C. , Christianson Hannah , Liu Justin , Santucci Vincent , Sims Payton , Schilder Alex , Zajac-Cox Laura , Winner Taniel S. , Ting Lena H. , Kesar Trisha M.
Published: December 2022

A common perspective in post-stroke gait training is that walking at the fastest safe speed maximizes the quality of gait biomechanics, but effects on compensatory biomechanics and inter-limb asymmetry have not been widely characterized. It is unclear whether walking at the fastest speed maximizes the quality of (i.e., optimizes) post-stroke biomechanics across variables, individuals, and walking function levels. In low- (n=9) and high-functioning (n=9) stroke survivors walking at six individualized speeds, we determined if walking at the fastest speed optimized 16 biomechanical variables. Across participants, 46% of magnitude and 17% of asymmetry variables were optimized at the fastest speed, but the optimized variables differed across individuals. Some inter-limb asymmetry variables sustained large biomechanical costs, (i.e., biomechanical quality lost by walking at the fastest vs. the optimal speed; difference in Cohen’sd=0.1-0.7). In both groups, faster speeds were associated with increased (improved) paretic-leg trailing limb angle, peak ankle moment, and peak hip and ankle power magnitudes (all p<0.001), but changes in inter-limb asymmetry were individual-specific. Our findings suggest that treadmill training at the fastest safe speed does not maximize gait quality across individuals or biomechanical variables. More holistic, individual-specific gait quality metrics are needed to guide gait speed optimization during rehabilitation.
A transcriptome atlas ofStriga hermonthicagermination
Authors: Irafaha Gilles , Mutinda Sylvia , Mobegi Fredrick , Hale Brett , Omwenga George , Wijeratne Asela J. , Wicke Susann , Bellis Emily S. , Runo Steven
Published: December 2022

Societal Impact Statement

Witchweeds, parasitic plants of the genusStriga, are nicknamed “cereal killers” because of their devasting destruction of Africa’s most staple cereals, including maize, sorghum, millets, and upland rice. The parasite relies on biomolecules emitted from the host roots to germinate and therefore initiate its infectious lifecycle. Some sorghum varieties have evolved to not produce effective germination stimulants, making them resistant to the parasite. Here, we assess genetic factors that underpinStrigagermination. We discuss how such knowledge can be used to develop newStrigamanagement strategies through the disruption of host-parasite communication exchange.

Seeds of the parasitic plantStrigaare dormant. They only germinate in response to biomolecules emitted from the host’s root exudate, strigolactones (SL). But, it is now emerging thatStrigagermination is a much more complex process regulated by crosstalk of hormone signaling pathways.

To further understand the genetic basis of the communication exchange betweenStrigaand its host sorghum, we performed a comparative transcriptomic analysis. We sought to identify major transcriptomic changes that define the germination process inStrigaand a set of genes that may contribute to the differences in germination rates.

Results showed that germination proceeds immediately after SL perception and is marked by a wave of transcriptional reprogramming to allow for metabolic processes of energy mobilization. Cluster analysis using self-organizing maps (SOMs) revealed a time-phased and genotype-differentiated response to germination stimulation. The variation in germination was also a function of hormonal crosstalk. The early germination stage was associated with significant repression of genes in the abscisic acid (ABA) biosynthesis pathway. Other hormones influenced germination as follows: (i) ABA and auxin repressed germination, (ii) brassinosteroid, ethylene and jasmonic acid promoted germination, and (iii) cytokinin had a more prominent role post-germination rather than during germination. Perception of SL sets the germination programme leading to different rates of germination in sorghum followed by a complex hormonal regulation network that acts to either repress or enhance germination. These results have far-reaching implications for developingStrigamanagement strategies by disrupting hormonal communication exchange.
Human intestinal epithelial cells can internalize luminal fungi via LC3-associated phagocytosis
Authors: Cohen-Kedar Sarit , Barda Efrat Shaham , Rabinowitz Keren Masha , Keizer Danielle , Abu-Taha Hannan , Schwartz Shoshana , Kaboub Kawsar , Baram Liran , Sadot Eran , White Ian , Wasserberg Nir , Wolff-Bar Meirav , Levy-Barda Adva , Dotan Iris
Published: December 2022

Intestinal epithelial cells (IECs) are the first to encounter luminal microorganisms and actively participate in intestinal immunity. We reported that IECs express the β-glucan receptor Dectin-1, and respond to commensal fungi and β-glucans. In phagocytes, Dectin-1 mediates LC3 associated phagocytosis (LAP) utilizing autophagy components to process extracellular cargo. Dectin-1 can mediate phagocytosis of β-glucan-containing particles by non-phagocytic cells. We aimed to determine whether human IECs phagocytose β-glucan-containing fungal particles via LAP. Zymosan (β-glucan particle) and Heat-killed and UV inactivatedC. albicanswere phagocytosed by monolayers of human colonic (n=18) and ileal (n=4) organoids and IEC lines. LAP was identified by LC3 and Rubicon recruitment to phagosomes and lysosomal processing of internalized particles was demonstrated by co-localization with lysosomal dyes and LAMP2. Phagocytosis was significantly diminished by blockade of Dectin-1, actin polymerization and NAPDH oxidases. Our results show that human IECs sense luminal fungal particles and internalize them via LAP. This novel mechanism of luminal sampling suggests that IECs may contribute to the maintenance of mucosal tolerance towards commensal fungi.
Nested circuits mediate the decision to vocalize
Authors: Xiao Shuyun , Michael Valerie , Mooney Richard
Published: December 2022

Vocalizations facilitate mating and social affiliation, but may also inadvertently alert predators and rivals. Consequently, the decision to vocalize depends on brain circuits that can weigh and compare these potential benefits and risks. Male mice produce ultrasonic vocalizations (USVs) during courtship to facilitate mating and female mice produce USVs to promote social affiliation with each other. Previously we showed that a specialized set of neurons in the midbrain periaqueductal gray (PAG) are an obligatory gate for USV production in both male and female mice, and that both PAG-USV neurons and USVs can be switched on by their inputs from the preoptic area (POA) of the hypothalamus and switched off by their inputs from neurons on the border between the central and medial amygdala (AmgC/M-PAGneurons) (Michael et al., 2020). Here we show that the USV-suppressing AmgC/M-PAGneurons are strongly activated by predator cues or during social contexts that suppress USV production in male and female mice. Furthermore, a subset of USV-promoting POA neurons that provide input to the PAG-USV region also extend axon collaterals to the amygdala, where they directly inhibit AmgC/M-PAGneurons. Accordingly, AmgC/M-PAGneurons, along with POAPAGand PAG-USV neurons, form a nested hierarchical circuit in which environmental and social information converges to influence the decision to vocalize.
A spatial code for temporal cues is necessary for sensory learning
Authors: Bagur Sophie , Bourg Jacques , Kempf Alexandre , Tarpin Thibault , Bergaoui Khalil , Guo Yin , Ceballo Sebastian , Schwenkgrub Joanna , Verdier Antonin , Puel Jean Luc , Bourien Jérôme , Bathellier Brice
Published: December 2022

The temporal structure of sensory inputs contains essential information for their interpretation by the brain1–9. Sensory systems represent these temporal cues through two codes: the temporal sequences of neuronal activity and the spatial patterns of neuronal firing rate3,7,10–20. However, it is still unknown which of these two coexisting codes causally drives sensory decisions3,10,20,21. To separate their contributions, we designed an optogenetic stimulation paradigm in the mouse auditory cortex to generate neuronal activity patterns differing exclusively along their temporal or spatial dimensions. Training mice to discriminate these patterns shows that they efficiently learn to discriminate spatial but not temporal patterns, indicating that spatial representations are necessary for sensory learning. In line with this result, we observed, based on large-scale neuronal recordings of the auditory system, that the auditory cortex is the first region in which spatial patterns efficiently represent temporal auditory cues varying over several hundred milliseconds. This feature is shared by the deep layers of neural networks trained to categorise time-varying sounds. Therefore, the emergence of a spatial code for temporal sensory cues is a necessary condition to associate temporally structured stimuli to decisions. We expect this constraint to be crucial for re-engineering perception by cortical stimulation.
PyDESeq2: a python package for bulk RNA-seq differential expression analysis
Authors: Muzellec Boris , Teleńczuk Maria , Cabeli Vincent , Andreux Mathieu
Published: December 2022

We present PyDESeq2, a python implementation of the DESeq2 workflow for differential expression analysis on bulk RNA-seq data. This implementation achieves better precision, allows speed improvements on large datasets, as shown in experiments on TCGA data, and can be more easily interfaced with modern python-based data science tools.

Availability and Implementation

PyDESeq2 is released as an open-source software under the MIT license. The source code is available on GitHub athttps://github.com/owkin/PyDESeq2.

Contact

boris.muzellec@owkin.com
A bibliometric analysis of gender in microbiology collaborations
Authors: Wheatley Rachel M. , Ogunlana Lois
Published: December 2022

Women are underrepresented in senior academic positions within microbiology globally. Studies show that gender bias affects the progression of women in academia, but there is evidence that improving conscious awareness of bias can improve equity in this regard. Here we carry out a bibliometric analysis of review articles within the microbiology field to investigate the statistical associations with author gender. We analyse the publication data from 1857 review articles published between 2010 and 2022 in three leading microbiology review journals: Nature Reviews Microbiology, Trends in Microbiology, and Annual Review of Microbiology. We find a significant association between the gender of the lead author and the gender of co-authors in multi-author publications. Review articles with men lead authors have a significantly reduced proportion of women co-authors compared to reviews with women lead authors. Given the existing differences in the proportions of men and women in lead author positions, this association may have important consequences for the relative visibility of women in microbiology, along with potential negative impacts on scientific output relating to reduced collaboration diversity. We further probe associations between gender and citation metrics, acknowledgement of contributions, and publishing during the Covid-19 pandemic within microbiology reviews.
Genome and Genetic Engineering of the House Cricket (Acheta domesticus): Applications for Sustainable Agriculture
Authors: Dossey Aaron T. , Oppert Brenda , Chu Fu-Chyun , Lorenzen Marcé D. , Scheffler Brian , Simpson Sheron , Koren Sergey , Johnston J. Spencer , Kataoka Kosuke , Ide Keigo
Published: December 2022

The house cricket,Acheta domesticus, is one of the most farmed insects worldwide and the foundation of an emerging industry for the use of insects as a sustainable food source. Edible insects present a promising alternative for protein production amid a plethora of recent reports on climate change and biodiversity loss largely driven by agriculture. As with other agricultural crops, genetic resources are needed to improve crickets for food and other applications. We present the first high quality annotated genome assembly ofA. domesticuswhich was assembled from long read data and scaffolded to chromosome level from long range data, providing information on promoters and genes needed for genetic manipulation. Gene groups that may be useful for improving the value of these insects to farmers were manually annotated, mainly genes related to immunity. Metagenome scaffolds in theA. domesticusassembly, including those from bacteria, other microbes and viruses such as Invertebrate Iridescent Virus 6 (IIV6), were submitted in a separate accession as host-associated sequences. We demonstrate both CRISPR/Cas9-mediated knock-in and knock-out of selected genes and discuss implications for the food, pharmaceutical and other industries. RNAi was demonstrated to disrupt the function of thevermilioneye-color gene to produce a useful white-eye biomarker phenotype. We are utilizing these data to develop base technologies and methodologies for downstream commercial applications, including the generation of more nutritious and disease resistant crickets as well as lines producing valuable bioproducts such as vaccines and antibiotics. We also discuss how this foundational research can play a critical role in utilizing the largest, most diverse yet almost entirely untapped biological resource on Earth: Class Insecta.

Significance Statement

Sequencing and assembly of the genome of the house cricket has led to improvements in farmed insects for food, pharmaceutical and other applications.
Monitoring the battlefield: Antimicrobial resistance, antibiofilm patterns and virulence factors ofAcinetobacter baumanniiisolates from hospital system
Authors: Awour Silas Onyango
Published: December 2022

Hospital-acquired contagions are on the increase and are a substantial cause of clinical and financial burden for healthcare systems. While contagion control plays a major role in curtailing the spread of outbreak organisms, it is not always effective. One organism of particular concern isAcinetobacter baumannii, due to both its persistence in the hospital setting and its ability to acquire antibiotic resistance.A. baumanniihas appeared as a nosocomial pathogen that displays high levels of resistance to antibiotics, and remains resilient against traditional cleaning measures with resistance to Colistin increasingly reported. Given the costs associated and magnitude with hospital acquired infections, and the rise in multidrug-resistant organisms, it is worth re-evaluating our current approaches and observing for substitutes or aides-de-camp to traditional antibiotics therapies. The aims of this study was to determine antimicrobial resistance, antibiofilm patterns and virulence factors ofAcinetobacter baumanniiisolates from hospital system. Among the five drugs used (Amikacin, Gentamicin, Meropenem, Tigecycline and Tazobactam) it was revealing that all the isolates show resistance to all the drugs. It was revealed that 3 isolates show resistance at difference antimicrobial classes in isolate05/JOOTRH/22and17/JOOTRH/22were able to produce all type of the virulence enzymes while isolate11/JOOTRH/22was able to produce all except protease enzyme. The isolates showed that the biofilm formation inhibitory effects of the various concentrations (0.5, 0.25, 0.125, 0.0625 and 0.03125 mg ml−1) were significantly lower than that of the positive control, an indication that biofilm formation was inhibited at these concentrations
METTL3 maintains epithelial homeostasis through m6A-dependent regulation of chromatin modifiers
Authors: Maldonado López Alexandra M. , Huang Sijia , Pacella Gina , Ko Eun Kyung , Shen Hui , Stoute Julian , Sinkfield Morgan , Anderson Amy , Prouty Stephen , Li Hua-Bing , Seykora John T. , Liu Kathy Fange , Capell Brian C.
Published: December 2022

The balance between epithelial stemness and differentiation requires the precise regulation of gene expression programs. Epitranscriptomic RNA modifications have been implicated in both epithelial development as well as cancers. However, the underlying mechanisms are poorly understood. Here, we show that deletion of the m6A methyltransferase, METTL3, impairs the m6A-mediated degradation of numerous mRNA transcripts encoding critical chromatin modifying enzymes, resulting in widespread gene expression abnormalities as well as both aberrant cutaneous and oral epithelial phenotypesin vivo. Collectively, these results offer new insights into a new layer of gene regulation within epithelial surface tissues and will inform future epitranscriptomic studies within epithelial cancer and developmental biology.
Neurodegeneration Risk Factor,EIF2AK3(PERK), Influences Tau Protein Aggregation
Authors: Park Goonho , Xu Ke , Chea Leon , Kim Kyle , Safarta Lance , Song Keon-Hyoung , Wu Jian , Park Soyoung , Min Hyejung , Hiramatsu Nobuhiko , Han Jaeseok , Lin Jonathan H.
Published: December 2022

Tauopathies are neurodegenerative diseases caused by pathologic misfolded tau protein aggregation in the nervous system. Population studies implicateEIF2AK3(eukaryotic translation initiation factor 2 alpha kinase 3), better known asPERK(protein kinase R-like endoplasmic reticulum kinase), as a genetic risk factor in several tauopathies. PERK is a key regulator of intracellular proteostatic mechanisms – Unfolded Protein Response (UPR) and Integrated Stress Response (ISR). Previous studies found that tauopathy-associated PERK variants encoded functional hypomorphs with reduced signalingin vitro. But, it remained unclear how altered PERK activity led to tauopathy. Here, we chemically or genetically modulated PERK signaling in cell culture models of tau aggregation and found that PERK pathway activation prevented tau aggregation while inhibition exacerbated tau aggregation. In primary tauopathy patient brain tissues, we found that reduced PERK signaling correlated with increased tau neuropathology. We found that tauopathy-associated PERK variants targeted the ER luminal domain; and two of these variants damaged hydrogen bond formation. Our studies support that PERK activity protects against tau aggregation and pathology. This may explain why people carrying hypomorphic PERK variants have increased risk for developing tauopathies. Finally, our studies identify small molecule augmentation of PERK signaling as an attractive therapeutic strategy to treat tauopathies by preventing tau pathology.
A set of orthogonal versatile interacting peptide tags for imaging cellular proteins
Authors: Suyama Alexa , Devlin Kaylyn L. , Macias-Contreras Miguel , Doh Julia K. , Shinde Ujwal , Beatty Kimberly E.
Published: December 2022

Genetic tags are transformative tools for investigating the function, localization, and interactions of cellular proteins. Most studies today are reliant on selective labeling of more than one protein to obtain comprehensive information on a protein’s behavior in situ. Some proteins can be analyzed by fusion to protein tag, such as green fluorescent protein, HaloTag, or SNAP-Tag. Other proteins benefit from labeling via small peptide tags, such as the recently reported versatile interacting peptide (VIP) tags. VIP tags enable observations of protein localization and trafficking with bright fluorophores or nanoparticles. Here we expand the VIP toolkit by presenting two new tags: TinyVIPER and PunyVIPER. These two tags were designed for use with MiniVIPER for labeling up to three distinct proteins at once in living cells. Labeling is mediated by the formation of a high affinity, biocompatible heterodimeric coiled coil. Each tag was validated by fluorescence microscopy, including observation of transferrin receptor 1 trafficking in live cells. We verified that labeling via each tag is highly specific, with no cross-reactivity between the three VIP tags under cellular conditions. Lastly, the self-sorting tags were used for simultaneous labeling of three protein targets (i.e., TOMM20, histone 2B, and actin), highlighting their utility for multicolor microscopy. MiniVIPER, TinyVIPER, and PunyVIPER are small and robust peptide tags for selective labeling of cellular proteins.
ARID1A-deficient cells promote endometrial carcinoma progression and dissemination by reprograming tumor microenvironment
Authors: Megino-Luque Cristina , Matias-Guiu Xavier , Eritja Núria
Published: December 2022

AT-rich interactive domain-containing protein 1A (ARID1A) loss-of-function mutation accompanied by a loss of ARID1A protein expression is frequently observed in endometrial carcinomas (EC). However, the mechanisms underlying this loss of ARID1A involved in the progression and dissemination of EC have been poorly studied and understood. Tumor microenvironment (TME) is reprogramed by cancer cells and have a high influence in aggressive behaviours of solid tumors. TME, and specially the stromal component, has a clear impact on the progression and aggressiveness of EC, but little is known about its activation, signalling and functions. Thus, the main aim of this study was to analyse the role of EC ARID1A loss in TME reprograming and its implication in endometrial tumor progression and aggressiveness. Here, using different endometrialin vitroandin vivomodels, we show that endometrial tumor cells with altered expression ofARID1Apromote the modulation and activation of the TME. We demonstrate that ARID1A depleted endometrial tumor cells induce aggressive behaviour in neighbouring endometrial tumor cells with wild-type ARID1A expression and the recruitment and activation of endometrial stromal cells (ESC). Interestingly, these pro-tumoral signals spread through the bloodstream supporting ARID1A wild-type EC cells aggressiveness. Finally, we show that ARID1A altered tumor cells display a different secretion profile and express significative high levels of chemokines in the TME. Taken together, our data demonstrate ARID1A depleted endometrial tumor cells reprograms TME promoting progression and dissemination of EC through chemokine secretion.