bluuebunny/crossref_metadata_2025 huggingface dataset:
Red and processed meat consumption and food insecurity are associated with hypertension; analysis of the National Health and Nutrition Examination Survey data, 2003–2016
Authors: Ba Djibril M. , Gao Xiang , Chinchilli Vernon M. , Liao Duanping , Richie John P. , Al-Shaar Laila
Published: November 2021

Objective:

This study examined the joint association of red and processed meat intake and food insecurity with hypertension.

Methods:

Adult participants of the National Health and Nutrition Examination Survey 2003–2016 were included. Total red meat intake was estimated using 24 h dietary recalls. Food insecurity was defined as having three or more affirmative responses using the Food Security Survey Module. Hypertension was defined as having mean SBP of at least 130 mmHg or DBP of at least 85 mmHg or use of antihypertensive drugs. Multivariable surveylogistic regression models were used to examine the independent and joint associations of total red meat and food insecurity with hypertension.

Results:

A total of 31 314 participants [mean (SE) age of 46.8 (0.3) years] were included, of whom 18.3% were food insecure. Total red meat consumption and food insecurity were independently associated with higher odds of hypertension. Compared with the first quintile of total red meat intake, participants in the fourth and fifth quintiles of total red meat intake had 29 and 39% higher odds of hypertension, respectively (P = 0.003). These associations were stronger among food insecure participants (P value for interaction <0.001). Substituting one serving/day of poultry, fish, eggs, dairy products, or plant-based protein sources for total red meat was each associated with 8–15% lower odds of hypertension.

Conclusion:

This study provides further evidence regarding the health hazards of total red meat consumption in relation with hypertension and calls for more awareness among food insecure groups.
Prognostic significance of pretreatment 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) in patients with primary T cell lymphomas
Authors: Zhang Jian-Hua , Zhao Jing , Fan Yan , Fu Zhan-Li , Zhang Xu-Chu , Liu Meng , Zhao Guang-Yu , Cen Xi-Nan , Chen Xue-Qi , Ning Jing , Li Xiang , Wang Rong-Fu
Published: November 2021

Objective

T cell lymphomas are associated with an aggressive worse prognosis. This study is designed to assess T cell lymphomas using 18F-FDG PET/CT.

Methods

Sixty-four patients with newly diagnosed T cell lymphomas underwent PET/computed tomography (PET/CT) scans, 47 cases who were fully followed up were retrospectively reviewed and analyzed. Overall survival (OS) and progression-free survival (PFS) were recorded for prognosis. We measured the maximum standardized uptake value (SUVmax) in all cases, analyzed the correlation between SUVmax and survival and other clinicopathologic parameters. Kaplan–Meier log-rank tests were then used to compare the survival of high and low PET/CT parameter groups, and multivariate Cox proportional hazards regression analysis was carried out to identify predictors of OS and PFS.

Results

With a median follow-up of 26.5 (range 0.7–117.5) months, the 1-, 2- and 3-year OS were 75.6, 61.7 and 49.2%, and PFS were 49.3, 39.9 and 29.9%, respectively in 47 patients. Among them, 33 cases progressed with a median time of 9.5 (0.7–115.0) months, and 26 patients died with a median survival time of 26.5 (0.7–117.5) months. Multivariate analysis showed the following independent prognostic factors for OS: age >60 years (P = 0.002), SUVmax >9.7 (P = 0.009) and extranodal involvement of more than one site (P = 0.018). In addition, lactate dehydrogenase level (P = 0.003) and B symptoms (P = 0.018) were independent risk factors for PFS.

Conclusion

Pretherapy SUVmax may serve as an independent predictor of outcome in patients with newly diagnosed T cell lymphomas.
Congenital neutropenia: disease models guiding new treatment strategies
Authors: Touw Ivo P.
Published: November 2021

Purpose of review

Myeloid diseases are often characterized by a disturbed regulation of myeloid cell proliferation, survival, and maturation. This may either result in a severe paucity of functional neutrophils (neutropenia), an excess production of mature cells (myeloproliferative disorders) or in clonal expansions of dysplastic or immature myeloid cells (myelodysplasia and acute myeloid leukemia). Although these conditions can be regarded as separate entities, caused by the accumulation of distinct sets of somatic gene mutations, it becomes increasingly clear that they may also evolve as the prime consequence of a congenital defect resulting in severe neutropenia. Prominent examples of such conditions include the genetically heterogeneous forms of severe congenital neutropenia (SCN) and Shwachman-Diamond Syndrome. CSF3 treatment is a successful therapy to alleviate neutropenia in the majority of these patients but does not cure the disease nor does it prevent malignant transformation. Allogeneic stem cell transplantation is currently the only therapeutic option to cure SCN, but is relatively cumbersome, e.g., hampered by treatment-related mortality and donor availability. Hence, there is a need for new therapeutic approaches.

Recent findings

Developments in disease modeling, amongst others based on induced pluripotent stem cell and CRISPR/Cas9 based gene-editing technologies, have created new insights in disease biology and possibilities for treatment. In addition, they are fueling expectations for advanced disease monitoring to prevent malignant transformation.

This review highlights the recent progress made in SCN disease modeling and discusses the challenges that are still ahead of us to gain a better understanding of the biological heterogeneity of the disease and its consequences for patient care.
Is Grade Group 1 (Gleason score 3 + 3 = 6) adenocarcinoma of the prostate really cancer?
Authors: Epstein Jonathan I.
Published: November 2021

Purpose of review

Whether Grade Group 1 (GG1) prostate cancer is really cancer remains controversial.

Recent findings

Favoring renaming GG1 with a noncancerous diagnosis are: fear of the term cancer, which will lead to overtreatment of GG1; and indolence of GG1. Favor designating GG1 as cancer are: morphologically, GG1 may be indistinguishable from GG2 to GG5 and GG1 is invasive (lacks basal cells), can show perineural invasion and extraprostatic extension; molecularly, GG1 has many of the hallmarks of prostate cancer; calling GG1 noncancer would lead to inconsistencies and confusion in reporting; sampling error with GG1 on biopsy can miss higher grade cancer; removing the label of cancer in men with GG1 on biopsy may make it challenging to insure follow-up during active surveillance; the prognosis of treated GG1 may not be the same if GG1 called noncancer and not treated; with Grade Group terminology, GG1 is more intuitive to patients as lowest grade cancer; and patients are increasingly adopting active surveillance, recognizing that not all prostate cancers are the same and GG1 can be followed carefully and safely on active surveillance.

There is strong support for retaining the carcinoma designation for GG1.
Management of Multiple Skeletal Tuberculosis Wounds Complicated With Multiple Deep Sinus Tracts
Authors: Zhang Yinhua , Zhou Hui , Wu Xifang , Xia Beinan , Wang Fudong , Zhu Jun
Published: November 2021

BACKGROUND:

Tuberculosis (TB) is a leading infectious disease worldwide. It rarely occurs in the scapula and toe joints and is easily misdiagnosed. Without prompt treatment, the associated lesions can spread to surrounding soft tissues such as joint capsules, muscles, tendons, and fascia. In severe cases, the bones and articular surfaces can become significantly damaged; it is not uncommon for deep skeletal TB wounds with sinus tracts to form, which are very difficult to treat. We report our successful wound care management approach for one patient with multiple skeletal TB complicated with multiple deep sinus tracts.

CASE:

The patient was treated with anti-TB medications, and wound and bone debridement (sharps, surgical) combined with vacuum-shielded drainage (VSD) (Kula, CG Bio Co Ltd, Gyeonggi-do, South Korea) to fill the sinus tract. We removed the caseous (cheese-like) necrotic tissue, purulent drainage, and necrotic tissue at the base of the wound to ensure optimal wound care. Throughout the course of treatment, we selected different types of dressings to maintain moist wound healing and absorb excessive drainage. After 144 days of treatment, the wound and deep sinus tracts completely healed.

CONCLUSIONS:

Wounds related to skeletal TB with multiple sinus tracts are difficult to manage and heal. We found our wound protocol that included timely debridement and use of VSD was effective for the management of these complex wounds. Specifically, our approach filled the dead space in the sinus tract, removed excessive drainage, promoted the growth of granulation tissue, and overall promoted tissue healing.
Neurofilament light protein as a biomarker in depression and cognitive function
Authors: Travica Nikolaj , Berk Michael , Marx Wolfgang
Published: November 2021

Purpose of review

Converging evidence suggest axonal damage is implicated in depression and cognitive function. Neurofilament light protein, measured within serum and cerebrospinal fluid, may be a biomarker of axonal damage. This article examines the emerging evidence implicating neurofilament light protein in depression and cognitive function.

Recent findings

Preliminary cross-sectional and case–control studies in cohorts with depression have yielded inconsistent results regarding the association between neurofilament light protein and symptomatology. However, these studies had methodological limitations, requiring further investigation. Importantly, neurofilament light protein concentrations may be a marker of progression of cognitive decline and may be associated with cognitive performance within cognitively intact cohorts.

Axonal damage is implicated in the neuropathology of depression and cognitive dysfunction. Consequently, neurofilament light protein is an emerging biomarker with potential in depression and cognitive function. Results are more consistent for cognition, requiring more research to assess neurofilament light protein in depression as well as other psychiatric disorders. Future longitudinal studies are necessary to determine whether neurofilament light protein can predict the onset and progression of depression and measure the effectiveness of potential psychiatric interventions and medications.
Repeat Subcutaneous Administration of REGEN-COV® in Adults is Well-Tolerated and Prevents the Occurrence of COVID-19
Authors: Isa Flonza , Forleo-Neto Eduardo , Meyer Jonathan , Zheng Wenjun , Rasmussen Scott , Armas Danielle , Oshita Masaru , Brinson Cynthia , Folkerth Steven , Faria Lori , Heirman Ingeborg , Sarkar Neena , Musser Bret J. , Bansal Shikha , O’Brien Meagan P. , Turner Kenneth C. , Ganguly Samit , Mahmood Adnan , Dupljak Ajla , Hooper Andrea T. , Hamilton Jennifer D. , Kim Yunji , Kowal Bari , Soo Yuhwen , Geba Gregory P. , Lipsich Leah , Braunstein Ned , Yancopoulos George D. , Weinreich David M. , Herman Gary A. ,   the COVID-19 Multi-dose Trial Team
Published: November 2021

Background

Data show that a single dose of casirivimab and imdevimab (REGEN-COV®) is effective in treating hospitalized individuals and outpatients with COVID-19 and in post-exposure prophylaxis. We present results from a phase 1, double-blind, placebo-controlled trial evaluating the safety, tolerability, and efficacy of repeat monthly doses of subcutaneous (SC) REGEN-COV in uninfected adult volunteers who were healthy or had chronic stable medical conditions.

Methods

Subjects were randomized (3:1) to SC REGEN-COV 1200 mg or placebo dosed every 4 weeks for up to 6 doses. The primary and secondary endpoints evaluated the safety, pharmacokinetics, and immunogenicity of multiple-dose administration of REGEN-COV. Efficacy was evaluated by the incidence of COVID-19 or SARS-CoV-2 seroconversion.

Results

In total, 969 subjects were treated. Repeat monthly dosing of SC REGEN-COV led to a 92.4% relative risk reduction in clinically-defined COVID-19 compared to placebo (3/729 [0.4%] vs 13/240 [5.4%]; odds ratio: 0.07 [95% CI, 0.01–0.27]), and a 100% reduction in laboratory-confirmed COVID-19 (0/729 vs 10/240 [4.2%]; odds ratio 0.00). Development of anti-drug antibodies was low (<5% subjects). No grade ≥3 injection-site reactions (ISRs) or hypersensitivity reactions were reported. A slightly higher percentage of subjects reported TEAEs with REGEN-COV (54.9%) than placebo (48.3%), due to ISRs (all grade 1-2). Serious adverse events were rare and occurred at similar percentages in the REGEN-COV and placebo groups. No deaths were reported in the 6-month treatment period.

Conclusions

Repeated monthly administration of 1200 mg SC REGEN-COV was well-tolerated with low immunogenicity, and showed a substantial risk reduction in COVID-19 occurrence.

(ClinicalTrials.gov identifier, NCT04519437)
First-in-clinical application of a time-gated diffuse correlation spectroscopy system at 1064nm using superconducting nanowire single photon detectors
Authors: Poon Chien-Sing , Langri Dharminder S. , Rinehart Benjamin , Rambo Timothy M. , Miller Aaron J. , Foreman Brandon , Sunar Ulas
Published: November 2021

Recently proposed time-gated DCS (TG-DCS) has significant advantages compared to conventional CW-DCS, but it is still in an early stage and clinical capability has yet to be established. The main challenge for TG-DCS is the lower SNR when gating for the deeper travelling late photons. Longer wavelengths, such as 1064nm have a smaller effective attenuation coefficient and a higher power threshold in humans, which significantly increases the SNR. Here, we demonstrate the clinical utility of TG-DCS at 1064nm in a case study on a patient with severe traumatic brain injury admitted to the neuroscience intensive care unit (NSICU). We showed a significant correlation between TG-DCS early (ρ = 0.67) and late (ρ = 0.76) gated against invasive thermal diffusion flowmetry. We also analyzed TG-DCS at high temporal resolution (50 Hz) to elucidate pulsatile flow data. Overall, this study demonstrates the first clinical translation capability of the TG-DCS system at 1064nm using superconducting nanowire single photon detector.
Structural and functional characterization of NEMO cleavage by SARS-CoV-2 3CLpro
Authors: Hameedi Mikhail Ali , Prates Erica T. , Garvin Michael R. , Mathews Irimpan , Kirtley Amos B , Demerdash Omar , Bechthold Mark , Iyer Mamta , Rahighi Simin , Kneller Daniel W. , Kovalevsky Andrey , Irle Stephan , Vuong Van-Quan , Mitchell Julie C. , Labbe Audrey , Galanie Stephanie , Wakatsuki Soichi , Jacobson Daniel
Published: November 2021

In addition to its essential role in viral polyprotein processing, the SARS-CoV-2 3C-like (3CLpro) protease can cleave human immune signaling proteins, like NF-κB Essential Modulator (NEMO) and deregulate the host immune response. Here, in vitro assays show that SARS-CoV-2 3CLpro cleaves NEMO with fine-tuned efficiency. Analysis of the 2.14 Å resolution crystal structure of 3CLpro C145S bound to NEMO226-235 reveals subsites that tolerate a range of viral and host substrates through main chain hydrogen bonds while also enforcing specificity using side chain hydrogen bonds and hydrophobic contacts. Machine learning- and physics-based computational methods predict that variation in key binding residues of 3CLpro- NEMO helps explain the high fitness of SARS-CoV-2 in humans. We posit that cleavage of NEMO is an important piece of information to be accounted for in the pathology of COVID-19.
Paratype: A genotyping framework and an open-source tool for Salmonella Paratyphi A
Authors: Tanmoy Arif M. , Hooda Yogesh , Sajib Mohammad S. I. , Silva Kesia E. da , Iqbal Junaid , Qamar Farah N. , Luby Stephen P. , Dougan Gordon , Dyson Zoe A. , Baker Stephen , Garrett Denise O. , Andrews Jason R. , Saha Samir K. , Saha Senjuti
Published: November 2021

Background

Salmonella enterica serovar Paratyphi A (Salmonella Paratyphi A) is the primary causative agent of paratyphoid fever, which is responsible for an estimated 3.4 million infections annually. However, little genomic information is available on population structure, antimicrobial resistance (AMR), and spatiotemporal distribution of the pathogen. With rising antimicrobial resistance and no licensed vaccines, genomic surveillance is important to track the evolution of this pathogen and monitor transmission.

Results

We performed whole-genome sequencing of 817 Salmonella Paratyphi A isolates collected from Bangladesh, Nepal, and Pakistan and added publicly available 562 genomes to build a global database representing 37 countries, covering 1917-2019. To track the evolution of Salmonella Paratyphi A, we used the existing lineage scheme, developed earlier based on a small dataset, but certain sub-lineages were not homologous, and many isolates could not be assigned a lineage. Therefore, we developed a single nucleotide polymorphism based genotyping scheme, Paratype, a tool that segregates Salmonella Paratyphi A into three primary and nine secondary clades, and 18 genotypes. Each genotype has been assigned a unique allele definition located on a conserved gene. Using Paratype, we identified genomic variation between different sampling locations and specific AMR markers, and mutations in the O2-polysaccharide synthesis locus, a candidate for vaccine development.

Conclusions

This large-scale global analysis proposes the first genotyping tool for Salmonella Paratyphi A. Paratype has already been released (https://github.com/CHRF-Genomics/Paratype) as an open-access, command-line tool and is being adopted for large scale genomic analysis. This tool will assist future genomic surveillance and help inform prevention and treatment strategies.
Curating, collecting, and cataloguing global COVID-19 datasets for the aim of predicting personalized risk
Authors: Khatami Sepehr Golriz , Russo Maria Francesca , Domingo-Fernández Daniel , Zaliani Andrea , Mubeen Sarah , Gadiya Yojana , Sargsyan Astghik , Karki Reagon , Gebel Stephan , Ruppa Surulinathan Ram Kumar , Lage-Rupprecht Vanessa , Archipovas Saulius , Mingrone Geltrude , Jacobs Marc , Claussen Carsten , Hofmann-Apitius Martin , Kodamullil Alpha Tom ,   the COPERIMOplus consortium
Published: November 2021

The COVID-19 data catalogue is a repository that provides a landscape view of COVID-19 studies and datasets as a putative source to enable researchers to develop personalized COVID-19 predictive risk models. The COVID-19 data catalogue currently contains over 400 studies and their relevant information collected from a wide range of global sources such as global initiatives, clinical trial repositories, publications and data repositories. Further, the curated content stored in this data catalogue is complemented by a web application, providing visualizations of these studies, including their references, relevant information such as measured variables, and the geographical locations of where these studies were performed. This resource is one of the first to capture, organize and store studies, datasets and metadata in the area of COVID-19 in a comprehensive repository. We are convinced that our work will facilitate future research and development of personalized predictive risk models of COVID-19.
Continued Effectiveness of COVID-19 Vaccination among Urban Healthcare Workers during Delta Variant Predominance
Authors: Lan Fan-Yun , Sidossis Amalia , Iliaki Eirini , Buley Jane , Nathan Neetha , Bruno-Murtha Lou Ann , Kales Stefanos N.
Published: November 2021

Background

Data on COVID-19 vaccine effectiveness (VE) among healthcare workers (HCWs) during periods of delta variant predominance are limited.

Methods

We followed a population of urban Massachusetts HCWs (45% non-White) subject to epidemiologic surveillance. We accounted for covariates such as demographics and community background infection incidence, as well as information bias regarding COVID-19 diagnosis and vaccination status.

Results and Discussion

During the study period (December 16, 2020 to September 30, 2021), 4615 HCWs contributed to a total of 1,152,486 person-days at risk (excluding 309 HCWs with prior infection) and had a COVID-19 incidence rate of 5.2/10,000 (114 infections out of 219,842 person-days) for unvaccinated person-days and 0.6/10,000 (49 infections out of 830,084 person-days) for fully vaccinated person-days, resulting in an adjusted VE of 82.3% (95% CI: 75.1–87.4%). For the secondary analysis limited to the period of delta variant predominance in Massachusetts (i.e., July 1 to September 30, 2021), we observed an adjusted VE of 76.5% (95% CI: 40.9–90.6%). Independently, we found no re-infection among those with prior COVID-19, contributing to 74,557 re-infection-free person-days, adding to the evidence base for the robustness of naturally acquired immunity.
Details of “conversion therapy” practices and concordance with legislative definition: Findings from a non-probability community-based survey in Canada, 2020
Authors: Salway Travis , Tiwana Amrit , Schillaci-Ventura Julia , Watt Sarah , Muse Erika , Ashley Florence
Published: November 2021

Background

“Conversion therapy” practices (CTP) refer to a heterogeneous set of treatments and activities that share the common goal of suppressing, “repairing,” or otherwise preventing expressions of transgender, lesbian, gay, bisexual, or queer identities. This study aimed to elicit details from those with direct experience and assess concordance between CTP experiences and the definition of CTP included in federal legislation aiming to deter CTP.

Methods

We conducted an anonymous online survey of adults (>18 years) in Canada between August 18 and December 2, 2020. Participants were recruited through social media, CTP survivor networks, and word-of-mouth.

Results

Of 51 respondents with direct experience of CTP, 16 were transgender, 34 were cisgender. Most respondents lived in Alberta, British Columbia, Ontario, or Quebec. 49% experienced CTP in a licensed healthcare provider office, 45% at a faith-based organization, and 36% at an unlicensed counselor office (categories not mutually exclusive). Age at first CTP experience ranged from 2 to 44 years of age (mean: 17.8 years; median: 17 years). Respondents experienced CTP for <1 year to 33 years (mean: 4.6 years; median: 2 years). Fifty percent of those with direct experience of CTP indicated that the proposed legislative definition of CTP did not fully encompass their personal experience.

Interpretation

Results from this Canadian survey of adults with experience of CTP indicate that legislative attempts to ban CTP must be expanded (e.g., to include adults and practices that do not concord with previously drafted definitions) and paired with other prevention efforts.
Schema support for forming inferences in the human brain
Authors: Paulus J.P. , Vignali C. , Coutanche M.N.
Published: November 2021

Associative inference, the process of drawing novel links between existing knowledge to rapidly integrate associated information, is supported by the hippocampus and neocortex. Within the neocortex, the medial prefrontal cortex (mPFC) has been implicated in the rapid cortical learning of new information that is congruent with an existing framework of knowledge, or schema. How the brain integrates associations to form inferences, specifically how inferences are represented, is not well understood. In this study, we investigate how the brain uses schemas to facilitate memory integration in an associative inference paradigm (A-B-C-D). We conducted two event-related fMRI experiments in which participants retrieved previously learned direct (AB, BC, CD) and inferred (AC, AD) associations between word pairs for items that are schema congruent or incongruent. Additionally, we investigated how two factors known to affect memory, a delay with sleep, and reward, modulate the neural integration of associations within, and between, schema. Schema congruency was found to benefit the integration of associates, but only when retrieval immediately follows learning. RSA revealed that neural patterns of inferred pairs (AC) in the PHc, mPFC, and posHPC were more similar to their constituents (AB and BC) when the items were schema congruent, suggesting that schema facilitates the assimilation of paired items into a single inferred unit containing all associated elements. Furthermore, a delay with sleep, but not reward, impacted the assimilation of inferred pairs. Our findings reveal that the neural representations of overlapping associations are integrated into novel representations through the support of memory schema.

Significance Statement

Our ability to draw novel links between pieces of existing knowledge allows us to understand how information in memory is related. Existing knowledge (memory ‘schema’) can facilitate learning, and then integration, of new related information. We ask how the human brain uses schema to form links between related pieces of information, and how sleep and reward affect this process. Our results suggest that memory schema helps pieces of knowledge become a single inferred unit in the brain’s memory systems. A delay with sleep between learning and retrieval, though not reward, is important for how schema achieve this.
Mutagenic distinction between the receptor-binding and fusion subunits of the SARS-CoV-2 spike glycoprotein and its upshot
Authors: Penner Robert
Published: November 2021

We observe that a residue R of the spike glycoprotein of SARS-CoV-2 which has mutated in one or more of the current Variants of Concern or Interest or under Monitoring rarely participates in a backbone hydrogen bond if R lies in the S1 subunit and usually participates in one if R lies in the S2 subunit. A partial explanation for this based upon free energy is explored as a potentially general principle in the mutagenesis of viral glycoproteins. This observation could help target future vaccine cargos for the evolving coronavirus as well as more generally. A study of the Delta and Omicron variants suggests that Delta was an energetically necessary intermediary in the evolution from Wuhan-Hu-1 to Omicron.
Lytic phages displayed protective effects against soft rot-causing Pectobacterium sp.
Authors: Parena Aeron Jade S. , Silva Benji Brayan I. , Mercado Rae Mark L. , Sendon Adelbert Adrian A. , Signabon Freddiewebb B. , Balidion Johnny F. , Encabo Jaymee R.
Published: November 2021

Soft rot caused by Pectobacterium sp. is responsible for significant losses in vegetable production worldwide. Methods for the effective control of soft rot are limited and are primarily based on good agricultural practices. The use of bacteriophages as biocontrol agents appears to be a promising alternative to combat phytopathogens. In this study, we investigated the efficacy of lytic phages recovered from symptomatic tissues and environmental samples against soft rot caused by Pectobacterium carotovorum subsp. carotovorum. Three bacteriophage isolates, designated as vB_PcaP-A3, vB_PcaM-D1, and vB_PcaM-J3, were observed to effectively lyse P. carotovorum subsp. carotovorum. Phage vB_PcaP-A3 exhibited virion morphology similar to the members of the podovirus group, while phages vB_PcaM-D1 and vB_PcaM-J3 showed myovirus morphology based on transmission electron microscopy. The optimal multiplicity of infection (MOI) differed greatly among the three phages. All three phages survived incubations at 30°C, 40°C and 50°C and pH conditions ranging from 3.0 to 9.0, but were all inactivated at 60°C and at pH 12. Both monophage and cocktail preparations were effective in inhibiting the growth of P. carotovorum subsp. carotovorum in the in vitro challenge tests. In the semi-in planta assays, while treatment with cocktail preparations completely inhibited the development of soft rot in tissue slices, monophage treatments not only resulted in significant reduction of tissue maceration in slices, but also showed protective effect against soft rot in tubers. Overall, these results demonstrate the efficacy of phages vB_PcaP-A3, vB_PcaM-D1, and vB_PcaM-J3 for the biocontrol of soft rot caused by P. carotovorum subsp. carotovorum.
PPAR-delta acts as a metabolic master checkpoint for metastasis in pancreatic cancer
Authors: Parejo-Alonso Beatriz , Barneda David , Trabulo Sara , Courtois Sarah , Compte-Sancerni Sara , Ruiz-Cañas Laura , Zheng Quan , Tang Jiajia , Chen Minchun , Guo Zhenyang , Schmitz Ulf , Irún Pilar , Penin-Peyta Laure , Crusz Shanthini M. , Cano-Galiano Andres , Lopez-Escalona Sergio , Jagust Petra , Espiau-Romera Pilar , Yuneva Mariia , Lin Meng-Lay , Lanas Angel , Sainz Bruno , Heeschen Christopher , Sancho Patricia
Published: November 2021

Summary

In pancreatic cancer, emerging evidence suggests that PPAR-δ overexpression is associated with tumor progression and metastasis, but a mechanistic link is still missing. Here we now show that PPAR-δ acts as the integrating upstream regulator for the metabolic rewiring, which is preceding the subsequent initiation of an invasive/metastatic program. Specifically, paracrine and metabolic cues regularly found in the metastasis-promoting tumor stroma consistently enhance, via induction of PPAR-δ activity, the glycolytic capacity and reserve of pancreatic cancer cells, respectively, accompanied by decreased mitochondrial oxygen consumption. Consequently, genetic or pharmacological inhibition of PPAR-δ results in reduced invasiveness and metastasis. Mechanistically, PPAR-δ acts by shifting the MYC/PGC1A balance towards MYC, enhancing metabolic plasticity. Targeting MYC similarly prevents the metabolic switch and subsequent initiation of invasiveness. Therefore, our data demonstrate that PPAR-δ is a key initiator for the metabolic reprogramming in pancreatic cancer, thereby acting as a checkpoint for the phenotypic change towards invasiveness. These findings provide compelling evidence for a novel treatment strategy to combat pancreatic cancer progression.
Telomerase and Alternative Lengthening of Telomeres coexist in the regenerating zebrafish caudal fins
Authors: Martínez-Balsalobre Elena , Anchelin-Flageul Monique , Alcaraz-Pérez Francisca , García-Castillo Jesús , Hernández-Silva David , Mione Maria C , Mulero Victoriano , Cayuela María L.
Published: November 2021

Telomeres are essential for chromosome protection and genomic stability, and telomerase function is critical to organ homeostasis. Zebrafish has become a useful vertebrate model for understanding the cellular and molecular mechanisms of regeneration. The regeneration capacity of the caudal fin of wild-type zebrafish is not affected by repetitive amputation, but the behavior of telomeres during this process has not yet been studied. In this study, the regeneration process was characterized in a telomerase deficient zebrafish model. Moreover, the regenerative capacity after repetitive amputations and at different ages was studied. Regenerative efficiency decreases with aging in all genotypes and surprisingly, telomere length is maintained even in telomerase deficient genotypes. Our results suggest that telomere length can be maintained by the regenerating cells through the recombination-mediated Alternative Lengthening of Telomeres (ALT) pathway, which is likely to support high rates of cell proliferation during the tailfin regeneration process. As far as we know, this is the first animal model to study ALT mechanism in regeneration, which opens a wealth of possibilities to study new treatments of ALT dependent processes.
Nascent adhesions differentially regulate lamellipodium velocity and persistence
Authors: Carney Keith R. , Khan Akib M. , Samson Shiela C. , Mittal Nikhil , Han Sangyoon J. , Mendoza Michelle C. , Bidone Tamara C.
Published: November 2021

Cell migration is essential to physiological and pathological biology. Migration is driven by the motion of a leading edge, in which actin polymerization pushes against the edge and adhesions transmit traction to the substrate while membrane tension increases. How the actin and adhesions synergistically control edge protrusion remains elusive. We addressed this question by developing a computational model in which the Brownian ratchet mechanism governs actin filament polymerization against the membrane and the molecular clutch mechanism governs adhesion to the substrate (BR-MC model). Our model predicted that actin polymerization is the most significant driver of protrusion, as actin had a greater effect on protrusion than adhesion assembly. Increasing the lifetime of nascent adhesions also enhanced velocity, but decreased the protrusion’s motional persistence, because filaments maintained against the cell edge ceased polymerizing as membrane tension increased. We confirmed the model predictions with measurement of adhesion lifetime and edge motion in migrating cells. Adhesions with longer lifetime were associated with faster protrusion velocity and shorter persistence. Experimentally increasing adhesion lifetime increased velocity but decreased persistence. We propose a mechanism for actin polymerization-driven, adhesion-dependent protrusion in which balanced nascent adhesion assembly and lifetime generates protrusions with the power and persistence to drive migration.
Live imaging of the co-translational recruitment of XBP1 mRNA to the ER and its processing by diffuse, non-polarized IRE1α
Authors: Gómez-Puerta Silvia , Ferrero Roberto , Hochstoeger Tobias , Zubiri Ivan , Chao Jeffrey A. , Aragón Tomás , Voigt Franka
Published: November 2021

Endoplasmic reticulum (ER) to nucleus homeostatic signalling, known as the unfolded protein response (UPR), relies on the non-canonical splicing of XBP1 mRNA. The molecular switch that initiates splicing is the oligomerization of the ER stress sensor and UPR endonuclease IRE1α. While IRE1α can form large clusters that have been proposed to function as XBP1 processing centers on the ER, the actual oligomeric state of active IRE1α complexes as well as the targeting mechanism that recruits XBP1 to IRE1α oligomers, remain unknown.

Here, we used a single molecule imaging approach to directly monitor the recruitment of individual XBP1 transcripts to the ER surface. We confirmed that stable ER association of unspliced XBP1 mRNA is established through HR2-dependent targeting and relies on active translation. In addition, we show that IRE1α-catalyzed splicing mobilizes XBP1 mRNA from the ER membrane in response to ER stress. Surprisingly, we find that XBP1 transcripts are not recruited into large IRE1α clusters, which only assemble upon overexpression of fluorescently-tagged IRE1α during ER stress. Our findings support a model where ribosome-engaged, ER-poised XBP1 mRNA is processed by functional IRE1α assemblies that are homogenously distributed throughout the ER membrane.
Generating weighted and thresholded gene coexpression networks using signed distance correlation
Authors: Pardo-Diaz Javier , Poole Philip S. , Beguerisse-Díaz Mariano , Deane Charlotte M. , Reinert Gesine
Published: November 2021

Even within well-studied organisms, many genes lack useful functional annotations. One way to generate such functional information is to infer biological relationships between genes or proteins, using a network of gene coexpression data that includes functional annotations. Signed distance correlation has proved useful for the construction of unweighted gene coexpression networks. However, transforming correlation values into unweighted networks may lead to a loss of important biological information related to the intensity of the correlation. Here introduce a principled method to constructweightedgene coexpression networks using signed distance correlation. These networks contain weighted edges only between those pairs of genes whose correlation value is higher than a given threshold. We analyse data from different organisms and find that networks generated with our method based on signed distance correlation are more stable and capture more biological information compared to networks obtained from Pearson correlation. Moreover, we show that signed distance correlation networks capture more biological information than unweighted networks based on the same metric. While we use biological data sets to illustrate the method, the approach is general and can be used to construct networks in other domains.

Data and code availability

https://github.com/javier-pardodiaz/sdcorGCN
Nieman-Pick Type C2 proteins in Aedes aegypti: Their Structure-Function relationships and Expression in Uninfected versus Virus-infected Mosquitos
Authors: Thambi Prathigna Jaishankar , Modahl Cassandra M. , Kini R. Manjunatha
Published: November 2021

Aedes aegypti is a major vector that transmits arboviruses through the saliva injected into the host. Salivary proteins help in uninterrupted blood intake and enhance the transmission of pathogens. We studied Nieman-Pick Type C2 (NPC2) proteins, a superfamily of saliva proteins that play important role in arbovirus infections. In vertebrates, a single conserved gene encodes for the NPC2 protein that functions in cholesterol trafficking. Arthropods, in contrast, have several genes that encode for divergent NPC2 proteins. We compared the sequences of 20 A. aegypti NPC2 proteins to the cholesterol-binding residues of human and bovine, and fatty acid-binding residues of ant NPC2 proteins. We identified four and one mosquito NPC2 proteins as potential sterol- and fatty acid-binding proteins, respectively. From the published data, we analysed the expression of NPC2 genes in various tissues and their differential expression in midgut and salivary gland post-arbovirus infections. NPC2 genes are downregulated rather than upregulated in virus-infected tissues. Interestingly, AAEL012064 is the only gene that is downregulated in both the midgut and salivary gland in all virus infections. In addition, AAEL001650 is downregulated in the salivary gland infected with CHIKV, DENV2 or ZIKV. This gene in the midgut is downregulated infected with DENV1 but upregulated with DENV2. We studied the variation in cis elements in the promoter regions of two groups of closely related NPC2 genes and the expression of relevant transcription factors (TFs). In the midgut infected with DENV1 or DENV2, six TFs (CRE-BP1, AP1, c-Jun, c-Fos, Odd, and NF-kB) appear to play an opposing role in the expression of AAEL006854. Two TFs (RXR-beta/alpha and USF) have a potential role in the downregulation of AAEL009556 in CHIKV-infected midgut and salivary gland. Similarly, two TFs (COUP and Ftz) may have a key role in the downregulation of AAEL009555 and AAEL009556 in DENV2-infected salivary gland.
Detection of insect health with deep learning on near-infrared sensor data
Authors: Bick Emily , Edwards Sam , De Fine Licht Henrik H.
Published: November 2021

Conventional monitoring methods for disease vectors, pollinators or agricultural pests require time-consuming trapping and identification of individual insects. Automated optical sensors that detect backscattered near-infrared modulations created by flying insects are increasingly used to identify and count live insects, but do not inform about the health status of individual insects. Here we show that deep learning in trained convolutional neural networks in conjunction with sensors is a promising emerging method to detect infected insects. Health status was correctly determined in 85.6% of cases as early as two days post infection with a fungal pathogen. The ability to monitor insect health in real-time potentially has wide-reaching implications for preserving pollinator biodiversity and the rapid assessment of disease carrying individuals in vector populations.

One sentence summary

Automated optical sensors distinguish between fungus-infected and healthy insects.
Learning a new class of multisensory associations: High-density electrophysiological mapping of the temporal course of audio-visual object processing
Authors: Vercillo Tiziana , Freedman Edward G. , Ewen Joshua B. , Molholm Sophie , Foxe John J.
Published: November 2021

Multisensory objects that are frequently encountered in the natural environment lead to strong associations across a distributed sensory cortical network, with the end result experience of a unitary percept. Remarkably little is known, however, about the cortical processes sub-serving multisensory object formation and recognition. To advance our understanding in this important domain, the present study investigated the brain processes involved in learning and identification of novel visual-auditory objects. Specifically, we introduce and test a rudimentary three-stage model of multisensory object-formation and processing. Thirty adults were remotely trained for a week to recognize a novel class of multisensory objects (3D shapes paired to complex sounds), and high-density event related potentials (ERPs) were recorded to the corresponding unisensory (shapes or sounds only) and multisensory (shapes and sounds) stimuli, before and after intensive training. We identified three major stages of multisensory processing: 1) an early, multisensory, automatic effect (<100 ms) in occipital areas, related to the detection of simultaneous audiovisual signals and not related to multisensory learning 2) an intermediate object-processing stage (100-200 ms) in occipital and parietal areas, sensitive to the learned multisensory associations and 3) a late multisensory processing stage (>250 ms) that appears to be involved in both object recognition and possibly memory consolidation. Results from this study provide support for multiple stages of multisensory object learning and recognition that are subserved by an extended network of cortical areas.
Spatially regulated protease activity in lymph nodes renders B cell follicles a sanctuary for retention of intact antigens
Authors: Aung Aereas , Cui Ang , Soleimany Ava P. , Bukenya Maurice , Lee Heya , Cottrell Christopher A. , Silva Murillo , Kirkpatrick Jesse D. , Gregory Justin R. , Amlashi Parastoo , Remba Tanaka , Froehle Leah M. , Xiao Shuhao , Abraham Wuhbet , Adams Josetta , Suh Heikyung , Huyett Phillip , Kwon Douglas S. , Hacohen Nir , Schief William R. , Bhatia Sangeeta N. , Irvine Darrell J.
Published: November 2021

The structural integrity of vaccine antigens is critical, as antigen degradation in vivo could eliminate neutralizing epitopes and create competing B cell responses against irrelevant breakdown products. Using FRET imaging and imaging zymography, we found that protease activity and antigen breakdown are spatially heterogeneous in lymph nodes. Following protein immunization, antigens are rapidly degraded in the subcapsular sinus, paracortex, and interfollicular regions of the tissue. By contrast, the follicles and follicular dendritic cell (FDC) networks exhibit low protease activity and antigen degradation rates. Immunization regimens targeting antigen rapidly to FDCs led to germinal centers (GCs) where responses to intact antigen were highly dominant, while traditional bolus immunizations led to weaker GC responses where more GC B cells bound to breakdown products than intact antigen. Thus, spatially-compartmentalized antigen proteolysis impacts humoral immunity and can be exploited to enhance vaccine-induced production of antibody responses against key pathogen structural epitopes.
Built on sand: the shaky foundations of simulating single-cell RNA sequencing data
Authors: Crowell Helena L. , Morillo Leonardo Sarah X. , Soneson Charlotte , Robinson Mark D.
Published: November 2021

With the emergence of hundreds of single-cell RNA-sequencing (scRNA-seq) datasets, the number of computational tools to analyse aspects of the generated data has grown rapidly. As a result, there is a recurring need to demonstrate whether newly developed methods are truly performant – on their own as well as in comparison to existing tools. Benchmark studies aim to consolidate the space of available methods for a given task, and often use simulated data that provide a ground truth for evaluations. Thus, demanding a high quality standard for synthetically generated data is critical to make simulation study results credible and transferable to real data.

Here, we evaluated methods for synthetic scRNA-seq data generation in their ability to mimic experimental data. Besides comparing gene- and cell-level quality control summaries in both one- and two-dimensional settings, we further quantified these at the batch- and cluster-level. Secondly, we investigate the effect of simulators on clustering and batch correction method comparisons, and, thirdly, which and to what extent quality control summaries can capture reference-simulation similarity.

Our results suggest that most simulators are unable to accommodate complex designs without introducing artificial effects; they yield over-optimistic performance of integration, and potentially unreliable ranking of clustering methods; and, it is generally unknown which summaries are important to ensure effective simulation-based method comparisons.
Cryo-EM of the yeast VOcomplex reveals distinct binding sites for macrolide V-ATPase inhibitors
Authors: Keon Kristine A. , Benlekbir Samir , Kirsch Susanne H. , Müller Rolf , Rubinstein John L.
Published: November 2021

Vacuolar-type adenosine triphosphatases (V-ATPases) are proton pumps found in almost all eukaryotic cells. These enzymes consist of a soluble catalytic V1region that hydrolyzes ATP and a membrane-embedded VOregion responsible for proton translocation. V-ATPase activity leads to acidification of endosomes, phagosomes, lysosomes, secretory vesicles, and the trans-Golgi network, with extracellular acidification occurring in some specialized cells. Small molecule inhibitors of V-ATPase have played a crucial role in elucidating numerous aspects of cell biology by blocking acidification of intracellular compartments, while therapeutic use of V-ATPase inhibitors has been proposed for treatment of cancer, osteoporosis, and some infections. Here, we determine structures of the isolated VOcomplex fromSaccharomyces cerevisiaebound to two well-known macrolide inhibitors: bafilomycin A1 and archazolid A. The structures reveal different binding sites for the inhibitors on the surface of the proton-carrying c ring, with only a small amount of overlap between the two sites. Binding of both inhibitors is mediated primarily through van der Waals interactions in shallow pockets and suggests that the inhibitors block rotation of the ring. Together, these structures indicate the existence of a large chemical space available for V-ATPase inhibitors that block acidification by binding the c ring.