bluuebunny/crossref_metadata_2025 huggingface dataset:
A KARRIKIN INSENSITIVE2 paralog in lettuce mediates highly sensitive germination responses to karrikinolide
Authors: Martinez Stephanie E , Conn Caitlin E , Guercio Angelica M , Sepulveda Claudia , Fiscus Christopher J , Koenig Daniel , Shabek Nitzan , Nelson David C
Published: July 2022

Karrikins (KARs) are chemicals in smoke that can enhance germination of many plants. Lettuce (Lactuca sativa) cv. Grand Rapids germinates in response to nanomolar karrikinolide (KAR1). Lettuce is much less responsive to KAR2 or a mixture of synthetic strigolactone analogs, rac-GR24. We investigated the molecular basis of selective and sensitive KAR1 perception in lettuce. The lettuce genome contains two copies of KARRIKIN INSENSITIVE2 (KAI2), which in Arabidopsis (Arabidopsis thaliana) encodes a receptor that is required for KAR responses. LsKAI2b is more highly expressed than LsKAI2a in dry achenes and during early stages of imbibition. Through cross-species complementation assays in Arabidopsis, we found that an LsKAI2b transgene confers robust responses to KAR1, but LsKAI2a does not. Therefore, LsKAI2b likely mediates KAR1 responses in lettuce. We compared homology models of KAI2 proteins from lettuce and a fire-follower, whispering bells (Emmenanthe penduliflora). This identified pocket residues 96, 124, 139, and 161 as candidates that influence the ligand specificity of KAI2. Further support for the importance of these residues was found through a broader comparison of pocket residues among 281 KAI2 proteins from 184 asterid species. Almost all KAI2 proteins had either Tyr or Phe identity at position 124. Genes encoding Y124-type KAI2 are more broadly distributed in asterids than in F124-type KAI2. Substitutions at residues 96, 124, 139, and 161 in Arabidopsis KAI2 produced a broad array of responses to KAR1, KAR2, and rac-GR24. This suggests that the diverse ligand preferences observed among KAI2 proteins in plants could have evolved through relatively few mutations.
Was John Donne a Catholic?: Conversion, Conformity, and Early Modern English Confessional Identities
Authors: Morrissey Mary
Published: July 2022

John Donne is usually treated as a convert from Roman Catholicism, and he is often said to have been brought up as a recusant Catholic. This article challenges these assumptions about Donne’s background, showing them to rely too heavily on the surviving records of his mother’s family. By considering the surviving evidence on other members of Donne’s family (his father and stepfather in particular), and by comparing Donne’s choices with those of other young men from similar families, we can understand Donne’s religious identity as one shaped by conformity rather than conversion. This does not mean that Donne ‘merely’ conformed without conscientiously choosing the teaching (and the teaching authority) of the Church of England over that of the Roman Catholic Church. It is to argue that, when an adult Donne described himself as someone who had been a member of the Church of England since his baptism, he cannot therefore be said to have converted to Protestantism. Donne decided on his religious allegiance when he was of an age to make that choice, and his decision is not recorded by anyone other than himself because it was unremarkable and legal.
Belief Convergence under Misspecified Learning: A Martingale Approach
Authors: Frick Mira , Iijima Ryota , Ishii Yuhta
Published: July 2022

We present an approach to analyse learning outcomes in a broad class of misspecified environments, spanning both single-agent and social learning. We introduce a novel “prediction accuracy” order over subjective models and observe that this makes it possible to partially restore standard martingale convergence arguments that apply under correctly specified learning. Based on this, we derive general conditions to determine when beliefs in a given environment converge to some long-run belief either locally or globally (i.e. from some or all initial beliefs). We show that these conditions can be applied, first, to unify and generalize various convergence results in previously studied settings. Second, they enable us to analyse environments where learning is “slow”, such as costly information acquisition and sequential social learning. In such environments, we illustrate that even if agents learn the truth when they are correctly specified, vanishingly small amounts of misspecification can generate extreme failures of learning.
A NATIONAL SURVEY OF TRACEABILITY OF ACTIVITY METERS IN LITHUANIAN HOSPITALS
Authors: Skovorodko Kirill , Gudelis Arūnas
Published: July 2022

The activity of prescribed radiopharmaceuticals, which are administered for diagnostic and therapeutic purposes, strongly depends on the accuracy of the measuring equipment used in nuclear medicine. This study presents the current status of uncertainty measurements of activity meters used in Lithuanian hospitals. During 2016–2021, the Ionizing Radiation Metrology Laboratory of the Center for Physical Sciences and Technology, which is the National Metrology Institute, performed a comparison of activity meters in the nuclear medicine departments of Lithuanian hospitals. Responses of 16 activity meters that were used in the daily hospital practice were compared with the reference standard. In total, around 150 measurements of activity of diagnostic, therapeutic and calibration radionuclides in different sources and geometries were fulfilled. The results of the maximum deviation were determined to be 8.9% for calibration sources, 18.3% for diagnostic radionuclides and 20.1% for radionuclides used for therapeutic purposes.
Concluding Reflections from the former UNHRC Special Rapporteur on Violence Against Women, its Causes and Consequences (2009–15)
Authors: Manjoo Rashida
Published: July 2022

This concluding chapter provides an overview of the chapters, as well as briefly highlighting the relevant normative frameworks applicable to the issues addressed in this special edition journal. The authors have addressed structural, institutional, and individual gaps and challenges in the refugee protection sphere and have raised concerns about the lack of adequate acknowledgement of gendered aspects of the asylum frameworks and processes, and crucially the differential impact thereof. The gaps in the legally binding instruments governing this area of human rights protection, and the minimal attention to the connection between theory and practice and its resulting consequences, are highlighted by some authors.
The effects of varying levels of trace mineral supplementation on performance, carcass characteristics, mineral balance, and antibody concentrations in feedlot cattle
Authors: Lippy Brittany A , Robison Colton A , Wilson Blake K
Published: July 2022

The objective of this experiment was to determine the effects of increasing trace mineral (TM) supplementation on finishing cattle performance, carcass characteristics, TM balance, and antibody concentrations. Commercial Angus steers (n = 240; body weight, BW = 291 kg ± 27.4) were stratified by arrival BW and source and randomly assigned to 1 of 4 experimental treatments in a randomized complete block design (12 pens/treatment; 5 steers/pen). All steers underwent a TM depletion period for a minimum of 42-d prior to the administration experimental treatments. Treatments included a negative control (CON) in which cattle received no additional TM supplementation or TM supplementation treatments in which cattle received added Co, Cu, I, Mn, Se, or Zn from inorganic TM sources at 2016 Nutrient Requirements of Beef Cattle (NASEM) requirement levels (1X), at 2 times NASEM requirements (2X), or at 4 times NASEM requirements (4X). Selenium was included at 0.1, 0.2, and 0.3 mg/kg for 1X, 2X, and 4X respectively, based on federal law. There was no difference in overall BW, average daily gain (ADG), dry matter intake (DMI), or gain to feed (G:F) due to TM supplementation (CON vs. SUPP P ≥ 0.47). There was no difference in hot carcass weight, rib eye area, fat thickness, dressing percentage, marbling score, or USDA Yield Grade due to TM supplementation (CON vs. SUPP P ≥ 0.30). One steer was chosen at random from each pen to be evaluated for serum and liver TM status and antibody concentrations to common respiratory viruses. There was a treatment × day interaction for serum Co and liver Cu and Se (P < 0.0001). Serum Co was greatest for the 4X treatment from d 28 through harvest. Liver Cu was greatest for the 2X and 4X treatments from d 56 through harvest. Liver Se was greatest for 2X and 4X from d 28 through harvest. Serum Zn was greatest for the 4X treatment (P = 0.02). There was an effect of day on liver Co, Fe, Mn, Mo, and Zn (P ≤ 0.0001) and serum Cu, Mn, Mo, Se, and Zn (P ≤ 0.002). Individual TM concentrations differed over time; however, none were ever considered deficient or toxic based on published reference ranges. There was an effect of time on bovine viral diarrhea virus Type 1A, bovine herpesvirus type 1, and bovine parainfluenza 3 virus antibody concentrations (P ≤ 0.0001). Supplementation of TM above NASEM requirements did not affect overall cattle performance, carcass characteristics, or antibody concentrations, but did affect the storage and circulation of certain TM.
Phenotypic Pattern of Early Versus Later-Onset Pediatric Inflammatory Bowel Disease in a Eurasian Country
Authors: S. Akkelle Bilge , Ertem Deniz , Volkan Burcu , Tutar Engin
Published: July 2022

Objectives:

It is not clear whether the characteristics of pediatric inflammatory bowel disease (IBD) differ between Eastern and Western countries. The aim of this study was to analyze the characteristics of PIBD in Turkey, according to the age at diagnosis.

Methods:

The data of 176 children with IBD who were followed in our center were analyzed. Patients were divided into early (EO-IBD, onset at 2 to <10 years) and later-onset (LO-IBD, 10 to ≤17 years) IBD according to the age at diagnosis. Patients’ data with ulcerative colitis (UC) and Crohn’s disease (CD) were compared.

Results:

Of 176 patients, 47 (26.7%) were diagnosed with EO-IBD. Patients with early-onset ulcerative colitis (EO-UC) had the highest rate of family history of IBD (17.6%). Pancolitis was the most common form of UC regardless of the age at onset. The rate of moderate-severe disease activity in later-onset UC (62.5%) was higher than in EO-UC (37.5%). A higher rate of extraintestinal manifestations was observed in EO-IBD patients, particularly in EO-UC (38.2%) than in LO-IBD patients. Patients with early-onset CD (EO-CD) had predominantly colonic involvement and nonstricturing, nonpenetrating disease behavior. The rate of perianal disease in patients with later-onset CD (LO-CD) (64.5%) was noticeably higher than those with EO-CD (23%).

Conclusions:

Our results suggest that patients with EO-UC represented a distinct phenotype with a mild disease activity, high rate of extraintestinal symptoms, and a high proportion of family history. The analysis of our IBD cohort also demonstrated remarkably high rate of perianal disease, particularly in patients with LO-CD.
Comorbidities of Child Malnutrition in Low- and Medium-Income Countries: A Systematic Review
Authors: Moate Tshepiso , Rabie Tinda , Minnie Catharina , Mäenpää Anne
Published: July 2022

The study intended to review the best evidence on prevalence, diagnosis, and treatment outcomes of comorbidities associated with child malnutrition. The study design was a systematic review of quantitative studies. Critical appraisal tools were used to assess the methodological quality of the studies. Data were extracted according to the predetermined data extraction table. Data were further analyzed narratively according to the set study objectives and main concepts. Fifteen studies were eligible to include in the review. All 15 studies reported on the prevalence of 4 child malnutrition-associated comorbidities. Five (n = 5/15) studies reported on length of hospitalization/stay, 10 (n = 10) studies on recovery rate, and 9 (n = 9/15) studies on mortality rate as treatment outcomes of child malnutrition associated comorbidities. The most prevalent child malnutrition associated comorbidities were tuberculosis, pneumonia, gastroenteritis, and anemia. The treatment outcomes identified included the length of hospitalization/stay, recovery rate, and mortality rate. Screening of prevalent comorbidities in children admitted with malnutrition should be standard procedure in practice. More research needs to be done on the diagnosis of under-5 child malnutrition associated comorbidities.
Exercise in the Aquatic Environment for People With Primary Hip Osteoarthritis: A Systematic Review and Meta-analyses
Authors: Geigle Paula Richley , Van Wingerden Anita , Biondi Marti , Gangaway Janet , Modica Stephen , Morris David , Salem Yasser , Thein Brody Lori
Published: July 2022

Background and Purpose:

More than 31 million Americans experience activity limitations related to hip osteoarthritis (OA), and aquatic exercise is one management option. To guide aquatic-based exercise practice, the available evidence-based data (quantity and quality) of aquatic environment exercise for people with primary hip OA was evaluated.

Methods:

A systematic search was conducted from 2004 to 2020 using 8 databases: PubMed, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), the Cochrane Central Register of Controlled Trials (CENTRAL), the Cochrane Library, EMBASE, Allied and Complementary Medicine Database (AMED), Science Citation Index Expanded, ISI Proceedings (Web of Science), and REHABDATA. The extracted data included information related to authors, study design, participant characteristics (demographics, time since diagnosis, comorbidity), intervention details (setting, type, water temperature and depth, and dosage parameters such as frequency, intensity, duration and length), outcome measures, and adverse events.

Results:

There were 196 studies identified, with 136 studies screened at the abstract level with 48 resultant studies, reviewed at the full-text level with 9 resultant publications included in this quantitative analyses (7 randomized controlled trials [RCTs] and 2 non-RCTs). Individuals with hip OA who participated in prescribed aquatic exercise experienced improved overall lower extremity function including range of motion, strength, balance, gait, function performance (p = .00; standardized mean difference [SMD] = 0.30; SE = 0.07; I
2 = 0), and pain (p = .00; SMD = 0.34; SE = 0.12; I
2 = 45) but no change in quality of life (p = .07; SMD = 0.15; SE = 0.08; I
2 = 0).

Discussion and Conclusion:

For individuals with primary hip OA, prescribed exercise in an aquatic environment improved lower extremity function, balance, and pain outcomes. To improve consistent, evidence-driven aquatic intervention for individuals experiencing limitations secondary to hip OA, these researchers recommend that schedule individual or staff time to review these systematic review results, establish a user-friendly dosage rubric including these minimum intensity and aquatic environment parameters, and discuss the evidence-driven suggested outcomes and include other specific standardized outcomes for their facility, as well as a means to efficiently document these outcomes.
Intensity of Aquatic Physical Activity Is Best When Tailored to the Participants' Mental and Physical Capabilities: An Exploratory Study
Authors: Barrios Nathalie , Sames Carol , Allen Amy , Vieira Edgar R. , Boolani Ali
Published: July 2022

Background:

Aquatic exercise has been shown to modify feelings of energy and fatigue in patients with chronic diseases. However, we are unaware of studies that have explored individual characteristics such as personality traits, sleep quality, and physical functioning that can determine whether or not a patient's mood improves with aquatic exercise. The purpose of this study was to identify individual characteristics associated with participants who reported a decline in feelings of energy or an increase in feelings of fatigue after a group aquatic exercise session.

Methods:

Participants were recruited from a community group aquatic program and asked to complete a series of surveys to assess their health status, sleep quality, and predisposition to feelings of energy and fatigue (trait energy and fatigue). Participants also completed a series of objective functional assessments. Current feelings of mental and physical energy and fatigue were measured on random days over multiple occasions before and after aquatic exercise. Participants were split into groups based on whether they reported an increase or decrease in feelings of energy and fatigue.

Results:

Participants (n = 11) completed a minimum of 2 sessions where mood was measured, and all 11 reported an increase in feelings of physical energy compared with the start of each session. All but one participant reported an improvement in feelings of mental energy. Interestingly, 4 participants reported an increase in feelings of physical fatigue, while 5 reported an increase in feelings of mental fatigue after exercise. All participants who reported an increase in feelings of physical fatigue also reported an increase in feelings of mental fatigue. When comparing the 2 groups, those who reported an increase in feelings of fatigue after exercise also reported low social functioning when compared with those who reported a decrease in feelings of fatigue.

Discussion:

Positive mood responses to exercise are associated with continued participation; therefore, this study provides insight into identifying individuals who consistently feel fatigued and may be less likely to complete an aquatic exercise program. These results suggest that either the modality or intensity of exercise may need to be changed for people with low social functioning as they may experience increased feelings of fatigue after a session of aquatic exercise. Future research with larger sample sizes is needed.
Compression for Lower Extremity Venous Disease and Lymphedema (CLEVDAL)
Authors: Ratliff Catherine R. , Yates Stephanie , McNichol Laurie , Gray Mikel
Published: July 2022

The Wound, Ostomy and Continence Nurses (WOCN) Society charged a task force with updating the venous leg ulcer (VLU) algorithm to include the addition of lymphedema with the new title of “Compression for Lower Extremity Venous Disease and Lymphedema (CLEVDAL).” As part of the process, the task force was charged to develop consensus-based statements to serve as clinical guidance related to CLEVDAL. The 3-member task force assisted by a moderator completed a scoping literature review to identify recommendations supported by research to qualify as evidence-based and to identify areas where guidance is needed to provide CLEVDAL. Based on the findings of the scoping review, the WOCN Society convened a panel of experts to develop consensus statements to direct care for those with lower extremity venous disease and lymphedema. These consensus statements underwent a second round of content validation with a different panel of clinicians with expertise in venous disease and lymphedema management. This article reports on the scoping review and subsequent evidence-based statements, along with the generation and validation of consensus-based statements to assist clinical decision-making in the CLEVDAL algorithm.
Long-term Suprapubic Catheter–Related Care Requirements When Living at Home
Authors: Sweeney Alyson
Published: July 2022

PURPOSE:

The purpose of this study was to develop a best practice guideline specific to the health care needs of adults living at home with a long-term suprapubic catheter (SPC).

DESIGN:

Guided by the theory of social constructionism, a mixed-methods, 2-phased study design enabled an integration of experiences and consensus from 2 groups of experts.

SUBJECTS AND SETTING:

The first group of experts involved 10 people living with a long-term SPC at home. The second group comprised 23 nurses who provided care to people living with a long-term SPC at home.

METHODS:

During phase 1, semistructured in-depth interviews were completed to explore people's day-to-day self-care practices and support needs when living at home with a long-term SPC. These data were evaluated via thematic analysis. The themes identified in phase 1 provided the phase 2 question framework in the development of a 3-round Delphi survey involving the expert nurse group. The first round elicited the respondents' opinions on specific aspects of SPC-related care. Using qualitative content analysis, practice statements were generated and used in subsequent survey rounds. The respondents rated their level of agreement to each statement. The guideline comprises the statements that achieved consensus.

RESULTS:

The 6 elements of the best practice guideline contracted using this mixed-methods study were psychological support needs, cystostomy site care, SPC replacement, drainage equipment practices, complication avoidance and management, and planning ahead.

CONCLUSIONS:

This best practice document provides a valuable resource to guide health professionals, promoting standardized best practices when caring for persons living at home with an SPC.
Use of a Sacral Foam Dressing to Prevent Pressure Injury in At-Risk Subacute Hospitalized Older Adults
Authors: Lovegrove Josephine , Fulbrook Paul , Miles Sandra J.
Published: July 2022

PURPOSE:

The purpose of this pilot study was to inform a future trial aimed at comparing the effectiveness of a prophylactic sacral dressing plus standard care to standard care only to reduce sacral pressure injuries (PIs) in at-risk older adults admitted to a subacute hospital setting.

DESIGN:

A pilot study with a pragmatic, open-label, randomized controlled trial design.

SAMPLE AND SETTING:

One hundred thirty participants were randomized (intervention n = 66, 50.8%; control n = 64, 49.2%). Protocol violations occurred in 48 participants (intervention n = 33, 68.8%; control n = 15, 31.3%). The study setting was a subacute hospital inpatient care unit located in Queensland, Australia.

METHODS:

Participants were randomly allocated 1:1 to the intervention (prophylactic dressing plus standard care) or control group (standard care). Standard care included regular PI risk and skin assessments, and selection and implementation of preventive interventions (eg, support surfaces and increased repositioning) from a PI prevention care plan. The sacral dressing was applied for intervention participants immediately following recruitment. Ward and research staff collected data and assessed skin integrity daily; participants were followed up until onset of a PI or up to 28 days without PI occurrence. In addition, retrospective chart reviews were undertaken to verify PI occurrences. Patient comfort and dressing utility were also evaluated.

RESULTS:

Two (3.0%) participants in the intervention group and 1 (1.6%) in the control group developed a sacral PI. The difference was not statistically significant. Only 1 PI was recorded prospectively, while 2 PIs were identified via retrospective chart review. Participants rated dressing comfort highly, particularly during the first 2 weeks, and nurses rated utility highly. Based on the intention-to-treat results, a sample size of 1799 per arm would be required in a definitive trial.

CONCLUSIONS:

A definitive trial is feasible and warranted. However, the large sample size required in a definitive trial indicates the need for multiple sites.
Effects of psoriasis and psoralen exposure on the somatic mutation landscape of the skin
Authors: Olafsson Sigurgeir , Rodriguez Elke , Lawson Andrew R.J. , Abascal Federico , Jones Philip H. , Gerdes Sascha , Martincorena Iñigo , Weidinger Stephan , Campbell Peter J. , Anderson Carl A.
Published: July 2022

Somatic mutations are hypothesised to play a role in many non-neoplastic diseases. These diseases may also shape the somatic mutation landscape of affected tissues after onset. We performed whole-exome sequencing of 1182 microbiopsies dissected from lesional and non-lesional epidermis from 111 patients with psoriasis, a chronic inflammatory disease of the skin, to search for evidence that somatic mutations in keratinocytes may influence the disease process and to characterise the effects of the disease on the mutation landscape of the epidermis. We show that psoriasis is associated with increased mutation burden of the cell-intrinsic signatures SBS1 and SBS5 but not of UV-light, which remains the dominant mutagen in psoriatic skin. Despite the hyperproliferation of keratinocytes that characterises psoriasis, lesional skin remains highly polyclonal, showing no evidence of spread of clones carrying potentially pathogenic mutations. We find that the selection forces operating in the epidermis remain mostly unchanged in psoriasis and the mutational landscape continues to be dominated by clones carrying mutations in genes recurrently mutated in normal squamous epithelia. There is evidence of positive selection in previously reported driver genes, NOTCH1, NOTCH2, TP53, FAT1 and PPM1D and we also identify four driver genes (GXYLT1, CHEK2, ZFP36L2 and EEF1A1), that have not been previously described in studies of normal skin but which we hypothesise are selected for in squamous epithelium irrespective of disease status. We describe the mutagenic effects of psoralens, a class of chemicals previously found in some sunscreens and which remain a part of a common photochemotherapy treatment for psoriasis (psoralens and UV-A, PUVA). Psoralens leave a distinct mutational signature in the genomes of exposed cells that is tightly linked with transcription, showing evidence of both transcription-coupled repair and transcription-coupled damage. These results suggest that somatic mutations in keratinocytes are unlikely to influence the pathogenesis of psoriasis and that while psoriasis has only modest effect on the mutation landscape of the skin, PUVA treatment has the potential to exert a unique and larger effects.
Building an Open Representation for Biological Protocols
Authors: Bartley Bryan , Beal Jacob , Rogers Miles , Bryce Daniel , Goldman Robert P. , Keller Benjamin , Lee Peter , Biggers Vanessa , Nowak Joshua , Weston Mark
Published: July 2022

Laboratory protocols are critical to biological research and development, yet difficult to communicate and reproduce across projects, investigators, and organizations. While many attempts have been made to address this challenge, there is currently no available protocol representation that is unambiguous enough for precise interpretation and automation, yet simultaneously abstract enough to enable reuse and adaptation. The Protocol Activity Markup Language (PAML) is a free and open protocol representation aiming to address this gap, building on a foundation of UML, Autoprotocol, and SBOL RDF. PAML provides a representation both for protocols and for records of their execution and the resulting data, as well as a framework for exporting from PAML for execution by either humans or laboratory automation. PAML is currently implemented in the form of an RDF knowledge representation, specification document, and Python library, can be exported for execution as either a manual “paper protocol” or Autoprotocol, and is being further developed as an open community effort.
A molecular phenotypic map of Malignant Pleural Mesothelioma
Authors: Di Genova Alex , Mangiante Lise , Sexton-Oates Alexandra , Voegele Catherine , Fernandez-Cuesta Lynnette , Alcala Nicolas , Foll Matthieu
Published: July 2022

Background

Malignant Pleural Mesothelioma (MPM) is a rare understudied cancer associated with exposure to asbestos. So far, MPM patients have benefited marginally from the genomics medicine revolution due to the limited size or breadth of existing molecular studies. In the context of the MESOMICS project, we have performed the most comprehensive molecular characterization of MPM to date, with the underlying dataset made of the largest whole genome sequencing series yet reported, together with transcriptome sequencing and methylation arrays for 120 MPM patients.

Results

We first provide comprehensive quality controls for all samples, of both raw and processed data. Due to the difficulty in collecting specimens from such rare tumors, a part of the cohort does not include matched normal material. We provide a detailed analysis of data processing of these tumor-only samples, showing that all somatic alteration calls match very stringent criteria of precision and recall. Finally, integrating our data with previously published multi-omic MPM datasets (n=374 in total), we provide an extensive molecular phenotype map of MPM based on the multi-task theory. The generated map can be interactively explored and interrogated on the UCSC TumorMap portal (https://tumormap.ucsc.edu/?bookmark=746c4bc0e8bc4eb5f280cdd8lc7dcc783955faf2e2b493d0d205b7dle92b98c4).

Conclusions

This new high quality MPM multi-omics dataset, together with the state-of-art bioinformatics and interactive visualization tools we provide, will support the development of precision medicine in MPM that is particularly challenging to implement in rare cancers due to limited molecular studies.
Irgm proteins attenuate inflammatory disease in mouse models of genitalChlamydiainfection
Authors: Dockterman Jacob , Everitt Jeffrey I. , Wallace Graham , Coers Jörn
Published: July 2022

Chlamydiaeare obligate intracellular bacterial pathogens that may cause genital pathology via induction of destructive host immune responses. Human-adaptedChlamydia trachomatiscauses inflammatory disease in human hosts but is easily cleared in mice, and mouse-adaptedChlamydia muridarumestablishes a productive and pathogenic infection in murine hosts. While numerous anti-chlamydial host resistance factors have been discovered in mice and humans alike, little is known about host factors promoting host fitness independent of host resistance. Here, we show that interferon-inducible immunity-related GTPase M (Irgm) proteins function as such host factors ameliorating infection-associated sequalae in the murine female genital tract, thus characterizing Irgm proteins as mediators of disease tolerance. Specifically, we demonstrate that mice deficient for all three murine Irgm paralogs (pan-Irgm-/-) are defective for cell-autonomous immunity toC. trachomatis, which correlates with an early and transient increase in bacterial burden and sustained hyperinflammationin vivo. In contrast, upon infection of pan-Irgm-/-mice withC. muridarum, bacterial burden is unaffected, yet genital inflammation and scarring pathology are nonetheless increased, demonstrating that Irgm proteins can promote host fitness without altering bacterial burden. Additionally, pan-Irgm-/-mice display increased granulomatous inflammation in genitalChlamydiainfection, implicating Irgm proteins in the regulation of granuloma formation and maintenance. These findings demonstrate that Irgm proteins regulate pathogenic immune responses toChlamydiainfectionin vivo, establishing an effective infection model to examine the immunoregulatory functions and mechanisms of Irgm proteins.

Importance

In response to genitalChlamydiainfection, the immune system mounts a proinflammatory response to resist the pathogen, yet inflammation must be tightly controlled to avoid collateral damage and scarring to host genital tissue. Variation in the humanIRGMgene is associated with susceptibility to autoinflammatory diseases but its role in ameliorating inflammatory diseases caused by infections is poorly defined. Here we use mice deficient for all three murine Irgm paralogs to demonstrate that Irgm proteins not only provide host resistance toChlamydiainfections but also limit associated inflammation in the female genital tract. In particular, we find that murine Irgm expression prevents granulomatous inflammation, which parallels inflammatory diseases associated with variants in humanIRGM. Our findings therefore establish genitalChlamydiainfection as a useful model to study the roles for Irgm proteins in both promoting protective immunity and limiting pathogenic inflammation.
Biologics for pediatric atopic dermatitis A protocol of A systematic review and meta - analysis
Authors: Cao Rui , Lu Jiaxing , Chen Zhao
Published: July 2022

Background

Atopic dermatitis is a common chronic pruritic inflammatory skin disease, tends to occur in children. The objective of this study is to evaluate the treatment of pediatric atopic dermatitis with Biologics, as biologics continue to emerge for atopic dermatitis (AD)

Methods

The databases we will search include Embase, Cochrane Library, Web of Science, the and PubMed of RCTs from inception to 15st May 2022. The primary outcomes The proportion of patients with EASI 75 as the primary outcome,. The secondary outcomes incloud NRS, DLQI score and adverse reaction incidence.Studies will be screened by two independent authors. They will assess the risk of bias of the final included studies according to the RCTs bias risk evaluation tool in Cochrane System Review Manual 5.1.0. Meta-analysis will be performed using RevMan 5.3 software.

Results

The research results will provide a reference for the clinical application of biological agents in pediatric atopic dermatitis.

Conclusion

We aims to evaluate the efficacy and safety of biologics in pediatric atopic dermatitis and provide evidence-based data for clinical application

Ethics and dissemination

The study does not collect raw data and personal information, does not involve jeopardizing the rights of the participants. Ethical approval was not required. The results may be reported in publications and the media

PROSPERO registration number

CRD42022319052

(https://www.crd.york.ac.uk/PROSPERO/#joinuppage)
Addiction and Rational Choice: Evidence from an Eye Tracking Experiment with Cigarette Packages
Authors: Gerstenblüth Mariana , Harris Jeffrey E. , Triunfo Patricia
Published: July 2022

We asked 97 current cigarette smokers to make 12 binary choices between experimental packages with varying warnings and background colors. Each participant had to decide which of the two packages contained cigarettes less risky for his health. Confronted with repugnant, threatening images, these smokers nonetheless made choices that were context independent, adhered to transitivity, and consistent with an additive utility model. Eye tracking measurements confirmed that the choices of 65 percent of participants were further compatible with a noise-reducing lexicographic utility model. This subset of participants smoked significantly more cigarettes per day. Our findings support a model in which addiction permits the smoker to suppress aversive stimuli and negative emotions that would otherwise interfere with short-term rational decision making.
Human Gene and Microbial Analyses Suggest Immunotherapy-like Mechanisms in Complete Response to Radiotherapy in Rectal Cancer
Authors: Sulit A.K. , Wilson K. , Pearson J. , Silander O.K. , Michael M. , Ramsay R. , Heriot A. , Frizelle F. , Purcell R.
Published: July 2022

The treatment of rectal cancer usually involves total mesorectal excision, with preoperative chemoradiotherapy (CRT) that is aimed at downstaging tumors before surgical procedure. CRT response varies, with some patients completely responding to CRT and negating the need for surgery, and some patients not responding to the treatment at all. Identifying biomarkers of response to CRT would be beneficial in identifying whether a treatment would confer benefits to a patient while allowing them to avoid unnecessary morbidities and mortalities. While previous studies have attempted to identify such biomarkers, none have reached clinical utility which may be due to heterogeneity of the cancer. In this paper, we explored potential human gene and microbial biomarkers, and their possible contributions to the mechanisms of complete response to chemoradiotherapy. We carried out RNA sequencing on pairs of tumor and normal tissue from patients pre-surgery and analysed host gene expression and microbiome content. We discovered that the majority of enriched human genes in tumors of complete responders involve immunoglobulins, and enriched gene sets include complement and B-cell activation, and host response against viruses. This indicates involvement of immune responses in complete response to CRT. Among the enriched gene sets is the term defense response to bacterium, indicating a role of the microbiome in response to CRT. We discovered bacteria such as Ruminococcaceae bacterium and Bacteroides thetaiotaomicron to be abundant in tumors of complete responders. Both microbes have a history of being beneficial in treatment of cancers with immunotherapy, further emphasizing the role of immune responses in beneficial response to CRT. These results identify potential genetic and microbial biomarkers to CRT in rectal cancer, as well as offer a potential mechanism of complete response to CRT that may benefit further testing in the laboratory.
The slowdown of growth rate controls the single-cell distribution of biofilm matrix production via a SinI-SinR-SlrR network
Authors: Chen Zhuo , Zarazúa-Osorio Brenda , Srivastava Priyanka , Fujita Masaya , Igoshin Oleg A.
Published: July 2022

In Bacillus subtilis, a master regulator Spo0A controls several cell-differentiation pathways. Under moderate starvation, phosphorylated Spo0A (Spo0A~P) induces biofilm formation by indirectly activating genes controlling matrix production in a subpopulation of cells via a SinI-SinR-SlrR network. Under severe starvation, Spo0A~P induces sporulation by directly and indirectly regulating sporulation gene expression. However, what determines the heterogeneity of individual cell fates is not fully understood. In particular, it is still unclear why, despite being controlled by a single master regulator, biofilm matrix production and sporulation are mutually exclusive on a single-cell level. In this work, with mathematical modeling, we showed that the fluctuations in the growth rate and the intrinsic noise amplified by the bistability in the SinI-SinR-SlrR network could explain the single-cell distribution of matrix production. Moreover, we predicted an incoherent feed-forward loop: the decrease in the cellular growth rate activates matrix production by increasing in Spo0A phosphorylation level but represses it via changing the relative concentrations of SinR and SlrR. Experimental data provide evidence to support model predictions. In particular, we demonstrate how the degree to which matrix production and sporulation appear mutually exclusive is affected by genetic perturbations.

Importance

The mechanisms of cell-fate decisions are fundamental to our understanding of multicellular organisms and bacterial communities. However, even for the best-studied model systems we still lack a complete picture of how phenotypic heterogeneity of genetically identical cells is controlled. Here, using B. subtilis as a model system, we employ a combination of mathematical modeling and experiments to explain the population-level dynamics and single-cell level heterogeneity of biofilm gene expression. The results demonstrate how the two cell fates, biofilm matrix production and sporulation, can appear mutually exclusive without explicitly inhibiting one another. Such a mechanism could be used in a wide range of other biological systems.
Deciphering the conformations and dynamics of FG-nucleoporins in situ
Authors: Yu M. , Heidari M. , Mikhaleva S. , Tan P.S. , Mingu S. , Ruan H. , Reinkermeier C.D. , Obarska-Kosinska A. , Siggel M. , Beck M. , Hummer G. , Lemke E.A.
Published: July 2022

The ∼120 MDa nuclear pore complex (NPC) acts as a gatekeeper for the molecular traffic between the nucleus and the cytosol. Small cargo readily passes through the transport channel, yet large cargo requires specialized nuclear transport receptors. While the scaffold structure that anchors the NPC in the double-layered nuclear envelope has been resolved to remarkable details, the spatial organization of intrinsically disordered nucleoporins (NUPs) within the central channel remains enigmatic. These so-called FG-NUPs account for about one-third of the total mass of the NPC and form the actual transport barrier. Here we combined site-specific fluorescent labeling in non-fixed cells and fluorescent lifetime imaging microscopy (FLIM) to directly decipher the conformations of an essential constituent of the permeability barrier, NUP98, inside the functioning NPCs using Fluorescence resonance energy transfer (FRET). With detailed measurements of the distance distribution of eighteen NUP98 segments combined with coarse-grained modeling, we mapped the uncharted biochemical environment inside the nanosized transport channel. We found that ‘good-solvent’ conditions for a polymer dominate the inside of the nanosized NPC, expand the FG-domain in situ and facilitate nuclear transport, in sharp contrast to the collapsed NUP98 FG-chain in aqueous solution. The combination of fluorescence microscopy, high-resolution electron tomography, and molecular simulation opens a window into the so-far unresolved organization of the FG-NUPs at the center of NPC function, allowing us to reconcile scientific models of nuclear transport.
A fungal secondary metabolism gene cluster enables mutualist-pathogen transition in root endophyteColletotrichum tofieldiae
Authors: Hiruma Kei , Aoki Seishiro , Utami Yuniar Devi , Okamoto Masanori , Kawamura Nanami , Nakamura Masami , Ohmori Yoshihiro , Sugita Ryohei , Tanoi Keitaro , Sato Toyozo , Iwasaki Wataru , Saijo Yusuke
Published: July 2022

Plant-associated fungi show diverse lifestyles from pathogenic to mutualistic to the host; however, the principles and mechanisms through which they shift the lifestyles require elucidation. The root fungusColletotrichum tofieldiae(Ct) promotesArabidopsis thalianagrowth under phosphate limiting conditions. We reveal aCtstrain, designatedCt3, that severely inhibits plant growth.Ct3pathogenesis occurs through activation of host abscisic acid (ABA) pathways via a fungal secondary metabolism gene cluster related to sesquiterpene ABA and botrydial (BOT) biosynthesis. ABA-BOT cluster activation during root infection suppresses host nutrient uptake-related genes and changes the mineral contents, suggesting its role in manipulating host nutrition states. Conversely, disruption or environmental suppression of the cluster rendersCt3beneficial for plant growth, in a manner dependent on host phosphate starvation response regulators. Our findings indicate that a fungal metabolism cluster provides a means by which infectious fungi modulate lifestyles along the parasitic–mutualistic continuum in fluctuating environments.
Mycobacterium tuberculosis requires the outer membrane lipid phthiocerol dimycocerosate for starvation-induced antibiotic tolerance
Authors: Block Alisha M. , Namugenyi Sarah B. , Palani Nagendra P. , Brokaw Alyssa M. , Zhang Leanne , Beckman Kenneth B. , Tischler Anna D.
Published: July 2022

Tolerance of Mycobacterium tuberculosis to antibiotics contributes to the long duration of tuberculosis (TB) treatment and the emergence of drug-resistant strains. M. tuberculosis drug tolerance is induced by nutrient restriction, but the genetic determinants that promote antibiotic tolerance triggered by nutrient limitation have not been comprehensively identified. Here, we show that M. tuberculosis requires production of the outer membrane lipid phthiocerol dimycocerosate (PDIM) to tolerate antibiotics under nutrient-limited conditions. We developed an arrayed transposon (Tn) mutant library in M. tuberculosis Erdman and used orthogonal pooling and transposon sequencing (Tn-seq) to map the locations of individual mutants in the library. We screened a subset of the library (~1,000 mutants) by Tn-seq and identified 32 and 102 Tn mutants with altered tolerance to antibiotics in stationary phase and phosphate-starved conditions, respectively. Two mutants recovered from the arrayed library, ppgK::Tn and clpS::Tn, showed increased susceptibility to two different drug combinations in both nutrient-limited conditions, but their phenotypes were not complemented by the Tn-disrupted gene. Whole genome sequencing revealed single nucleotide polymorphisms in both the ppgK::Tn and clpS::Tn mutants that prevented PDIM production. Complementation of the clpS::Tn ppsD Q291* mutant with ppsD restored PDIM production and antibiotic tolerance, demonstrating that loss of PDIM sensitized M. tuberculosis to antibiotics. Our data suggest that drugs targeting production of PDIM, a critical M. tuberculosis virulence determinant, have the potential to enhance the efficacy of existing antibiotics, thereby shortening TB treatment and limiting development of drug resistance.

IMPORTANCE

Mycobacterium tuberculosis causes 10 million cases of active TB disease and over 1 million deaths worldwide each year. TB treatment is complex, requiring at least 6 months of therapy with a combination of antibiotics. One factor that contributes to the length of TB treatment is M. tuberculosis phenotypic antibiotic tolerance, which allows the bacteria to survive prolonged drug exposure even in the absence of genetic mutations causing drug resistance. Here we report a genetic screen to identify M. tuberculosis genes that promote drug tolerance during nutrient starvation. Our study revealed the outer membrane lipid phthiocerol dimycocerosate (PDIM) as a key determinant of M. tuberculosis antibiotic tolerance triggered by nutrient starvation. Our study implicates PDIM synthesis as a potential target for development of new TB drugs that would sensitize M. tuberculosis to existing antibiotics to shorten TB treatment.
β-catenin activity induces an RNA biosynthesis program promoting therapy resistance in T Acute Lymphoblastic Leukemia
Authors: García-Hernández Violeta , Arambilet David , Guillén Yolanda , Lobo-Jarne Teresa , Gekas Christos , Vega-García Nerea , Sentis Inés , Trincado Juan Luis , Márquez-López Ian , Heyn Holger , Camos Mireia , Espinosa Lluis , Bigas Anna
Published: July 2022

Understanding the molecular mechanisms that contribute to the appearance of chemotherapy resistant cell populations is necessary to improve cancer treatment. We have now investigated the role of β-catenin/CTNNB1 in the evolution of T-Acute Lymphoblastic Leukemia (T-ALL) patients and its involvement in therapy resistance. We have identified a specific gene signature that is directly regulated by β-catenin, TCF/LEF factors and ZBTB33/Kaiso in T-ALL cell lines, which is highly and significantly represented in 5 out of 6 refractory patients from a cohort of 40 children with T-ALL. By subsequent refinement of this gene signature, we found that a subset of β-catenin target genes involved with RNA-processing function are sufficient to segregate T-ALL refractory patients in three independent cohorts. We demonstrate the implication of β-catenin in RNA and protein synthesis in T-ALL and provide experimental evidence that β-catenin is crucial for the cellular response to chemotherapy, mainly in the cellular recovery phase after treatment.

We propose that combination treatments involving chemotherapy plus β-catenin inhibitors will enhance chemotherapy response and prevent disease relapse in T-ALL patients.