bluuebunny/crossref_metadata_2025 huggingface dataset:
Mouse models of type 1 diabetes and their use in skeletal research
Authors: Kalaitzoglou Evangelia , Fowlkes John L. , Thrailkill Kathryn M.
Published: June 2022

Purpose of review

In this review, we describe the three primary mouse models of insulin-deficiency diabetes that have been used to study the effects of type 1 diabetes (T1D) on skeletal outcomes. These models include streptozotocin (chemically)-induced diabetes, autoimmune-mediated diabetes (the nonobese diabetes mouse), and a mutation in the insulin gene (the Akita mouse). We then describe the skeletal findings and/or skeletal phenotypes that have been delineated using these models.

Recent findings

Humans with T1D have decreased bone mineral density and an increased risk for fragility fracture. Mouse models of insulin-deficiency diabetes (hereafter denoted as T1D) in many ways recapitulate these skeletal deficits. Utilizing techniques of microcomputed tomography, bone histomorphometry, biomechanical testing and fracture modeling, bone biomarker analysis, and Raman spectroscopy, mouse models of T1D have demonstrated abnormalities in bone mineralization, bone microarchitecture, osteoblast function, abnormal bone turnover, and diminished biomechanical properties of bone.

Mouse models have provided significant insights into the underlying mechanisms involved in the abnormalities of bone observed in T1D in humans. These translational models have provided targets and pathways that may be modifiable to prevent skeletal complications of T1D.
Insulin resistance and skeletal health
Authors: Lei Wang Shin , Kindler Joseph M.
Published: June 2022

Purpose of review

Bone fragility is a complication of type 2 diabetes (T2D), and insulin resistance is suspected to contribute to diabetes-related bone deficits. This article provides an overview of emerging clinical research involving insulin resistance and bone health by summarizing recent publications, identifying existing knowledge gaps, and suggesting ‘next steps’ for this evolving field of research.

Recent findings

Clinical studies in children and adults report greater bone density in people with increased insulin resistance, but these associations are often attenuated when adjusting for body size. Advancements in bone imaging methods allow for assessment of nuanced characteristics of bone quality and strength that extend beyond standard bone mineral density assessment methods. For example, several recent studies focusing on lumbar spine trabecular bone score, a relatively new measure of trabecular bone quality from dual-energy X-ray absorptiometry, have reported generally consistent inverse associations with insulin resistance. Longitudinal studies using advanced imaging methods capable of evaluating trabecular bone microstructure and strength, such as high-resolution peripheral quantitative computed tomography, are lacking. Studies in younger individuals are sparse, but emerging data suggest that peak bone mass attainment might be threatened by diabetes progression, and increased visceral fat, suppressed muscle-bone unit, advanced glycation end-products, sedentary lifestyle, and poor diet quality might contribute to diabetes effects on bone. Prospective studies during the transition from adolescence to young adulthood are required.

Insulin resistance is a main feature of T2D, which is suspected to contribute to subclinical diabetes-related threats to bone health. Future clinical studies should focus on the critical years surrounding peak bone mass and peak bone strength attainment using contemporary imaging techniques.
The future of laser technology in kidney stones
Authors: Kallidonis Panagiotis , Vagionis Athanasios
Published: June 2022

Purpose of review

The aim of this study was to present the recent and promising innovations of the new laser technologies used for the treatment of renal stones.

Recent findings

Taking advantage of pulse modulation, new technologies such as the Moses effect, the Virtual basket and the Vapor tunnel have been introduced. These technologies seem to improve lithotripsy efficacy by reducing retropulsion and increasing the stone ablation rate.

High-power laser lithotripsy has arisen in everyday clinical practice in some centres. The combination of equal efficacy and safety levels compared with the low-power laser lithotripsy and significantly reduced operative time could explain this trend.

Thulium fibre laser is an innovative type of laser-emitting machine that offers a lot of advantages compared with its predecessors. The different mechanism of creating the laser pulse offers new possibilities in laser lithotripsy and perhaps in the future thulium fibre laser could replace Ho:YAG as the golden standard for laser lithotripsy.

Laser lithotripsy is heavily based on technological equipment. The continuous improvement of available lasers increases the endoscopic lithotripsy levels of efficacy and safety.
Basal cell carcinoma of the prostate: a case report responding to the FGFR inhibitor pemigatinib and literature review
Authors: Rebhan Katharina , Wasinger Gabriel , Hassler Melanie R. , Shariat Shahrokh F. , Compérat Eva M.
Published: June 2022

Purpose of review

Due to the limited number of cases, there are no guidelines for basal cell carcinoma (BCC) of the prostate. This review combines an unpublished case report of a 55-year-old patient with BCC with an assessment of the latest literature.

Recent findings

BCC of the prostate has previously been described in only approximately 140 cases. We describe the diagnostic process, including the uropathological and DNA-sequencing results, which allowed us to start an experimental treatment with pemigatinib. BCC of the prostate is associated with an aggressive biological and clinical behavior, such as recurrence and metastasis. Several immunohistochemical stainings are available to differentiate BCC from adenocarcinoma of the prostate. Based on pathology and results from next-generation sequencing (NGS), patients can be offered targeted therapies.

With the aid of histological work-up and immunostaining, prostatic BCC can be accurately diagnosed. Our patient underwent radical prostatectomy and staged extended lymphadenectomy due to lymph node recurrence. The patient subsequently developed progressive disease and was treated with the FGFR-inhibitor pemigatinib. The patient's liver metastasis significantly responded. The present case confirms the possibility of aggressive behavior of prostatic BCC and highlights the importance of a thorough uropathological and molecular biological analysis with a precision medicine strategy.
Device-assisted intravesical chemotherapy treatment for nonmuscle invasive bladder cancer: 2022 update
Authors: Vartolomei Mihai Dorin , Ferro Matteo , Roth Beat , Teoh Jeremy Yuen-Chun , Gontero Paolo , Shariat Shahrokh F.
Published: June 2022

Purpose of review

To critically analyze the oncological outcomes and safety profile of device-assisted intravesical chemotherapy studies reported in 2021. Studies were considered eligible if they included patients with nonmuscle invasive blood cancer (NMIBC), had a prospective or retrospective design, included at least 10 patients, were published in 2021, and assessed the oncological impact of device-assisted intravesical chemotherapy and/or reported standardized adverse effects (AEs).

Recent findings

Eight new studies reported oncological outcomes after hyperthermic intravesical chemotherapy (HIVEC). In Bacillus Calmette-Guérin (BCG) naive patients, the reported 2-yr. recurrence-free survival (RFS) ranged from 70.7% to 82.4%, with one study reporting 2 yr. progression free survival (PFS) of 92%. In both BCG naive and BCG refractory patients, the reported 1-yr. RFS ranged from 60.5% to 70% and PFS was 94% in one study. For radiofrequency-induced HIVEC, the reported 5-yr. estimates were 38%for RFS and 91.5%for PFS. Regarding AEs, 10.2% of patients had severe AEs. Six studies reported AEs after HIVEC; the majorities were grade 1–2 AEs.

Data coming from the studies published in the last years provides support for a consolidating role of device-assisted intravesical chemotherapy as a safe and effective alternative first- or second-line adjuvant treatment of patients with NMIBC.
Quality Metrics to Assess Cytopathology Practice Patterns: Focus on Thyroid Fine-Needle Aspiration Cytology
Authors: Vander Laan Paul A.
Published: June 2022

Quality assurance measures in the cytology laboratory help ensure accurate and consistent diagnoses. For thyroid fine-needle aspirations (FNAs), various cytologist performance metrics have been proposed to help monitor and explain cytologist practice patterns. Thoughtful implementation of metrics such as diagnostic category utilization rates, ratios of key diagnostic categories, surgical outcome data, and correlation with ancillary molecular testing results have been proposed to help minimize the use of indeterminate diagnostic categories in thyroid FNAs, such as atypia of undetermined significance. Development of laboratory dashboards coupled with periodic confidential feedback to the cytopathologist or cytotechnologist can help monitor and correct practice patterns that fall outside target norms.
Successful Identification of a Neoplastic Tissue Contaminant in Surgical Pathology
Authors: Anderson Jessica D. , Amin Mitual B. , Bernacki Kurt D.
Published: June 2022

Tissue contamination, where extraneous tissue becomes embedded into the paraffin block or fixed onto the slide, is a relatively common quality issue in surgical pathology and can occur at any step between specimen collection by the clinician and slide coverslipping. We report a case of tissue contamination within a paraffin block and describe our subsequent investigation, which was successful in identifying the source of contamination.
Data-Driven Decision-Making in Support of Managing Pathology Laboratories
Authors: Dahl Julia , Myers Jeffrey L. , Pantanowitz Liron
Published: June 2022

Pathology laboratories generate large amounts of patient and operational data, usually housed in laboratory information systems. Linking that information to other data sources for data mining and analytics is essential to inform decision-making by multiple stakeholders to effectively manage the pathology laboratory. We review and illustrate examples of how data-driven decision-making can support laboratory operations, resource management, personnel performance and productivity, quality assurance, and business activities. The application of dashboards and informatics tools for data-driven decision-making in pathology is highlighted.
Reporting Critical/Urgent/Significant Results in Anatomic Pathology: The Devil Is in the Details
Authors: Kallen Michael Edward , Otis Christopher N. , Staats Paul N.
Published: June 2022

Critical value reporting is an important facet of laboratory management and represents a significant potential challenge in patient care delivery, as well as a high-value target for quality improvement initiatives in both anatomic and clinical pathology settings. A recurring problem concerns successfully contacting unavailable health care providers with unexpected and/or time-sensitive results. We report a case of an incidentally detected and unexpected finding of tumor cells in a routine hip arthroplasty, in a patient under surgical management for a variety of chronic issues including peripheral arterial disease and traumatic fall. The abnormal result proved to be the first presentation of a widely disseminated metastatic melanoma. Although multiple associated health care providers were successfully contacted with the unexpected finding and acknowledged awareness of the concern for metastatic melanoma, one provider was not successfully contacted with the pathology result, leading to frustrations among multiple parties and a slight delay in appropriate patient referral. The sequence of events presents an opportunity to review standards of care regarding urgent diagnosis reporting in anatomic pathology and assess the published literature surrounding this issue.
Barriers and facilitators to lower extremity orthotic compliance in the pediatric population: A scoping review of the literature
Authors: Marcotte David , Ferri Erica , Xue Xiaotong , Katsolis Anastasia , Rajotte Elise , Cardiff Katrina , Preuss Richard
Published: June 2022

Despite the purported benefits of lower extremity orthotics in the literature, pediatric compliance rates remain low. This scoping review synthesized the available literature regarding barriers and facilitators to lower extremity orthotic compliance in the pediatric population using the framework of the International Classification of Functioning, Disability and Health: Children and Youth (ICF). A comprehensive search of MEDLINE, EMBASE, and CINAHL was conducted on May 11, 2021, and of PsycInfo on May 12, 2021. Article reference lists and gray literature were also searched. A total of 81 articles were included. Factors described in at least four articles were labeled as universal barriers or facilitators. In the International Classification of Functioning, Disability and Health: Children and Youth domain of Body Functions/Body Structures, universal barriers were present in the global mental functions, experience of self and time, sensory functions, function of joints and bones, and structures related to the skin subcategories, with no universal facilitators identified. For the Activity Limitations/Participation Restrictions domain, one universal facilitator was identified in the mobility subcategory. In the Environmental Contextual Factors domain, universal barriers were found in the attitudes of immediate and extended family and societal attitude subcategories, with both universal barriers and facilitators found in support & relationships: immediate and extended family, support and relationships: health professionals, services, systems, and policies, and products and technology. The reviewed literature strongly emphasizes the importance of proper orthotic fit and comfort, and the child’s experience of self, for lower extremity orthotic compliance, along with multiple environmental factors.
Opinions on noninvasive sensory feedback of upper limb prosthetic users
Authors: Smither F. Clay , Andrews Karen L. , Scrabeck Tyson L. , Lennon Ryan J. , Zhao Kristin D.
Published: June 2022

Background:

Restoring touch perception for individuals with upper extremity limb loss is an ambitious task. It is important to understand how persons with upper limb loss think this would be best achieved.

Methods:

An anonymous online survey was developed to obtain data from prosthetic users. Participants ranked the perceived acceptability and effectiveness of noninvasive sensory feedback to areas of intact sensation not typically involved in sensory feedback (i.e., the arm). The focus was on 4 main types of haptic information—object contact, proprioception, surface texture, and grasp force—as well as how best to convey those senses with various stimuli. The users were asked to grade themselves in certain tasks and then analyze which tasks would be improved with sensory feedback. Associations were explored between demographic characteristics and interest in sensory feedback.

Results:

Nationally, prostheses providers sent more than 2000 email invitations to the online survey and received 142 unique responses. Responses indicated interest in sensory feedback through prosthetic limbs by individuals with upper limb loss. The most popular pairing of haptic information with sensory substitution was grasp force paired with gentle vibration. Tasks that most persons taking the survey agreed would benefit from sensory feedback were zipping a jacket, tying shoes, buttoning a shirt, and using a cup. No difference was observed in interest between sex and employment status, but a significant decrease (P = .004) was seen in interest among participants with more years of prosthetic use.

Discussion:

The results from this national survey of upper extremity prosthetic users can be used to help guide the development of noninvasive sensory feedback options.
Matched Versus Mixed COVID-19 Vaccinations in Korean Solid Organ Transplant Recipients: An Observational Study
Authors: Kang Ji-Man , Lee Juhan , Huh Kyu Ha , Joo Dong Jin , Lee Jae Geun , Kim Hye Rim , Kim Ha Yan , Lee Myeongjee , Jung Inkyung , Kim Min Young , Kim Sinyoung , Park Younhee , Kim Myoung Soo
Published: June 2022

Background.

Solid organ transplant recipients (SOTRs) are vulnerable to severe coronavirus disease 2019 (COVID-19) and exhibit poor antibody responses to COVID-19 vaccines. Herein, we compared the humoral immunogenicity of a mixed vaccine (ChAdOx1 nCoV-19 [ChAd]/BNT162b2 [BNT]) with that of conventional matched vaccines (mRNA, adenoviral vector [AdV-Vec]) in SOTRs.

Methods.

Serum samples were collected at Severance Hospital (Seoul, Korea) between September and October 2021 (14 d–5 mo after COVID-19 vaccination; V2). The severe acute respiratory syndrome coronavirus 2 antispike IgG titer (BAU/mL; ELISA) and neutralization inhibition (percentage; neutralization assay) were compared between vaccination groups overall and stratified by V2 (poststudy vaccination visit) timing.

Results.

Of the 464 participants, 143 (31%) received mRNA vaccines, 170 (37%) received AdV-Vec vaccines, and 151 (33%) received mixed vaccines (all ChAd/BNT). The geometric mean titer for the ChAd/BNT group was 3.2-fold higher than that of the AdV-Vec group (geometric mean ratio, 3.2; confidence interval, 1.9-5.4) but lower than that of the mRNA group (geometric mean ratio, 0.4; confidence interval, 0.2-0.7). Neutralization inhibition in the ChAd/BNT group was 32%, which was higher than that in the AdV-Vec group (21%; P < 0.001) but lower than that in the mRNA group (55%; P = 0.02). There was no difference in geometric mean titer by V2 timing (ChAd/BNT, 45 versus 31, days 14–60; mRNA, 28 versus 15, days 61–150).

Conclusions.

The ChAd/BNT group showed higher humoral immunogenicity than the AdV-Vec group, with similar immunogenicity to the mRNA vaccine. Nevertheless, immunogenicity following the primary vaccination series was poor in all vaccine groups, supporting the justification for booster vaccination in SOTRs.
Clinical features of UK Biobank subjects carrying protein-truncating variants in genes implicated in schizophrenia pathogenesis
Authors: Curtis David
Published: June 2022

Objective

The SCHEMA consortium has identified 10 genes in which protein-truncating variants (PTVs) confer a substantial risk of schizophrenia. This study aimed to determine whether carrying these PTVs was associated with neuropsychiatric impairment in the general population.

Methods

Phenotype fields of exome-sequenced participants in the UK Biobank who carried PTVs in these genes were studied to determine to what extent they demonstrated features of schizophrenia or had neuropsychiatric impairment.

Results

Following automated quality control and visual inspection of reads, 251 subjects were identified as having well-supported PTVs in one of these genes. The frequency of PTVs in CACNA1G was higher than that had been observed in SCHEMA cases, casting doubt on its role in schizophrenia pathogenesis, but otherwise rates were similar to those observed in SCHEMA controls. Numbers were too small to allow formal statistical analysis but in general carriers of PTVs did not appear to have high rates of psychiatric illness or reduced educational or occupational functioning. One subject with a PTV in SETD1A had a diagnosis of schizophrenia, one with a PTV in HERC1 had psychotic depression and two subjects seemed to have developmental disorders, one with a PTV in GRIN2A and one with a PTV in RBCC1. There seemed to be somewhat increased rates of affective disorders among carriers of PTVs in HERC1 and RB1CC1.

Conclusion

Carriers of PTVs did not appear to have subclinical manifestations of schizophrenia. Although PTVs in these genes can substantially increase schizophrenia risk, their effect seems to be dichotomous and most carriers appear psychiatrically well. This research has been conducted using the UK Biobank Resource.
Thermomonas flagellata sp. nov. and Thermomonas alba sp. nov., two novel members of the phylum Pseudomonadota isolated from hot spring sediments
Authors: Liu Ze-Tao , Dai Jun-Yi , Lian Zheng-Han , Liu Lan , Xian Wen-Dong , Li Meng-Meng , Fang Bao-Zhu , Jiao Jian-Yu , Li Wen-Jun
Published: June 2022

Two novel species, designated strains SYSU G04041T and SYSU G04536T, were isolated from hot spring sediments collected in Yunnan, PR China. Phenotypic and chemotaxonomic analyses, and whole-genome sequencing were used to determine the taxonomic positions of the candidate strains. Phylogenetic analysis using 16S rRNA gene sequence indicated that strain SYSU G04041T showed the highest sequence similarity to

Thermomonas haemolytica

A50-7-3T (97.5 %), and SYSU G04536T showed the highest sequence similarity to

Thermomonas hydrothermalis

SGM-6T (98.2 %). The strains could be differentiated from other species of the genus

Thermomonas

by their distinct phenotypic and genotypic characteristics. Cells of strains SYSU G04041T and SYSU G04536T were aerobic, motile and Gram-stain-negative. Growth both occurred optimally at 45 °C and pH 7.0 for SYSU G04041T and SYSU G04536T. In addition, the predominant respiratory quinone in both isolates was ubiquinone Q-8. The major fatty acids (>10 %) of strain SYSU G04041T were C16 : 0, iso-C15 : 0 and iso-C16 : 0, while the major fatty acids (>10 %) of strain SYSU G04536T were iso-C15 : 0 and iso-C16 : 0. The main detected polar lipids in strains SYSU G04041T and SYSU G04536T included phosphatidylethanolamine, diphosphatidylglycerol and phosphatidylglycerol. The G+C contents of the genomic DNA of strains SYSU G04041T and SYSU G04536T based on draft genomic sequences were 72.5 and 68.3 %, respectively. On the basis of phenotypic, genotypic and phylogenetic data, strains SYSU G04041T and SYSU G04536T represent two novel species of the genus

Thermomonas

, for which the names Thermomonas flagellata sp. nov. and Thermomonas alba sp. nov. are proposed, with the type strains SYSU G04041T (=CGMCC 1.19366T=KCTC 92228T) and SYSU G04536T (=CGMCC 1.19367T=KCTC 82839T), respectively.
DEVELOPMENT OF A COMPLEX INTERVENTION PACKAGE FOR DENGUE PREVENTION
Authors: Rajapaksha R. M. Nayani Umesha , Abeysena Chrishantha , Balasuriya Aindralal , Hetti Nimalka Pannila , Alagiyawanna Ajith , Manilgama Suranga
Published: June 2022

Introduction

Complex interventions are widely used in public health practices. Communication for Behavioural Impact (COMBI) is an effective method in planning for dengue control. The aim was to develop an intervention package to change behaviour to prevent dengue in a dengue endemic area of Sri Lanka.

Methods

Development of the intervention package was formulated according to two-phases including ‘Theoretical phase’ and ‘Modelling phase’ using a framework. World Health Organization 10 key steps in planning COMBI were followed in order to develop the present intervention package. A Situational-Market-Analysis-for-Communication-Keys (SMACK) was conducted in highest dengue endemic area in Kurunegala district to identify the Specific Behavioural Objectives (SBOO), which was conducted using mixed methodological approach followed by other steps of COMBI planning.

Results

The overall goal was to decrease morbidity and mortality due to dengue illness. The SBOO for the plan were to improve the proper waste management practices according to the ‘3R concept’ (Reduce-Reuse-Re-cycling) and to improve the dengue prevention practices by 30 minutes of weekly cleaning. The strategies were to conduct a community empowerment program to improve waste management and weekly practices on dengue prevention by conducting administrative mobilization and public-relationship, public-advocacy, community mobilization, personal selling, advertising, and point of service promotion. The plan was finalized after taking expert opinion with the participation of stakeholders by the management team.

Conclusion

Developing a COMBI plan for an area after the identification of SBOO would be feasible to implement in order to empower the community to prevent dengue and improve community health services.
Analysis of Whole-Genome Sequencing of SARS-CoV-2 Reveals Recurrent Mutations among Iranian Patients
Authors: Abbasian Mohammad Hadi , Mahdavi Bahar , Mahmanzar Mohammadamin , Tokhanbigli Samaneh , Mollapour Sisakht Mahsa , Moradi Bahman , Rahimian Karim
Published: June 2022

The authors have withdrawn their manuscript, which means that the paper will no longer be published. This decision was made because the authors used new approaches in analyzing a different sample size, which could result in different findings when compared to the previous version. The authors believe that the new data could be controversial, and therefore, they do not wish for their work to be cited as a reference for any project. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Persistent inflammation promotes endocannabinoid release and presynaptic cannabinoid 1 receptor desensitization
Authors: Bouchet Courtney A. , Janowsky Aaron , Ingram Susan L.
Published: June 2022

Pain therapies targeting the cannabinoid system are increasing with expansion of cannabis legalization but adaptations in the endogenous cannabinoid system during inflammatory pain could limit their efficacy. Presynaptic inhibition of GABA release mediated by cannabinoid 1 receptor (CB1R) agonists in the ventrolateral periaqueductal gray (vlPAG) is markedly reduced in male and female Sprague Dawley rats after persistent inflammation induced by Complete Freund’s Adjuvant (CFA). Inflammation results in increased endocannabinoid (eCB) synthesis and desensitization of presynaptic CB1Rs that is reversed by a GRK2/3 inhibitor, Compound 101. Despite CB1R desensitization, eCB activation of CB1Rs is maintained after inflammation. Depolarization-induced suppression of inhibition (DSI) in naïve animals is rapid and transient, but is prolonged in recordings after inflammation. Prolonged DSI is mediated by 2-arachidonoylglycerol (2-AG) indicating reduced monoacylglycerol lipase (MAGL) activity. These adaptations within the endogenous cannabinoid system have important implications for the development of future pain therapies targeting CB1Rs or MAGL.
SARS-CoV-2 breakthrough infection during the Delta-dominant epidemic and neutralizing antibodies against Omicron in comparison with the third dose of BNT162b2: a matched analysis
Authors: Yamamoto Shohei , Matsuda Kouki , Maeda Kenji , Oshiro Yusuke , Inamura Natsumi , Mizoue Tetsuya , Konishi Maki , Takeuchi Junko S. , Horii Kumi , Ozeki Mitsuru , Sugiyama Haruhito , Mitsuya Hiroaki , Sugiura Wataru , Ohmagari Norio
Published: June 2022

Background

Longitudinal data are lacking to compare booster effects of Delta breakthrough infection versus the third vaccine dose on neutralizing antibodies (NAb) against Omicron.

Methods

Participants were the staff of a national research and medical institution in Tokyo who attended serological surveys on June 2021 (baseline) and December 2021 (follow-up); in between, the Delta-dominant epidemic occurred. Of 844 participants who were infection-naïve and had received two doses of BNT162b2 at baseline, we identified 11 breakthrough infections during the follow-up. One control matched to each case was randomly selected from those who completed the booster vaccine and those who were unboosted by the follow-up. We used the generalized estimating equation model to compare live-virus NAb against Wuhan, Delta, and Omicron across groups.

Results

Persons who experienced breakthrough infection showed marked increases in NAb titers against Wuhan (4.1-fold) and Delta (5.5-fold), and 64% had detectable NAb against Omicron at follow-up, although the NAb against Omicron after breakthrough infection was 6.7- and 5.2-fold lower than that against Wuhan and Delta, respectively. The increase was apparent only in symptomatic cases and as high as in the third vaccine recipients. In contrast, these titers largely decreased (Wuhan, Delta) or remained undetected (Omicron) at follow-up in infection-naïve and unboosted persons.

Conclusions

Symptomatic breakthrough infection during the Delta predominant wave was associated with significant increases in NAb against Wuhan, Delta, and Omicron, similar to the third BNT162b2 vaccine. Given the much lower cross-NAb against Omicron than other virus types, however, infection prevention measures must be continued irrespective of vaccine and infection history while the immune evasive variants are circulating.

Key points

Symptomatic, not asymptomatic, SARS-CoV-2 breakthrough infection after the second BNT162b2 vaccination during the Delta-predominant wave enhanced neutralizing antibodies against Wuhan, Delta, and Omicron comparable to the three vaccine doses, although immunity against Omicron was much lower than Wuhan and Delta.
De Novo, Post-Zygotic, Inter-Tissue Mosaicism of Cell Autonomous ADNP Mutations in Autistic Individuals: Restricted Environmental Contribution
Authors: Mohiuddin Mohiuddin , Marusic Zlatko , Anicic Mirna , Anke Van Dijck , Cappuyns Elisa , Ludovico Rizzuti , Vitriolo Alessandro , Kleiman Gal Hacohen , Grigg Iris , Testa Giuseppe , Gozes Illana , Kooy R. Frank , Pearson Christopher E.
Published: June 2022

Many neurodevelopmental disorders, including autism, are caused by de novo mutations, that might arise as early as in the parental germline, during embryonic, fetal development, or as late as post-natal aging. Intra-tissue mutation-load variations could impact clinical presentation. One of the most common causes of autism is de novo mutations in ADNP. We developed an ultra-sensitive, highly-quantitative droplet digital PCR assay to determine ADNP mutation levels in patient tissues, including blood, teeth, hair, and 24 different tissues from a post-mortem de novo ADNP-mutated child (∼6-years old), including a transplanted liver from a non-mutant donor (retained for 22 months). Striking variations of ADNP mosaicism arose between tissues of the same individual. Mutation load differences were evident between post-mortem tissues, but not in the transplanted liver — supporting a cell autonomous genetic vulnerability to de novo mutations, arguing against a transferable environmentally-sensitive DNA damage/mutation predisposition. Variations between tissues suggest a developmental timing of the mutations. Most individuals showed at least one tissue with less than heterozygous mutations, where the presence of the homozygous non-mutant cells indicates that de novo ADNP mutations arose post-zygotically. Highly variable ADNP mosaicism between tissues, that within an individual can be less than heterozygous or approach homozygosity, indicate rapid ongoing post-zygotic, and possibly post-natal, somatic mutations, contributing to clinical variability.
Persistent Salmonella infections in humans are associated with mutations in the BarA/SirA regulatory pathway
Authors: Grote Alexandra , Piscon Bar , Manson Abigail L. , Livny Jonathan , Earl Ashlee M. , Gal-Mor Ohad
Published: June 2022

The bacterial pathogen Salmonella enterica is able to establish persistent infections, evading antibiotics and the host immune system and providing a reservoir for recrudescence and transmission to new hosts. Non-typhoidal serovars (NTS) of S. enterica can establish and maintain symptomatic and asymptomatic long term human infections that may predispose carriers to inflammatory bowel diseases and cancer. Defining the adaptations and host-pathogen interactions enabling these persistent infections is key to devising more effective strategies to combat and prevent persistent bacterial infections. Using comparative genomics of 639 Salmonella NTS isolates belonging to 49 serovars that were longitudinally obtained from 256 salmonelosis patients during different stages of infection, we identified numerous genetic variations accruing over time in strains isolated from the same patient. Many of these changes were found in the same gene across multiple patients and serovars. Among these variant loci, genes encoding global transcriptional regulators were found to be the most commonly mutated between early and late same-patient isolates. Genetic changes in the SirA/BarA two-component regulatory system were particularly frequent, with mutations identified in 24 independent patients. Comparative RNA-Seq analysis revealed that distinct mutations in sirA/barA that arose independently in late isolates of multiple patients lead to significantly diminished expression of virulence-associated genes encoded in the Salmonella Pathogenicity Islands (SPIs) 1 and 4, many of which are known to be critical for host cell invasion and the production of enteritis. Using the salmonellosis mouse model we showed that these mutations in sirA/barA genes confer attenuated virulence in-vivo. Taken together, these data suggest that selection of mutations in the SirA/BarA pathway facilitates persistent Salmonella infection in humans, possibly by attenuating Salmonella virulence and its ability to cause inflammation.
Molecular atlas reveals the tri-sectional spinning mechanism of spider dragline silk
Authors: Hu Wenbo , Jia Anqiang , Ma Sanyuan , Zhang Guoqing , Wei Zhaoyuan , Lu Fang , Luo Yongjiang , Zhang Zhisheng , Sun Jiahe , Yang Tianfang , Xia TingTing , Li Qinhui , Yao Ting , Zheng Jiangyu , Jiang Zijie , Xia Qingyou , Wang Yi
Published: June 2022

We performed the first molecular atlas of natural spider dragline silk production using genome assembly for the golden orb-web spider Trichonephila clavata and multiomics defining for the segmented major ampullate (Ma) gland: Tail, Sac, and Duct. We uncovered a hierarchical biosynthesis of spidroins, organic acids, lipids, and chitin in the sectionalized Ma gland dedicated to fine silk constitution. The ordered secretion of spidroins was achieved by the synergetic regulation of epigenetic and ceRNA signatures for genomic group-distributed spidroin genes. Single-cellular and spatial RNA profiling identified ten cell types with partitioned functional division determining the tri-sectional organization of the Ma gland. Convergent evolution and genetic manipulation analyses further validated that this tri-sectional architecture of the silk gland was analogous in silk-spinning animals and inextricably linked with silk formation. Our study provided multiple levels of data that significantly expand the knowledge of spider dragline silk generation and may eventually benefit spider-inspired fiber innovations.
Nuclear auxin signaling is essential for organogenesis but not for cell survival in the liverwort Marchantia polymorpha
Authors: Suzuki Hidemasa , Kato Hirotaka , Iwano Megumi , Nishihama Ryuichi , Kohchi Takayuki
Published: June 2022

Auxin plays pleiotropic roles in plant development via gene regulation upon perception by the receptors TRANSPORT INHIBITOR RESPONSE 1/AUXIN SIGNALING F-BOX (TIR1/AFBs). This nuclear auxin signaling (NAS) originated in the common ancestor of land plants. Although complete loss of TIR1/AFBs causes embryonic lethality in Arabidopsis thaliana, it is unclear whether the requirement for TIR1-mediated auxin perception in cell viability can be generalized. The model liverwort Marchanita polymorpha has a minimal NAS system with only a single TIR1/AFB, MpTIR1. Here we show by genetic, biochemical, and transcriptomic analyses that MpTIR1 functions as an evolutionarily conserved auxin receptor. Null mutants and conditionally knocked-out mutants of MpTIR1 were viable but incapable of forming any organs and grew as cell masses. Principal component analysis performed using transcriptomes at various developmental stages indicated that MpTIR1 is involved in the developmental transition from spores to organized thalli, during which apical notches containing stem cells are established. In Mptir1 cells, stem-cell- and differentiation-related genes were up- and down-regulated, respectively. Our findings suggest that, in M. polymorpha, NAS is dispensable for cell division but essential for three-dimensional body plans by establishing pluripotent stem cells for organogenesis, a derived trait of land plants.
High-resolution cross-species transcriptomic atlas of dorsal root ganglia reveals species-specific programs for sensory function
Authors: Jung Min , Dourado Michelle , Maksymetz James , Jacobson Amanda , Baca Miriam , Foreman Oded , Hackos David H. , Riol-Blanco Lorena , Kaminker Joshua S.
Published: June 2022

Sensory neurons of the dorsal root ganglion (DRG) play a crucial role in maintaining tissue homeostasis by sensing and initiating responses to stimuli. While most preclinical studies of DRGs are conducted in rodents, much less is known about the mechanisms of sensory perception in primates. We generated a transcriptome atlas of mouse, guinea pig, cynomolgus monkey, and human DRGs using a framework that implements a common laboratory workflow and multiple data-integration approaches to generate high-resolution cross-species mappings of sensory neuron subtypes. Using our atlas, we identified conserved core modules highlighting subtype-specific biological processes related to inflammatory response. We also identified divergent expression of key genes involved in DRG function, suggesting species-specific adaptations. Among these, we validated that Tafa4, a member of the druggable genome, was expressed in distinct populations of DRG neurons across species, highlighting species-specific programs that are critical for therapeutic development.
The role of M1 to M2 macrophage polarization in the etiology of idiopathic gastroparesis: GWAS perspective
Authors: Smieszek Sandra P. , Carlin Jesse L. , Xiao Changfu , Polymeropoulos Christos M. , Birznieks Gunther , Polymeropoulos Mihael H.
Published: June 2022

Gastroparesis is a serious medical condition characterized by delayed gastric emptying and symptoms of nausea, vomiting, bloating, fullness after meals, and abdominal pain. An innate immune dysregulation and injury to the interstitial cells of Cajal and other components of the enteric nervous system are likely central to the pathogenesis of gastroparesis. Thus far, little is known about the underlying genetic risk factors for gastroparesis. To ascertain these genetic risk factors for gastroparesis we conducted the first large whole-genome sequencing genome-wide association study (GWAS) analysis of gastroparesis patients.

The GWAS focused on idiopathic and diabetic gastroparesis cases as compared to matched controls as well as compared idiopathic versus diabetic cases. Amongst the top variants, we report a novel genetic risk variant for idiopathic gastroparesis - genetic association of the Solute Carrier Family 15 (SLC15) locus. This signal is driven by multiple variants with top missense variant SLC15A4:NM145648:exon2:c.T716C:p.V239A, rs33990080. SLC15A4 was shown to mediate M1-prone metabolic shifts in macrophages and guards immune cells from metabolic stress. The risk variant carriers have a significantly higher nausea score at baseline. We also delineated a number of statistically significant loci including novel ones as well as previously known loci such as HLA-DQB1 - rs9273363, variant associated with Type 1 diabetes..

The GWAS picture that is emerging implicates the role of the machinery of M1 to M2 macrophage polarization in the etiology of idiopathic gastroparesis. We suggest that macrophage polarization fate could lead to the destruction of the interstitial cells of Cajal which effectively leads to abnormal gastric emptying.
Mouse genomic rewriting and tailoring: synthetic Trp53 and humanized ACE2
Authors: Zhang Weimin , Golynker Ilona , Brosh Ran , Wudzinska Aleksandra M. , Zhu Yinan , Carrau Lucia , Damani-Yokota Payal , Khairallah Camille , Chalhoub Noor , Huang Emily , Ashe Hannah , Khanna Kamal M. , Maurano Matthew T. , Kim Sang Yong , tenOever Benjamin R. , Boeke Jef D.
Published: June 2022

Genetically Engineered Mouse Models (GEMMs) aid in understanding human pathologies and developing new therapeutics, yet recapitulating human diseases authentically in mice is challenging to design and execute. Advances in genomics have highlighted the importance of non-coding regulatory genome sequences controlling spatiotemporal gene expression patterns and splicing to human diseases. It is thus apparent that including regulatory genomic regions during the engineering of GEMMs is highly preferable for disease modeling, with the prerequisite of large-scale genome engineering ability. Existing genome engineering methods have limits on the size and efficiency of DNA delivery, hampering routine creation of highly informative GEMMs. Here, we describe mSwAP-In (mammalian Switching Antibiotic resistance markers Progressively for Integration), a method for efficient genome rewriting in mouse embryonic stem cells. We first demonstrated the use of mSwAP-In for iterative genome rewriting of up to 115 kb of the Trp53 locus, as well as for genomic humanization of up to 180 kb ACE2 locus in response to the COVID-19 pandemic. Second, we showed the hACE2 GEMM authentically recapitulated human ACE2 expression patterns and splicing, and importantly, presented milder symptoms without mortality when challenged with SARS-CoV-2 compared to the K18-ACE2 model, thus representing a more authentic model of infection.
Single-base precision design of CRISPR-Cas13b enables systematic silencing of oncogenic fusions
Authors: Hu Wenxin , Kumar Amit , Qi Shijiao , Sadras Teresa , Casan Joshua ML , Ma David , Brown Lauren M , Haber Michelle , Voskoboinik Ilia , Trapani Joseph A , Ekert Paul G , Fareh Mohamed
Published: June 2022

Precision oncology programs can rapidly identify oncogenic gene fusions in individual patients1–3. However, despite their established oncogenic status, the vast majority of gene fusions remain ‘undruggable’ due to the lack of specific inhibitory molecules4, 5. Here, we establish PspCas13b, a poorly characterized programmable RNA nuclease, as a versatile tool to silence various oncogenic fusion transcripts. Our Single-Base Tiled crRNA screens (SiBTil), unbiased computational analysis, and comprehensive spacer-target mutagenesis revealed key determinants of PspCas13b activity. De novo design of crRNAs harbouring basepaired or mismatched guanosine bases at key spacer positions greatly enhances the silencing efficacy of otherwise inefficient crRNAs, expanding the targeting spectrum of this enzyme. We also reveal the interface between mismatch tolerance and intolerance, which unlocks an unexpected single-base precision targeting capability of this RNA nuclease. Notably, our de novo design principles enable potent and selective silencing of various gene fusion transcripts and their downstream oncogenic networks, without off-targeting of non-translocated variants that share extensive sequence homology. We demonstrate that PspCas13b targeting the breakpoint of fusion transcripts enables efficient suppression of ancestral and single-nucleotide mutants (e.g. BCR-ABL1 T315I) that often drive clinical cancer relapse. Collectively, this study provides new design principles for PspCas13b programming to specifically recognise and degrade any ‘undruggable’ fusion oncogenic transcript, thus providing a new conceptual framework for personalized oncology.
Controlling stomatal aperture, a potential strategy for managing plant bacterial disease
Authors: Sakata Nanami , Ino Taiki , Hayashi Chinatsu , Ishiga Takako , Ishiga Yasuhiro
Published: June 2022

Bacterial blight of crucifers caused by Pseudomonas cannabina pv. alisalensis (Pcal) inflicts great damage on crucifer production. To explore efficient and sustainable strategies for Pcal disease control, we here investigated and screened for amino acids with reduced disease development. We found that exogenous foliar application with multiple amino acids reduced disease symptoms and bacterial populations in cabbage after spray-inoculation, but not syringe-inoculation. These results indicate that these amino acids showed a protective effect before Pcal entered plants. Therefore, we observed stomatal responses, which is a main gateway for Pcal entry into the apoplast, after amino acid treatments, and found several amino acids induce stomatal closure. Moreover, our findings demonstrated that reducing stomatal aperture width can limit bacterial entry into plants, leading to reduced disease symptoms. Therefore, managing stomatal aperture can be a new powerful strategy for controlling bacterial disease.
Ralstonia solanacearumalters root developmental programs in auxin-dependent and independent manners
Authors: Zhang Lu , Yu Gang , Xue Hao , Li Meng , Lozano-Durán Rosa , Macho Alberto P.
Published: June 2022

Microbial pathogens and other parasites can modify the development of their hosts, either as a target or a side effect of their virulence activities. The plant pathogenic bacteriumRalstonia solanacearum, causal agent of the devastating bacterial wilt disease, is a soil-borne microbe that invades host plants through their roots, and later proliferates in xylem vessels. In this work, we studied the early stages ofR. solanacearuminfection in the model plantArabidopsis thaliana, using anin vitroinfection system. In addition to the previously reported inhibition of primary root length and increase in root hair formation at the root tip, we observed an earlier xylem differentiation duringR. solanacearuminfection that occurs in a HrpG-dependent manner, suggesting that the pathogen actively promotes the development of the vascular system upon invasion of the root. Moreover, we found that the phytohormone auxin, of which the accumulation is promoted by the bacterial infection, is required for theR. solanacearum-triggered induction of root hair formation, but not earlier xylem differentiation. Altogether, our results shed light on the capacity ofR. solanacearumto induce alterations of root developmental pathways and on the role of auxin in this process.
Using a Whole Genome Co-expression Network to Inform the Functional Characterisation of Predicted Genomic Elements fromMycobacterium tuberculosisTranscriptomic Data
Authors: Stiens Jennifer , Tan Yen Yi , Joyce Rosanna , Arnvig Kristine B. , Kendall Sharon L. , Nobeli Irene
Published: June 2022

A whole genome co-expression network was created usingMycobacterium tuberculosistranscriptomic data from publicly available RNA-sequencing experiments covering a wide variety of experimental conditions. The network includes expressed regions with no formal annotation, including putative short RNAs and untranslated regions of expressed transcripts, along with the protein-coding genes. These unannotated expressed transcripts were among the best-connected members of the module sub-networks, making up more than half of the ‘hub’ elements in modules that include protein-coding genes known to be part of regulatory systems involved in stress response and host adaptation. This dataset provides a valuable resource for investigating the role of non-coding RNA, and conserved hypothetical proteins, in transcriptomic remodelling. Based on their connections to genes with known functional groupings and correlations with replicated host conditions, predicted expressed transcripts can be screened as suitable candidates for further experimental validation.