bluuebunny/crossref_metadata_2025 huggingface dataset:
The Natural History of Observed SDHx-Related Head and Neck Paragangliomas Using Three-Dimensional Volumetric Tumor Analysis
Authors: Tooker Evan L. , Wiggins Richard H. , Espahbodi Mana , Naumer Anne , Buchmann Luke O. , Greenberg Samantha E. , Patel Neil S.
Published: August 2023

Objective

Characterize the natural history and clinical behavior of head and neck paragangliomas (HNPGLs) in subjects with succinate dehydrogenase (SDHx) pathogenic variants using volumetric tumor measurements.

Study Design

Cohort study.

Setting

Tertiary academic referral center.

Patients

Subjects with SDHx HNPGLs under observation for at least 6 months with 2 or more magnetic resonance imaging or computed tomography scans.

Intervention(s)

Diagnostic interventions include next-generation sequencing, magnetic resonance imaging, and computed tomography. Therapeutic interventions include microsurgical resection or stereotactic radiosurgery.

Main Outcome Measure(s)

Radiographic progression was defined as a 20% or greater increase in volume. Cranial nerve (CN) functional outcomes were assessed using clinical documentation.

Results

A total of 19 subjects with 32 tumors met the inclusion criteria. Median radiographic follow-up was 2.2 years, and the median volumetric growth rate was 0.47 cm3/yr. Kaplan-Meier estimated rates of survival free of radiographic progression for all SDHx tumors at 1, 2, and 3 years were 69, 50, and 22%, respectively. No tumors developed new CN palsies during the period of observation.

Conclusions

Over intermediate-term follow-up, observation of treatment-naive SDHx-related HNPGLs did not result in new cranial neuropathy. Although indefinite observation is only appropriate for select cases, these data support an interval of observation to characterize growth rate in asymptomatic to minimally symptomatic patients, who are at high risk of treatment-related morbidity. Given the early age at diagnosis and high risk of bilateral multifocal phenotypes in SDHx HNPGL mutation carriers, these data may aid in optimizing patient tumor control and CN functional preservation. Further studies are necessary to determine whether pretreatment growth rate is correlated with clinical outcomes.
Influence of Visual Feedback on Roll Tilt Perceptual Training
Authors: Wagner Andrew R. , Merfeld Daniel M.
Published: August 2023

Hypothesis

We hypothesized that the addition of visual feedback during roll tilt perceptual training would yield a significant reduction in vestibular perceptual thresholds relative to a control group.

Background

We previously showed that roll tilt vestibular thresholds could be improved through a perceptual training protocol that used a simple auditory cue. Variability in training outcomes within the treatment group suggested that an auditory cue alone may be suboptimal for improving self-motion perception.

Methods

In 10 healthy adults, roll tilt vestibular thresholds, quantifying the smallest motion that can be reliably perceived, were measured before (“pretraining”) and after (“posttraining”) a training protocol designed to improve roll tilt perception. The protocol included 1,300 trials of 0.5 Hz whole-body roll tilt over 5 days, with participants being given both an auditory cue (“correct’ vs. “incorrect’) and visual feedback (viewing a stationary visual scene) after indicating their perceived direction of tilt. A control group (N = 10) underwent only the “pretraining” and “posttraining” assessments.

Results

The training group showed an average decrease in roll tilt vestibular thresholds of 1.7% ± 56%, with training outcomes varying widely. Three individuals showed an average increase in roll tilt thresholds of 69.7%, whereas the remaining seven adults showed an average decrease in thresholds of 32.3%.

Conclusion

These data show that visual feedback during roll tilt perceptual training leads to heterogenous outcomes, but in a subset of individuals, it may lead to improvements in perceptual precision. Additional work is needed to define the optimal training parameters, including feedback schema, before investigating potential clinical applications.
Realist Approach to Qualitative Data Analysis
Authors: Putri Arcellia Farosyah , Chandler Colin , Tocher Jennifer
Published: August 2023

Background

A realist approach has gained popularity in evaluation research, particularly in understanding causal explanations of how a program works (or not), the circumstances, and the observed outcomes. In qualitative inquiry, the approach has contributed to better theoretically based explanations regarding causal interactions.

Objective

The aim of this study was to discuss how we conducted a realist-informed data analysis to explore the causal interactions within qualitative data.

Methods

We demonstrated a four-step realist approach of retroductive theorizing in qualitative data analysis using a concrete example from our empirical research rooted in the critical realism philosophical stance. These steps include (a) category identification, (b) elaboration of context-mechanism-outcome configuration, (c) demi-regularities identification, and (d) generative mechanism refinement.

Results

The four-step qualitative realist data analysis underpins the causal interactions of important factors and reveals the underlying mechanisms. The steps produce comprehensive causal explanations that can be used by related parties—especially when making complex decisions that may affect wide communities.

Discussion

The core process of realist data analysis is retroductive theorizing. The four-step qualitative realist data analysis facilitates this theorizing by allowing the researcher to identify (a) patterns, (b) fluctuation of patterns, (c) mechanisms from collected data, and (d) to confirm proposed mechanisms.
Do Saliva-Saturated Spit Hoods Interfere With Ventilation?
Authors: Kroll Mark W. , Hail Stacey L. , Brave Michael A.
Published: August 2023

Spit hoods are used by law enforcement, officers in correctional facilities, and medical personnel during the restraint of agitated subjects that are actively spitting to prevent the transmission of droplet-transmitted pathogens. We could find no studies reporting on the time course of normal breathing to clear saliva from such a saturated spit hood. We purchased samples of 3 popular spit hood models and applied a section over the output of a pneumatic test system. We used a digital anemometer, digital manometer, and an inline controllable fan for back pressure and flow. The pressure was 3 mm Hg to match quiet breathing. The tested area was saturated with artificial saliva, and air pressure was applied while we recorded the pressure and airflow. Within 5 seconds, the spit hoods all cleared sufficient artificial saliva to allow 1 m/s of airflow, which exceeds that of an N95 mask with similar pressure. Commonly used spit hoods offer very low resistance to breathing even after being initially saturated with artificial saliva. Our results do not support the hypothesis that a saliva-filled spit hood might contribute to death.
Clinical Importance of the Lateral Tarsal Strip Procedure by a Single Experienced Oculoplastic Surgeon: 8 Years of Experience in a Tertiary Medical Center (Cross-Sectional Study)
Authors: Lee Hyunkyu , Shin Hyemi , Kim Jonghyun , Baek Sehyun
Published: August 2023

Lateral tarsal strip (LTS) is a simple surgical technique that can correct eyelid malposition. Clinical indications vary from involutional entropion and ectropion, lower eyelid laxity, and lower eyelid retraction to punctal and paralytic ectropion. Lateral tarsal strip mainly treats eyelid malposition by correcting horizontal laxity. Herein, the authors report the clinical indications for and effects of LTS. The authors retrospectively reviewed medical records of patients who underwent LTS by a single oculoplastic surgeon with 8 years of experience performing the procedure at Korea University Guro Hospital. The authors included 247 patients with 325 treated eyelids. Involutional entropion was the most common indication, accounting for 69 patients (27.94%) and 88 eyelids (27.08%). The second most common indication was lower eyelid laxity [n=44 patients (17.81%) and 68 eyelids (20.92%)]. Simultaneous surgery in addition to LTS was performed in 167 patients (67.6%) and 219 eyelids (67.4%); the most common was endoscopic dacryocystorhinostomy (DCR), which was performed in 50 patients (29.94%) and 80 eyelids (36.53%). Lateral tarsal strip can be performed alone or simultaneously with oculoplastic procedures for various indications. Overcorrection with fixation above the canthal angle is useful to reduce recurrence. This study aims to explain the clinical importance of the LTS procedure.
A Narrative Review of Eye-Tracking (ET) Assessment of Esthetic Endpoints in Plastic, Reconstructive, and Craniofacial Surgery
Authors: Atiyeh Bishara , Emsieh Saif , Hakim Christopher , Chalhoub Rawad , Habal Mutaz
Published: August 2023

Reporting of esthetic outcomes in plastic surgery relies classically on ill-defined endpoints and subjective measures very often from the patients’ and/or providers’ perspectives that are notoriously characterized by subjectivity and questionable solid scientific validation. With the recent trend of increasing demand for all types of esthetic medical and surgical interventions, there is an urgent need for reliable and objective outcome measures to quantitate esthetic outcomes and determine the efficacy of these interventions. The current review is intended to analyze available evidence regarding advantages as well as limitations of eye-tracking (ET) technology in objectively documenting esthetic outcomes of plastic, reconstructive, and craniofacial interventions. Although gaze pattern analysis is gaining more attention, ET data should be interpreted with caution; how a specific visual stimulus directly influences one’s sense of esthetics is still not clear. Furthermore, despite its great potentials, it is still too early to confirm or deny ET usefulness. Nevertheless, patient-reported outcomes being most indicative of an esthetic intervention success, measurement of patients’ satisfaction by ET technology could offer a major breakthrough in objective assessment of esthetic outcomes that need further in-depth investigation.

Evidence level:

Level III.
Profiles of bacterial communities and environmental factors associated with proliferation of malaria vector mosquitoes within the Kenyan Coast
Authors: Mutinda Josphat , Mwamburi Samuel Mwakisha , Oduor Kennedy Omondi , Vincent Omolo Maurice , Ntabo Regina Mongina , Gathiru James Muhunyu , Mwangangi Joseph , Nonoh James O. M.
Published: August 2023

Background. Since Anopheles mosquitoes which transmit and maintain the malaria parasite breed in the outdoor environment, there is an urgent need to manage these mosquito breeding sites. In order to elaborate more on the ecological landscape of mosquito breeding sites, the bacterial community structure and their interactions with physicochemical factors in mosquito larval habitats was characterised in Kwale County (Kenya), where malaria is endemic.

Methods. The physical characteristics and water physicochemical parameters of the habitats were determined and recorded. Water samples were also collected from the identified sites for total metagenomic DNA extraction in order to characterise the bacterial communities within the breeding sites.

Results and Discussion. Sites where mosquito larvae were found were described as positive and those without mosquito larvae as negative. Electrical conductivity, total dissolved solids, salinity and ammonia were lower in the rainy season than in the dry season, which also coincided with a high proportion of positive sites. Pseudomonadota was the most common phyla recovered in all samples followed by Bacteroidota and then Actinomycetota. The presence or absence of mosquito larvae in a potential proliferation site was not related to the bacterial community structure in the sampled sites, but was positively correlated with bacterial richness and evenness.

Conclusion. Generally, the presence of Anopheles mosquito larvae was found to be positively correlated with rainy season, bacterial richness and evenness, and negatively correlated with electrical conductivity, total dissolved solids, salinity and ammonia. The findings of this study have implications for predicting the potential of environmental water samples to become mosquito proliferation sites.
Genome-wide and constrained ordination-based analyses of EC code data support reclassification of the species of Massilia La Scola et al. 2000 into Telluria Bowman et al. 1993, Mokoshia gen. nov. and Zemynaea gen. nov.
Authors: Bowman John P.
Published: August 2023

Based on genome-wide data,

Massilia

species belonging to the clade including

Telluria mixta

LMG 11547T should be entirely transferred to the genus

Telluria

owing to the nomenclatural priority of the type species

Telluria mixta

. This results in the transfer of 35

Massilia

species to the genus

Telluria

. The presented data also supports the creation of two new genera since peripherally branching

Massilia

species are distinct from

Telluria

and other related genera. It is proposed that 13

Massilia

species are transferred to Mokoshia gen. nov. with the type species designated Mokoshia eurypsychrophila comb. nov. The species

Massilia arenosa

is proposed to belong to the genus Zemynaea gen. nov. as the type species Zemynaea arenosa comb. nov. The genome-wide analysis was well supported by canonical ordination analysis of Enzyme Commission (EC) codes annotated from genomes via pannzer2. This new approach was performed to assess the conclusions of the genome-based data and reduce possible ambiguity in the taxonomic decision making. Cross-validation of EC code data compared within canonical plots validated the reclassifications and correctly visualized the expected genus-level taxonomic relationships. The approach is complementary to genome-wide methodology and could be used for testing sequence alignment based data across genetically related genera. In addition to the proposed broader reclassifications, invalidly described species ‘Massilia antibiotica’, ‘Massilia aromaticivorans’, ‘Massilia cellulosiltytica’ and ‘

Massilia humi

’ are described as Telluria antibiotica sp. nov., Telluria aromaticivorans sp. nov., Telluria cellulosilytica sp. nov. and Pseudoduganella humi sp. nov., respectively. In addition,

Telluria chitinolytica

is reclassified as Pseudoduganella chitinolytica comb. nov. The use of combined genome-wide and annotation descriptors compared using canonical ordination clarifies the taxonomy of

Telluria

and its sibling genera and provides another way to evaluate complex taxonomic data.
AamA-mediated epigenetic control of genome-wide gene expression and phenotypic traits in Acinetobacter baumannii ATCC 17978
Authors: Yang Jihye , Son Yongjun , Kang Mingyeong , Park Woojun
Published: August 2023

Individual deletions of three genes encoding orphan DNA methyltransferases resulted in the occurrence of growth defect only in the aamA (encoding
Acinetobacter
Adenine Methylase A) mutant of

A. baumannii

strain ATCC 17978. Our single-molecule real-time sequencing-based methylome analysis revealed multiple AamA-mediated DNA methylation sites and proposed a potent census target motif (TTTRAATTYAAA). Loss of Dam led to modulation of genome-wide gene expression, and several Dam-target sites including the promoter region of the trmD operon (rpsP, rimM, trmD, and rplS) were identified through our methylome and transcriptome analyses. AamA methylation also appeared to control the expression of many genes linked to membrane functions (lolAB, lpxO), replication (dnaA) and protein synthesis (trmD operon) in the strain ATCC 17978. Interestingly, cellular resistance against several antibiotics and ethidium bromide through functions of efflux pumps diminished in the absence of the aamA gene, and the complementation of aamA gene restored the wild-type phenotypes. Other tested phenotypic traits such as outer-membrane vesicle production, biofilm formation and virulence were also affected in the aamA mutant. Collectively, our data indicated that epigenetic regulation through AamA-mediated DNA methylation of novel target sites mostly in the regulatory regions could contribute significantly to changes in multiple phenotypic traits in

A. baumannii

ATCC 17978.
Validity and reliability of inertial measurement units in active range of motion assessment in the hip joint
Authors: Stołowski Łukasz , Niedziela Maciej , Lubiatowski Przemysław , Piontek Tomasz
Published: August 2023

Measuring joint range of motion has traditionally occurred with a universal goniometer, inclinometer, or expensive laboratory systems. The popularity of the inertial measuremen unit (IMU) is growing, enabling the small even single portable device to measure the range of motion. Until now, they were not used to assess hip joint range of motion. Our study aimed to check the validity of IMU in assessing a hip range of motion and compare them to other measurement devices - universal goniometer and inclinometer. Twenty participants completed three hip movements (flexion in standing and prone internal and external rotation) on both hips. Two testers independently assessed each movement with a goniometer, digital inclinometer, and IMU at different time points. To assess the agreement of active hip ROM between devices, Intraclass Correlation Coefficient (ICC) and Bland-Altman analysis were used. Furthermore, inter-rater and intra-rater reliability were also assessed by using ICC and Bland-Altman analysis. Limits of agreement (LOA) were calculated using Bland-Altman plots. IMU showed good to excellent validity compared with the goniometer and digital inclinometer for all tested movements with ICCs ranging from 0.87-0.99 and LOAs <9°. Intra-rater reliability was good-to-excellent for all tested movements for all devices, with ICCs ranging from 0.87 to 0.99 and LOAs < 7°. Inter-rater reliability was lower and comparable for all measurement methods: moderate flexion (ICC: 0.58-0.59), LOAs <22,4 and poor for both rotations (ICC:-0.33-0.04), and LOAs < 7.8°). The present study shows that a single inertial measurement unit (RSQ Motion) could be successfully used to assess the active hip range of motion in healthy subjects with comparable to other methods accuracy.
Reply to Dages, et al. You AIn’t using it right: Artificial intelligence progress in allergy
Authors: Lawless Dylan
Published: August 2023

We present our playful yet serious response to Dages et al.’s letter on AI limitations in allergy, specifically the AI model, ChatGPT. Our lighthearted title, “You AIn’t using it right: Artificial intelligence progress in allergy,” belies our intent to show how AI tools can be used differently to yield reliable, factual information that can enhance the field of medical sciences. We demonstrate by using AI to build a computer program to download and analyse PubMed sources, summarise the content, provide supporting primary evidence, and produce figures to enlighten the reader. We believe that the correct and increasingly automated application of AI can revolutionize its use in medicine, catalyzing its evolution to deliver significant benefits. Therefore, while caution is required, we should not default to dismissing the power of these new tools.
DESIGNING, DEVELOPING AND VALIDATING A SET OF STANDARDIZED PEDIATRIC PICTOGRAMS TO SUPPORT PEDIATRIC-REPORTED GASTRODUODENAL SYMPTOMS
Authors: Humphrey Gayl , Keane Celia , Gharibans Armen , Andrews Christopher N. , Benitez Alain , Mousa Hayat , O’Grady Gregory
Published: August 2023

Objective

To develop and validate a set of static and animated pediatric gastroduodenal symptom pictograms.

Methods

There were three study phases: 1: Co-creation used experience design methods resulting in ten pediatric gastroduodenal symptom pictograms (static and animation); 2: an online survey to assess acceptability, face and content validity; and 3: a preference study. Phases 2 and 3 compared the novel paediatric pictograms with existing pictograms used with adult patients.

Results

Eight children aged 6-15 years (5 Female) participated in Phase 1, 69 children in Phase 2 (median age 13 years: IQR 9-15), and an additional 49 participants were included in Phase 3 (median age 15: IQR 12-17). Face and content validity were higher for the pediatric and animated pictogram sets compared to pre-existing adult pictograms (78% vs. 78% vs. 61%). Participants with worse gastric symptoms (lower PedsQL-GIS score) had superior comprehension of the pediatric pictograms (χ28< .001). The pediatric pictogram set was preferred by all participants over animation and adult (χ22< .001).

Conclusion

The co-creation phase resulted in the symptom concept confirmation and design of ten acceptable static and animated gastroduodenal pictograms with high face and content validity when evaluated with children aged 6 to 18. Validity was superior when children reported more problematic symptoms. Therefore, these pictograms could be used in clinical and research practice to enable standardized symptom reporting for children with gastroduodenal disorders.

Why is it important

▪

Diagnosis of gastroduodenal disorders of the gut-brain interaction (DGBI) in pediatrics is difficult as symptoms often overlap.

▪

Pediatric patients find identifying and distinguishing symptoms difficult.

▪

Validated gastroduodenal symptom pictograms have been found to help adults accurately report their symptoms and have been used effectively to standardize symptom monitoring, including continuous symptom reporting during investigations.

▪

There are no validated pediatric gastroduodenal symptom pictograms.

What we did

▪

Co-created a set of ten pediatric gastroduodenal symptom pictograms.

▪

Undertook a face and content validity study to assess the novel pictograms with 118 pediatric participants with a median PedsQL-GIS score of 86.1 (IQR 68.1-90.0).

The Outcome

▪

Designed a novel set of pictograms with face and content validity that were preferred over other sets, enabling acceptable, simple and validated pediatric patient reporting of their gastroduodenal symptoms.
Cancer and Circulatory Disease Risks for the Largest Solar Particle Events in the Space Age
Authors: Cucinotta Francis A. , Pak Sungmin
Published: August 2023

In this paper we use the NASA Space Cancer Risk (NSCR version 2022) model to predict cancer and circulatory disease risks using energy spectra representing the largest SPE’s observed in the space age. Because tissue dose-rates behind shielding for large SPE’s lead to low dose-rates (<0.2 Gy/h) we consider the integrated risk for several historical periods of high solar activity, including July-November, 1960 events and August-October 1989 events along with the February 1956 and August 1972 events. The galactic cosmic ray (GCR) contribution to risks is considered in predictions. Results for these largest historical events show risk of exposure induced death (REID) are mitigated to < 1.2% with a 95% confidence interval with passive radiation shielding of 20 g/cm2aluminum, while larger amounts would support the application of the ALARA principle. Annual GCR risks are predicted to surpass the risks from large SPEs by ∼30 g/cm2of aluminum shielding.
AI-Enhanced Integration of Genetic and Medical Imaging Data for Risk Assessment of Type 2 Diabetes
Authors: Huang Yi-Jia , Chen Chun-houh , Yang Hsin-Chou
Published: August 2023

Type 2 diabetes (T2D) is a global public health concern due to its increasing prevalence. Risk assessment and early detection of T2D are vital in improving individuals’ health, reducing the burden on health insurance, and enhancing well-being. This study leverages artificial intelligence (AI), specifically eXtreme Gradient Boosting (XGBoost), to develop predictive models for T2D based on genetic and medical imaging data. The study aims to establish a prediction model and identify high-risk subgroups for T2D within a cohort of 68,911 Taiwan Biobank (TWB) participants. The approach integrates the Polygenic Risk Score (PRS) and Multi-image Risk Score (MRS) with demographic factors and environmental exposures to assess T2D risk. The model’s performance is evaluated using the Area Under the Receiver Operating Curve (AUC). Results demonstrate that genetic information alone is insufficient for accurate T2D prediction (AUC = 0.73), whereas medical imaging data, including abdominal ultrasonography, vertebral artery ultrasonography, bone density scan, and electrocardiography, significantly improves prediction accuracy (AUC = 0.89). The best-performing model integrates genetic, medical imaging, and demographic variables (AUC = 0.94), successfully identifying subgroups at high risk of developing T2D. The study also presents an online risk assessment website for T2D. In summary, this research represents the first integration of genetic and medical imaging data for T2D risk assessment. The genetic-only model outperforms previous genetic prediction studies, and integrating genetic and medical imaging information significantly enhances prediction. By utilizing artificial intelligence to analyze genetic, medical imaging, and demographic factors, this study contributes to early detection and precision health of T2D.
Multiomic ALS signatures highlight sex differences and molecular subclusters and identify the MAPK pathway as therapeutic target
Authors: Caldi Gomes Lucas , Hänzelmann Sonja , Hausmann Fabian , Khatri Robin , Oller Sergio , Parvaz Mojan , Tzeplaeff Laura , Pasetto Laura , Gebelin Marie , Ebbing Melanie , Holzapfel Constantin , Fabrizio Columbro Stefano , Scozzari Serena , Knöferle Johanna , Cordts Isabell , Demleitner Antonia F. , Deschauer Marcus , Dufke Claudia , Sturm Marc , Zhou Qihui , Zelina Pavol , Sudria-Lopez Emma , Haack Tobias B. , Streb Sebastian , Kuzma-Kozakiewicz Magdalena , Edbauer Dieter , Pasterkamp R. Jeroen , Laczko Endre , Rehrauer Hubert , Schlapbach Ralph , Carapito Christine , Bonetto Valentina , Bonn Stefan , Lingor Paul
Published: August 2023

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease and lacks effective disease-modifying treatments. Here, we performed a multiomic analysis of the prefrontal cortex of 51 patients with sporadic ALS and 50 control subjects, as well as four transgenic mouse models of C9orf72-, SOD1-, TDP-43-, and FUS-ALS to characterize early and sex-specific disease mechanisms in ALS. Integrated analyses of transcriptomes, (phospho)proteomes, and miRNAomes revealed more pronounced changes in males. We identified transcriptome-based human ALS subclusters driven by the immune response, ECM, mitochondrial respiration, and RNA metabolism. The molecular signatures of human subclusters were reflected in specific mouse models. Individual and integrative multiomics analysis highlighted the mitogen-activated protein kinase pathway as an early disease-relevant mechanism. Its modulation by trametinib in vitro and in vivo validated that mitogen-activated protein kinase kinase 2 is a promising therapeutic target with beneficial effects in females.
Therapeutic inhibition of monocyte recruitment prevents checkpoint inhibitor-induced hepatitis
Authors: Gudd Cathrin LC , Atkinson Stephen R , Mitchell Eoin , Mawhin Marie-Anne , Turajlic Samra , Larkin James , Thursz Mark R , Goldin Robert D , Powell Nick , Antoniades Charalambos G , Woollard Kevin J , Possamai Lucia A , Triantafyllou Evangelos
Published: August 2023

Checkpoint inhibitor-induced hepatitis (CPI-hepatitis) is an emerging problem with the widening use of CPIs in cancer immunotherapy. Here, we developed a mouse model to characterise the mechanism of CPI-hepatitis and to therapeutically target key pathways driving this pathology. C57BL/6 wild-type (WT) mice were dosed with TLR9-agonist (TLR9-L) for hepatic priming combined with anti-CTLA-4 plus anti-PD-1 (CPI) or control (PBS) for up to 7 days. Co-administration of CPIs with TLR9-L induced liver pathology closely resembling human disease, with increased infiltration and clustering of granzyme B+perforin+CD8+T cells and CCR2+monocytes, 7 days post treatment. This was accompanied by apoptotic hepatocytes surrounding these clusters and elevated cytokeratin-18 and alanine transaminase plasma levels. Liver RNA sequencing identified key signalling pathways (JAK-STAT, NF-κB) and cytokine/chemokine networks (Ifnγ, Cxcl9, Ccl2/Ccr2) as drivers of CPI-hepatitis. Using this model, we show that CD8+T cells mediate hepatocyte damage in experimental CPI-hepatitis. However, their liver recruitment, clustering, and cytotoxic activity is dependent the presence of CCR2+monocytes. Absence of hepatic monocyte recruitment in Ccr2rfp/rfpmice and CCR2 therapeutic inhibition by cenicriciroc (CVC) in WT mice prevented CPI-hepatitis. In conclusion, using this newly established mouse model, we demonstrate a central role of liver infiltrating CCR2+monocyte interaction with cytotoxic CD8+T cells in the pathogenesis of CPI-hepatitis and highlight novel therapeutic targets.
H2-O deficiency promotes regulatory T cell differentiation and CD4 T cell hyperactivity
Authors: Welsh Robin A. , Song Nianbin , Park Chan-su , Peske J. David , Sadegh-Nasseri Scheherazade
Published: August 2023

Regulatory T cells (Treg) are crucial immune modulators, yet the exact mechanism of thymic Treg development remains controversial. Here, we present the first direct evidence for H2-O, an MHC class II peptide editing molecular chaperon, on selection of thymic Tregs. We provide evidence that lack of H2-O in the thymic medulla promotes thymic Treg development and leads to an increased peripheral Treg frequency. Single-cell RNA-sequencing (scRNA-seq) analysis of splenic CD4 T cells revealed not only of an enrichment of effector-like Tregs but also of activated CD4 T cells in the absence of H2-O. Our data support two concepts; a) lack of H2-O expression in the thymic medulla creates an environment permissive to Treg development and, b) that loss of H2-O drives increased basal auto-stimulation of CD4 T cells. These findings can help in better understanding of predispositions to autoimmunity and design of therapeutics for treatment of autoimmune diseases.
Genetic evidence for serum amyloid P component as a drug target for treatment of neurodegenerative disorders
Authors: Schmidt A Floriaan , Finan Chris , Chopade Sandesh , Ellmerich Stephan , Rossor Martin N , Hingorani Aroon D , Pepys Mark B
Published: August 2023

The direct causes of neurodegeneration underlying Alzheimer’s disease (AD) and many other dementias, are not known. Here we identify serum amyloid P component (SAP), a constitutive plasma protein normally excluded from the brain, as a potential drug target. After meta-analysis of three genome-wide association studies, comprising 44,288 participants,cis-Mendelian randomization showed that genes responsible for higher plasma SAP values are significantly associated with AD, Lewy body dementia and plasma tau concentration. These genetic findings are consistent with experimental evidence of SAP neurotoxicity and the strong, independent association of neocortex SAP content with dementia at death. Depletion of SAP from the blood and from the brain, as is provided by the safe, well tolerated, experimental drug, miridesap, may therefore contribute to treatment of neurodegeneration.
Expression of FIBCD1 by intestinal epithelial cells alleviates inflammation-driven tumorigenesis in a mouse model of colorectal cancer
Authors: Shahgoli Vahid Khaze , Dubik Magdalena , Pilecki Bartosz , Skallerup Sofie , Schmidt Sandra Gaedt , Detlefsen Sönke , Sorensen Grith L. , Holmskov Uffe , Baradaran Behzad , Moeller Jesper B.
Published: August 2023

Colorectal cancer (CRC) ranks as the third most prevalent cancer worldwide, highlighting the urgent need to address its development. Inflammation plays a crucial role in augmenting the risk of CRC development and actively contributes to all stages of tumorigenesis. Consequently, targeting early inflammatory responses in the intestinal tract to restore homeostasis holds significant potential for innovative therapeutic strategies against CRC. In this study, we employ transgenic mice that mimic human expression of Fibrinogen C domain containing 1 (FIBCD1), a chitin-binding transmembrane protein primarily present on intestinal epithelial cells (IECs). Previous research has highlighted FIBCD1’s ability to effectively suppress inflammatory responses and foster tissue homeostasis at mucosal barriers. Using the azoxymethane/dextran sodium sulfate mouse model, we demonstrate that FIBCD1 substantially impacts CRC development by significantly reducing intestinal inflammation and suppressing colorectal tumorigenesis. Moreover, we identify a soluble variant of FIBCD1, which is significantly increased in fecal matter during acute inflammation. Together, these findings suggest that FIBCD1 has the potential to be a novel molecular target in the context of colitis-associated colorectal cancer and emerges as an intriguing candidate for future research.
Somatomotor-Visual Resting State Functional Connectivity Increases After Two Years in the UK Biobank Longitudinal Cohort
Authors: Orlichenko Anton , Su Kuan-Jui , Tian Qing , Shen Hui , Deng Hong-Wen , Wang Yu-Ping
Published: August 2023

Purpose

Functional magnetic resonance imaging (fMRI) and functional connectivity (FC) have been used to follow aging in both children and older adults. Robust changes have been observed in children, where high connectivity among all brain regions changes to a more modular structure with maturation. In this work, we examine changes in FC in older adults after two years of aging in the UK Biobank longitudinal cohort.

Approach

We process data using the Power264 atlas, then test whether FC changes in the 2,722-subject longitudinal cohort are statistically significant using a Bonferroni-corrected t-test. We also compare the ability of Power264 and UKB-provided, ICA-based FC to determine which of a longitudinal scan pair is older.

Results

We find a 6.8% average increase in SMT-VIS connectivity from younger to older scan (fromρ= 0.39 toρ= 0.42) that occurs in male, female, older subject (>65 years old), and younger subject (<55 years old) groups. Among all inter-network connections, this average SMT-VIS connectivity is the best predictor of relative scan age, accurately predicting which scan is older 57% of the time. Using the full FC and a training set of 2,000 subjects, one is able to predict which scan is older 82.5% of the time using either the full Power264 FC or the UKB-provided ICA-based FC.

Conclusions

We conclude that SMT-VIS connectivity increases in the longitudinal cohort, while resting state FC increases generally with age in the cross-sectional cohort. However, we consider the possibility of a change in resting state scanner task between UKB longitudinal data acquisitions.
EZH2 synergizes with BRD4-NUT to drive NUT carcinoma growth through silencing of key tumor suppressor genes
Authors: Huang Yeying , Durall R. Taylor , Luong Nhi M. , Hertzler Hans J. , Huang Julianna , Gokhale Prafulla C. , Leeper Brittaney A. , Persky Nicole S. , Root David E. , Anekal Praju V. , Montero Llopis Paula D.L.M. , David Clement N. , Kutok Jeffery L. , Raimondi Alejandra , Saluja Karan , Luo Jia , Zahnow Cynthia A. , Adane Biniam , Stegmaier Kimberly , Hawkins Catherine E. , Ponne Christopher , Le Quan , Shapiro Geoffrey I. , Lemieux Madeleine E. , Eagen Kyle P. , French Christopher A.
Published: August 2023

NUT carcinoma (NC) is an aggressive carcinoma driven by the BRD4-NUT fusion oncoprotein, which activates chromatin to promote expression of pro-growth genes. BET bromodomain inhibitors (BETi) impede BRD4-NUT’s ability to activate genes and are thus a promising treatment but limited as monotherapy. The role of gene repression in NC is unknown. Here, we demonstrate that EZH2, which silences genes through establishment of repressive chromatin, is a dependency in NC. Inhibition of EZH2 with the clinical compound tazemetostat (taz) potently blocked growth of NC cells. Epigenetic and transcriptomic analysis revealed that taz reversed the EZH2-specific H3K27me3 silencing mark, and restored expression of multiple tumor suppressor genes while having no effect on key oncogenic BRD4- NUT-regulated genes.CDKN2Awas identified as the only gene amongst all taz-derepressed genes to confer resistance to taz in a CRISPR-Cas9 screen. Combined EZH2 inhibition and BET inhibition synergized to downregulate cell proliferation genes resulting in more pronounced growth arrest and differentiation than either inhibitor alone. In pre-clinical models, combined taz and BETi synergistically blocked growth and prolonged survival of NC-xenografted mice, with all mice cured in one cohort.

STATEMENT OF SIGNIFICANCE

Identification of EZH2 as a dependency in NC substantiates the reliance of NC tumor cells on epigenetic dysregulation of functionally opposite, yet highly complementary chromatin regulatory pathways to maintain NC growth. In particular, repression of CDKN2A expression by EZH2 provides a mechanistic rationale for combining EZH2i with BETi for the clinical treatment of NC.
The Enderstruder: An accessible open-source syringe extruder compatible with Ender series 3D printers
Authors: Cordova Domenic J. , Rodriguez Angel A. , Woodward Sabrina C. , Crosby Cody O.
Published: August 2023

Bioprinting has enabled the precise spatiotemporal deposition of cells and biomaterials, opening new avenues of research in tissue engineering and regenerative medicine. Although several open-source syringe extruder adaptations for bioprinters have been published and adopted by end users, only one has been specifically adapted for the Ender series, an affordable and open-source line of thermoplastic 3D printers. Here, we introduce the Enderstruder, a cost-effective extruder attachment that uses a standard 10 mL BD syringe, positions the stepper motor at the level of the gantry, enhances x-axis stability with a linear rail, and uses the originally included stepper motor, resulting in reduced cost and simplified assembly. Furthermore, we present an iterative process to fine-tune printing profiles for high-viscosity biomaterial inks. To facilitate the implementation of our work by other researchers, we provide fully editable Cura profiles for five commonly used biomaterials. Using these five materials to validate and characterize our design, we employ the Enderstruder to print established calibration patterns and complex shapes. By presenting the Enderstruder and its iterative development process, this study contributes to the growing repository of open-source bioprinting solutions, fostering greater accessibility and affordability for researchers in tissue engineering.

Specifications table
In-depth analysis ofKlebsiella aerogenesresistome, virulome and mobilome worldwide
Authors: Morgado Sergio , Fonseca Érica , Freitas Fernanda , Caldart Raquel , Vicente Ana Carolina
Published: August 2023

Klebsiella aerogenesis an emergent pathogen associated with outbreaks of carbapenem-resistant strains. To date, studies focusing onK. aerogeneshave been small-scale and/or geographically restricted. Here, we analyzed the epidemiology, resistome, virulome, and mobilome of this species based on 561 genomes, spanning all continents. Furthermore, we sequenced four new strains from Brazil (mostly from the Amazon region). Dozens of STs occur worldwide, but the pandemic clones ST93 and ST4 have prevailed in several countries. Almost all genomes were clinical, however, most of them did not carry ESBL or carbapenemases, instead, they carried chromosomal alterations (omp36,ampD,ampG,ampR) associated with resistance to β-lactams. Integrons were also identified, presenting gene cassettes not yet reported in this species (blaIMP,blaVIM,blaGES). Considering the virulence loci, the yersiniabactin and colibactin operons were found in the ICEKp10 element, which is disseminated in genomes of several STs, as well as an incomplete salmochelin cluster. In contrast, the aerobactin hypervirulence trait was observed only in one ST432 genome. Plasmids were common, mainly from the ColRNAI replicon, with some carrying resistance genes (mcr, blaTEM,blaNDM,blaIMP,blaKPC,blaVIM) and virulence genes (EAST1,senB). Interestingly, plasmids containing the colicin gene occurred in hundreds of genomes of different STs.
Sigmoni: classification of nanopore signal with a compressed pangenome index
Authors: Shivakumar Vikram S. , Ahmed Omar Y. , Kovaka Sam , Zakeri Mohsen , Langmead Ben
Published: August 2023

Improvements in nanopore sequencing necessitate efficient classification methods, including pre-filtering and adaptive sampling algorithms that enrich for reads of interest. Signal-based approaches circumvent the computational bottleneck of basecalling. But past methods for signal-based classification do not scale efficiently to large, repetitive references like pangenomes, limiting their utility to partial references or individual genomes. We introduce Sigmoni: a rapid, multiclass classification method based on ther-index that scales to references of hundreds of Gbps. Sigmoni quantizes nanopore signal into a discrete alphabet of picoamp ranges. It performs rapid, approximate matching using matching statistics, classifying reads based on distributions of picoamp matching statistics and co-linearity statistics. Sigmoni is 10-100×faster than previous methods for adaptive sampling in host depletion experiments with improved accuracy, and can query reads against large microbial or human pangenomes.
A unified model for interpretable latent embedding of multi-sample, multi-condition single-cell data
Authors: Madrigal Ariel , Lu Tianyuan , Soto Larisa M. , Najafabadi Hamed S.
Published: August 2023

Analysis of single cells across multiple samples and/or conditions encompasses a series of interrelated tasks, which range from normalization and inter-sample harmonization to identification of cell state shifts associated with experimental conditions. Other downstream analyses are further needed to annotate cell states, extract pathway-level activity metrics, and/or nominate gene regulatory drivers of cell-to-cell variability or cell state shifts. Existing methods address these analytical requirements sequentially, lacking a cohesive framework to unify them. Moreover, these analyses are currently confined to specific modalities where the biological quantity of interest gives rise to a singular measurement. However, other modalities require joint consideration of dual measurements; for example, modeling the latent space of alternative splicing involves joint analysis of exon inclusion and exclusion reads. Here, we introduce a generative model, called GEDI, to identify latent space variations in multi-sample, multi-condition single cell datasets and attribute them to sample-level covariates. GEDI enables cross-sample cell state mapping on par with the state-of-the-art integration methods, cluster-free differential gene expression analysis along the continuum of cell states in the form of transcriptomic vector fields, and machine learning-based prediction of sample characteristics from single-cell data. By incorporating gene-level prior knowledge, it can further project pathway and regulatory network activities onto the cellular state space, enabling the computation of the gradient fields of transcription factor activities and their association with the transcriptomic vector fields of sample covariates. Finally, we demonstrate that GEDI surpasses the gene-centric approach by extending all these concepts to the study of alternative cassette exon splicing and mRNA stability landscapes in single cells.
Origin and modern microbial ecology of secondary mineral deposits in Lehman Caves, Great Basin National Park, NV, USA
Authors: Havlena Zoë E. , Hose Louise D. , DuChene Harvey R. , Baker Gretchen M. , Powell Doug , Labrado Amanda L. , Brunner Benjamin , Jones Daniel S.
Published: August 2023

Lehman Caves is an extensively decorated, high desert cave that represents one of the main tourist attractions in Great Basin National Park, Nevada. Although traditionally considered a water table cave, recent studies identified abundant speleogenetic features consistent with a hypogenic and, potentially, sulfuric acid origin. Here, we characterized white mineral deposits in the Gypsum Annex (GA) passage to determine whether these secondary deposits represent biogenic minerals formed during sulfuric acid corrosion, and explored microbial communities associated with these and other mineral deposits throughout the cave. Powder X-ray diffraction (pXRD), scanning electron microscopy with electron dispersive spectroscopy (SEM-EDS), and electron microprobe analyses (EPMA) showed that, while most white mineral deposits from the GA contain gypsum, they also contain abundant calcite, silica, and other phases. Gypsum and carbonate-associated sulfate isotopic values of these deposits are variable, with δ34SV-CDTbetween +9.7‰ and +26.1‰, and do not reflect depleted values typically associated with replacement gypsum formed during sulfuric acid speleogenesis. Petrographic observations show that the sulfates likely co-precipitated with carbonate and SiO2phases. Taken together, these data suggest that the deposits resulted from later stage meteoric events and not during an initial episode of sulfuric acid speleogenesis. Most sedimentary and mineral deposits in Lehman Caves have very low microbial biomass, with the exception of select areas along the main tour route that have been impacted by tourist traffic. High-throughput 16S rRNA gene amplicon sequencing showed that microbial communities in GA sediments are distinct from those in other parts of the cave. The microbial communities that inhabit these oligotrophic secondary mineral deposits include OTUs related to known ammonia-oxidizingNitrosococcalesand Thaumarchaeota, as well as common soil taxa such as Acidobacteriota and Proteobacteria. This study reveals microbial and mineralogical diversity in a previously understudied cave and expands our understanding of the geomicrobiology of arid, hypogene cave systems.
Tafazzin Mediates Tamoxifen Resistance by Regulating Cellular Phospholipid Composition in ER-Positive Breast Cancer
Authors: Li Xuan , Zhang Yuan , Zhang Tengjiang , Zhao Luyang , Lin Christopher G. , Hu Haitian , Zheng Hanqiu
Published: August 2023

Tamoxifen is the frontline therapeutic agent for the estrogen receptor-positive (ER+) subtype of breast cancer patients, which accounts for 70-80% of total breast cancer incidents. However, clinical resistance to tamoxifen has become increasingly common, highlighting the need to identify the underlying cellular mechanisms. In our study, we employed a genome-scale CRISPR-Cas9 loss-of-function screen and validation experiments to discover that Tafazzin (TAZ), a mitochondrial transacylase, is crucial for maintaining the cellular sensitivity of ER+ breast cancer cells to tamoxifen and other chemotherapies. Mechanistically, we found that cardiolipin, whose synthesis and maturation rely on TAZ, is required to maintain cellular resistance to tamoxifen. Loss of metabolic enzymatic activity of TAZ causes ERα downregulation and therapy resistance. Interestingly, we observed that TAZ deficiency also led to the upregulation of lysophosphatidylcholine (LPC), which in turn suppressed ERα expression and nuclear localization, thereby contributing to tamoxifen resistance. LPC is further metabolized to lysophosphatidic acid (LPA), a bioactive molecule that supports cell survival. Thus, our findings suggest that the depletion of TAZ promotes tamoxifen resistance through an LPC-LPA phospholipid synthesis axis, and targeting this lipid metabolic pathway could restore cell susceptibility to tamoxifen treatment.