bluuebunny/crossref_metadata_2025 huggingface dataset:
Vimentin-targeted radiopeptide 99mTc-HYNIC-(tricine/EDDA)-VNTANST: a promising drug for pulmonary fibrosis imaging
Authors: Rezaeianpour Maliheh , Mazidi Seyed Mohammad , Nami Reza , Geramifar Parham , Mosayebnia Mona
Published: July 2023

Objective

Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by the accumulation of extracellular matrix. Because there is no effective treatment for advanced IPF to date, its early diagnosis can be critical. Vimentin is a cytoplasmic intermediate filament that is significantly up-regulated at the surface of fibrotic foci with a crucial role in fibrotic morphological changes.

Methods

In the present study, VNTANST sequence as a known vimentin-targeting peptide was conjugated to hydrazinonicotinic acid (HYNIC) and labeled with 99mTc. The stability test in saline and human plasma and log P determination were performed. Next, the biodistribution study and single photon emission computed tomography (SPECT) integrated with computed tomography (CT) scanning were performed in healthy and bleomycin-induced fibrosis mice models.

Results

The 99mTc-HYNIC-(tricine/EDDA)-VNTANST showed a hydrophilic nature (log P = −2.20 ± 0.38) and high radiochemical purity > 97% and specific activity (336 Ci/mmol). The radiopeptide was approximately 93% and 86% intact in saline and human plasma within 6 h, respectively. The radiopeptide was substantially accumulated in the pulmonary fibrotic lesions (test vs. control = 4.08 ± 0.08% injected dose per gram (ID/g) vs. 0.36 ± 0.01% ID/g at 90 min postinjection). SPECT-CT images in fibrosis-bearing mice also indicated the fibrotic foci and kidneys.

Conclusion

Because there is no available drug for the treatment of advanced pulmonary fibrosis, early diagnosis is the only chance. The 99mTc-HYNIC-(tricine/EDDA)-VNTANST could be a potential tracer for SPECT imaging of pulmonary fibrosis.
Joint ESPGHAN/NASPGHAN Guidelines on Childhood Eosinophilic Gastrointestinal Disorders Beyond Eosinophilic Esophagitis
Authors: Papadopoulou Alexandra , Amil‐Dias Jorge , Auth Marcus Karl‐Heinz , Chehade Mirna , Collins Margaret H. , Gupta Sandeep K. , Gutiérrez‐Junquera Carolina , Orel Rok , Vieira Mario C. , Zevit Noam , Atkins Dan , Bredenoord Albert J. , Carneiro Fatima , Dellon Evan S. , Gonsalves Nirmala , Menard‐Katcher Calies , Koletzko Sibylle , Liacouras Chris , Marderfeld Luba , Oliva Salvatore , Ohtsuka Yoshikazu , Rothenberg Marc E. , Strauman Alex , Thapar Nikhil , Yang Guan‐Yu , Furuta Glenn T.
Published: July 2023

Introduction

Eosinophilic gastrointestinal disorders beyond eosinophilic esophagitis (non‐EoE EGIDs) are rare chronic inflammatory disorders of the gastrointestinal (GI) tract. Diagnosis is based on clinical symptoms and histologic findings of eosinophilic inflammation after exclusion of a secondary cause or systemic disease. Currently, no guidelines exist for the evaluation of non‐EoE EGIDs. Therefore, the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) formed a task force group to provide consensus guidelines for childhood non‐EoE EGIDs.

Methods

The working group was composed of pediatric gastroenterologists, adult gastroenterologists, allergists/immunologists, and pathologists. An extensive electronic literature search of the MEDLINE, EMBASE, and Cochrane databases was conducted up to February 2022. General methodology was used in the formulation of recommendations according to the Appraisal of Guidelines for Research and Evaluation (AGREE) II and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to meet current standards of evidence assessment.

Results

The guidelines provide information on the current concept of non‐EoE EGIDs, disease pathogenesis, epidemiology, clinical manifestations, diagnostic and disease surveillance procedures, and current treatment options. Thirty‐four statements based on available evidence and 41 recommendations based on expert opinion and best clinical practices were developed.

Conclusion

Non‐EoE EGIDs literature is limited in scope and depth, making clear recommendations difficult. These consensus‐based clinical practice guidelines are intended to assist clinicians caring for children affected by non‐EoE EGIDs and to facilitate high‐quality randomized controlled trials of various treatment modalities using standardized, uniform disease definitions.
Intergenerational Trauma, Dependency, and Detachment
Authors: Spiel Shira , Szymanski Kate , Bornstein Robert
Published: July 2023

The literature on intergenerational transmission of trauma is predominantly focused on the mental health functioning of children and grandchildren of trauma survivors. Research shows that having a traumatized parent is related to increased psychopathology and dysfunctional attachment patterns in the next generation, but little is known about the effects of parental trauma on other aspects of interpersonal relating. The current study addresses this gap. Participants were young adult students from an urban college; individual and parental trauma histories, and indices of unhealthy dependency, dysfunctional detachment, and healthy dependency, were obtained. Results indicated that a wide range of parental traumas were positively correlated with dysfunctional detachment, but not related to destructive overdependence or healthy dependency. These results suggest that a wide range of parental traumas have a negative impact on the next generation's interpersonal dependency by fostering a tendency to distance themselves from close relationships.
Affective Temperaments in Differentiation Between Melancholic and Nonmelancholic Depression: A Case-Control Study
Authors: Tamada Yu , Inoue Takeshi , Sekine Atsushi , Toda Hiroyuki , Takeshima Minoru , Sasaki Masaaki , Fujimura Yota , Ohmae Susumu
Published: July 2023

The association between major depressive disorder (MDD) and personality traits has been extensively studied. However, differences in personality traits between patients with melancholic MDD (MEL) and nonmelancholic MDD (NMEL) remain unclear. In this study, we aimed to determine whether neuroticism, which has been associated with MDD, and the five affective temperament subtypes assessed by the Temperament Evaluation of Memphis, Pisa, Paris and San Diego-autoquestionnaire version (TEMPS-A) can be used to distinguish MEL and NMEL. A total of 106 patients with MDD (MEL, n = 52; NMEL, n = 54) and 212 age- and sex-matched healthy controls answered the Eysenck Personality Questionnaire-revised and the short version of TEMPS-A. In hierarchical logistic regression analysis, only depressive temperament scores were identified as a statistically significant feature distinguishing NMEL from MEL. Depressive temperament scores assessed by the short version of TEMPS-A were found to be significantly higher in NMEL patients than in MEL patients.
Prior COVID-19 Infection Predisposes to Worse Outcomes After Autologous Breast Reconstruction
Authors: Karius Alexander K. , Chen Jonlin , Tiongco Rafael Felix P. , Lagziel Tomer , Cooney Carisa M. , Broderick Kristen P.
Published: July 2023

Background

Major shifts in health care systems worldwide have occurred because of coronavirus disease 2019 (COVID-19). With nearly half of all Americans now having a history of COVID-19 infection, there is a pressing need to better understand the importance of prior COVID-19 infection as a potential surgical risk factor. The aim of this study was to investigate the impact of a history of prior COVID-19 infection on patient outcomes after autologous breast reconstruction.

Methods

We performed a retrospective study using the TriNetX research database, which contains deidentified patient records from 58 participating international health care organizations. All patients who underwent autologous breast reconstruction between March 1, 2020, and April 9, 2022, were included and were grouped based on history of a prior COVID-19 infection. Demographic, preoperative risk factors, and 90-day postoperative complication data were compared. Data were analyzed by propensity score–matched analysis on TriNetX. Statistical analyses were performed by Fisher exact, χ2, and Mann-WhitneyUtests as appropriate. Significance was set atPvalues of <0.05.

Results

Patients with a history of autologous breast reconstruction within our temporal study window (N = 3215) were divided into groups with (n = 281) and without (n = 3603) a prior COVID-19 diagnosis. Nonmatched patients with prior COVID-19 had increased rates of select 90-day postoperative complications, including wound dehiscence, contour deformities, thrombotic events, any surgical site complications, and any complications overall. Use of anticoagulant, antimicrobial, and opioid medications was also found to be higher in those with prior COVID-19.

After performing propensity-score matching, each cohort consisted of 281 patients without statistically significant differences between any baseline characteristics. When comparing outcomes between matched cohorts, patients with a history of COVID-19 had increased rates of wound dehiscence (odds ratio [OR], 1.90;P= 0.030), thrombotic events (OR, 2.83;P= 0.0031), and any complications (OR, 1.52;P= 0.037).

Conclusions

Our results suggest that prior COVID-19 infection is a significant risk factor for adverse outcomes after autologous breast reconstruction. Patients with a history of COVID-19 have 183% higher odds of postoperative thromboembolic events, warranting careful patient selection and postoperative management.
Orbitalization of Ethmoidal Sinus With Stacked Cross-linked Acellular Dermal Matrix: A New Strategy to Reconstruct Medial Orbital Wall Fracture
Authors: Park Tae Hwan
Published: July 2023

Background:

The use of an acellular dermal matrix (ADM) has not been reported in medial orbital wall fracture reconstruction previously. This study aimed to share our early experience with the cross-linked ADM as an allograft material for medial orbital wall reconstruction.

Methods:

In this study, the author evaluated the medical records and serial facial computed tomography scans of 27 patients with pure medial orbital wall fractures reconstructed by a single surgeon between May 2021 and March 2023. The author routinely approached the medial orbital wall with a retrocaruncular incision. Five out of 27 patients were reconstructed with trimmed, multiple folded, 1.0-mm-thick cross-linked ADM (MegaDerm; L&C Bio, South Korea).

Results:

All cases reconstructed with cross-linked ADM improved clinically and radiologically without complications. The serial computed tomography findings revealed that implanted cross-linked ADM successfully covered the defect while providing a significant volumizing effect.

Conclusions:

This is the first study to show the efficacy of cross-linked ADM for orbital medial wall fracture reconstruction. Our strategy of orbitalization of ethmoidal sinus with stacked cross-linked ADM would be an excellent surgical option.
A Cone Beam Computed Tomography Analysis of Bone Volume Variations of Extra-alveolar Region Based on Sex, Age, Vertical and Sagittal Facial Patterns
Authors: Ling Chuanliang , Shen Yuqing , Zhang Xian , Ding Xiaojun
Published: July 2023

Objectives:

The goal of this study is to measure mandibular buccal shelf (MBS) concerning angulation, bone volume, and cortical bone volume as well as bone depth and cortical bone depth of infrazygomatic crest (IZC) via cone beam computed tomography and evaluate the measurements according to sex, age, vertical, and sagittal facial types.

Materials and Methods:

This study collected lateral cephalograms and cone beam computed tomography scans from 100 individuals, which were used to observe angulation, bone and cortical bone volume entailing width and depth of MBS as well as the depth of IZC. FH-MP (mandibular plane angle) and A point-Nasion-B point were adopted to determine vertical and sagittal facial patterns respectively.

Results:

Bone widths at 6 mm and 11 mm to cementoenamel junction (CEJ) and cortical bone width at 6 mm to CEJ in MBS showed significant sex differences, while bone depths and cortical bone depths in IZC show significant age difference(P<0.05). Bone width and cortical bone width at 6 mm to CEJ at the mesial root and 11 mm to CEJ at both roots as well as angulations of MBS in the mandibular first molar region, bone depth and cortical bone depth at the maxillary first molar distal buccal root, and the proximity region were all correlated to FH-MP (P<0.05).

Conclusions:

Short-faced individuals of Asian ethnicity tend to have greater bone width, greater projection in MBS, and greater bone depth in the posterior region of IZC. The optimal implant sites are 11 mm apical to CEJ at the mandibular second molar distal root and 65° at the maxillary first molar mesial root.
Management of Mid-Facial Fracture Complicated by Pseudoaneurysm of Posterior Superior Alveolar Artery
Authors: Kim So Yeon , Kang Daihun
Published: July 2023

Facial fractures, particularly mid-facial fractures, can result in various complications, such as functional and esthetic problems. Prompt reconstruction of the fractured bones is crucial for restoring normal anatomy and function and preventing complications. However, such procedures can be complex and carry the risk of potential complications. The authors report the case of a 27-year-old man who underwent open reduction and internal fixation of the left zygomatic complex fracture and reconstruction of the left inferior orbital wall. During the surgery, heavy bleeding from the posterior superior alveolar artery due to a broken bone near the pterygomaxillary region caused a prolonged surgery time and the development of a pseudoaneurysm. The pseudoaneurysm was eventually treated with superselective transcatheter embolization using 25% N-Butyl cyanoacrylate glue. This case highlights the challenges in the management of mid-facial fractures and the potential complications that can arise during surgery, particularly when dealing with the pterygomaxillary region.
Donor Safety and Risk Factors of Pure Laparoscopic Living Donor Right Hepatectomy
Authors: Kim Sang-Hoon , Kim Ki-Hun , Cho Hwui-Dong , Suh Kyung-Suk , Hong Suk Kyun , Lee Kwang-Woong , Choi Gyu-Seong , Kim Jong Man , Choon Hyuck David Kwon , Cho Jai Young , Han Ho-Seong , Han Jaryung , Han Young Seok
Published: July 2023

Background:

Pure laparoscopic donor right hepatectomy (PLDRH) is not yet a standardized surgical procedure due to lack of data.

Objective:

The aim was to identify safety and risk factors of living donor after PLRDH in a Korean multicenter cohort study.

Methods:

This retrospective study included 543 patients undergoing PLRDH between 2010 and 2018 in five Korean transplantation centers. Complication rates were assessed and multivariate logistic regression analyses were performed to identify risk factors of open conversion, overall complications, major complications, and biliary complications.

Results:

Regarding open conversion, the incidence was 1.7% and the risk factor was body mass index (BMI) >30 kg/m2 (P=0.001, odds ratio [OR] 22.72, 95% confidence interval [CI] 3.56–146.39). Rates of overall, major (Clavien-Dindo classification III-IV), and biliary complications were 9.2%, 4.4%, and 3.5%, respectively. For overall complications, risk factors were graft weight >700 g (P=0.007, OR 2.66, 95% CI 1.31–5.41), estimated blood loss (P<0.001, OR 4.84, 95% CI 2.50–9.38), and operation time >400 minutes (P=0.01, OR 2.46, 95% CI 1.25–4.88). For major complications, risk factors were graft weight >700 g (P=0.002, OR 4.01, 95% CI 1.67–9.62) and operation time >400 minutes (P=0.003, OR 3.84, 95% CI 1.60–9.21). For biliary complications, risk factors were graft weight >700 g (P=0.01, OR 4.34, 95% CI 1.40–13.45) and operation time >400 minutes (P=0.01, OR 4.16, 95% CI 1.34–12.88).

Conclusions:

Careful donor selection for PLRDH considering BMI, graft weight, estimated blood loss, and operation time combined with skilled procedure can improve donor safety.
Outcomes of Elective and Non-elective Fenestrated-branched Endovascular Aortic Repair for Treatment of Thoracoabdominal Aortic Aneurysms
Authors: Dias-Neto Marina , Vacirca Andrea , Huang Ying , Baghbani-Oskouei Aidin , Jakimowicz Tomasz , Mendes Bernardo C. , Kolbel Tilo , Sobocinski Jonathan , Bertoglio Luca , Mees Barend , Gargiulo Mauro , Dias Nuno , Schanzer Andres , Gasper Warren , Beck Adam W. , Farber Mark A. , Mani Kevin , Timaran Carlos , Schneider Darren B. , Pedro Luis Mendes , Tsilimparis Nikolaos , Haulon Stéphan , Sweet Matthew P. , Ferreira Emília , Eagleton Matthew , Yeung Kak Khee , Khashram Manar , Jama Katarzyna , Panuccio Giuseppe , Rohlffs Fiona , Mesnard Thomas , Chiesa Roberto , Kahlberg Andrea , Schurink Geert Willem , Lemmens Charlotte , Gallitto Enrico , Faggioli Gianluca , Karelis Angelos , Parodi Ezequiel , Gomes Vivian , Wanhainen Anders , Habib Mohammed , Colon Jesus Porras , Pavarino Felipe , Baig Mirza S. , Gouveia e Melo Ryan Eduardo Costeloe De , Crawford Sean , Zettervall Sara L. , Garcia Rita , Ribeiro Tiago , Alves Gonçalo , Gonçalves Frederico Bastos , Kappe Kaj Olav , Mariko van Knippenberg Samira Elize , Tran Bich Lan , Gormley Sinead , Oderich Gustavo S. ,   On behalf of The International Multicenter Aortic Research Group
Published: July 2023

Objective:

To describe outcomes after elective and non-elective fenestrated-branched endovascular aortic repair (FB-EVAR) for thoracoabdominal aortic aneurysms (TAAAs).

Background:

FB-EVAR has been increasingly utilized to treat TAAAs; however, outcomes after non-elective versus elective repair are not well described.

Methods:

Clinical data of consecutive patients undergoing FB-EVAR for TAAAs at 24 centers (2006–2021) were reviewed. Endpoints including early mortality and major adverse events (MAEs), all-cause mortality, and aortic-related mortality (ARM), were analyzed and compared in patients who had non-elective versus elective repair.

Results:

A total of 2603 patients (69% males; mean age 72±10 year old) underwent FB-EVAR for TAAAs. Elective repair was performed in 2187 patients (84%) and non-elective repair in 416 patients [16%; 268 (64%) symptomatic, 148 (36%) ruptured]. Non-elective FB-EVAR was associated with higher early mortality (17% vs 5%, P<0.001) and rates of MAEs (34% vs 20%, P<0.001). Median follow-up was 15 months (interquartile range, 7–37 months). Survival and cumulative incidence of ARM at 3 years were both lower for non-elective versus elective patients (50±4% vs 70±1% and 21±3% vs 7±1%, P<0.001). On multivariable analysis, non-elective repair was associated with increased risk of all-cause mortality (hazard ratio, 1.92; 95% CI] 1.50–2.44; P<0.001) and ARM (hazard ratio, 2.43; 95% CI, 1.63–3.62; P<0.001).

Conclusions:

Non-elective FB-EVAR of symptomatic or ruptured TAAAs is feasible, but carries higher incidence of early MAEs and increased all-cause mortality and ARM than elective repair. Long-term follow-up is warranted to justify the treatment.
Neuroprotection of β-caryophyllene against cerebral ischemia/reperfusion injury by inhibiting P38 MAPK/NLRP3 signaling pathway
Authors: Zhao Hongxia , Deng Ling , Chen Sha , Wang Xuan , Dong Zhi
Published: July 2023

The main objective of our research was to explore the neuroprotective effect and underlying mechanism of β-caryophyllene (BCP) pretreatment against cerebral ischemia/reperfusion injury (CIRI). Neurological deficit score, infarct size, and sensorimotor function were assessed 24 h following reperfusion. Additionally, histopathological damage of neurons was evaluated using hematoxylin-eosin staining. The mRNA level of nod-like receptor family pyrin domain-containing 3 (NLRP3) was determined using quantitative real-time PCR. The expressions of p-p38, p38, NLRP3, procaspase-1, and ASC (apoptosis-associated speck-like protein containing a CARD) were measured using western blot analysis. The levels of interleukin-1β (IL-1β) and interleukin-18 (IL-18) were quantified utilizing the ELISA. Our findings indicated that BCP pretreatment significantly reduced the infarct volume, neurologic deficit score, sensorimotor deficits, histopathological damage, and expression of inflammatory factors. Besides, BCP pretreatment effectively suppressed the expression of p-p38, as well as the activation of NLRP3 inflammasome. The administration of anisomycin, an activator of p38 MAPK, was found to notably impede the favorable outcomes conferred by BCP pretreatment, which included reducing the infarct volume, improving the neurologic deficit score, mitigating the sensorimotor deficits, and attenuating the histopathological damage. Furthermore, anisomycin effectively reversed the suppressive impact of BCP on NLRP3 inflammasome activation. This research uncovered that pretreatment with BCP has the potential to alleviate CIRI by effectively suppressing the activation of NLRP3 inflammasome through the p38 MAPK signaling pathway.
Monitoring the battleground: Exploring Antimicrobial Resistance, Antibiofilm Trends, and Virulence Factors in Wound Bacterial Isolates.
Authors: Awuor Silas Onyango , Omwenga Eric O. , Mariita Richard M. , Musila Jonathan , Musyoki Stanslaus
Published: July 2023

There is an alarming increase in antibiotic resistance especially on common bacterial infections that could be attributed to extensive unregulated use of antibiotics.   Continuous strategic monitoring of antibiotic use and AMR trends becomes imperative. This serves as a motivation to a thorough evaluation of wound isolates for relevant bacteria and assessing their drug susceptibility patterns, which we report herein. This cross-sectional study aimed to decipher antibacterial resistance by examining samples collected from patients with chronic wounds seeking medication at Jaramogi Oginga Odinga Teaching and Referral Hospital (JOOTRH). Standard microbiological methods were employed to identify and characterize the bacterial pathogens. Analysis of the wound isolates revealed a significant presence of microbial growth, with a higher prevalence of59% isolates in male patients. Staphylococcus aureus 20.7%emerged as the most predominant pathogen, followed by Klebsiella spp.14.8%, P. aeruginosa spp. 14.8%, and E. coli 4.4% in the wound samples. Notably, Cotrimoxazole exhibited the highest antibacterial resistance 48.1%, followed by Clindamycin 25.9% and Erythromycin 25.9%, affecting both Gram-positive and Gram-negative bacteria. Furthermore, among the isolates, 75% were capable of producing haemolysin and protease, while 50% produced lipase and phospholipase, factors that enhance virulence and survival. These findings provide crucial insights into antimicrobial resistance in chronic wounds, emphasizing the importance of responsible antibacterial use in wound management. Additionally, they shed light on the need for developing more potent antibiotics for effectively treating chronic wounds.
Unraveling the Molecular Landscape of Congenital Pseudoarthrosis of the Tibia: Insights from a Comprehensive Analysis of 162 Probands
Authors: Zhu Guanghui , Li Nan , Zheng Yu , Wang Shunyao , Yang Ge , Liu Yaoxi , Xu Zongren , Huang Hui , Peng Huanhuan , Mei Haibo
Published: July 2023

Congenital pseudarthrosis of the tibia (CPT, HP:0009736), commonly known as bowing of the tibia, is a rare congenital tibia malformation characterized by spontaneous tibial fractures and the difficulty of reunion after tibial fractures during early childhood, with a very low prevalence between 1/250,000∼1/140,000. While 80%–84% of CPT cases present with neurofibromatosis type 1, caused by the mutations inNF1, the underlying cause of CPT is still unclear. Considering the congenital nature and the low prevalence of CPT, we hypothesized that the rare genomic mutations may contribute to CPT. In this study, we conducted whole exome sequencing on 159 patients with CPT and full-length transcriptome sequencing on an additional 3 patients with CPT. The data analysis showed there were 179 significantly up-regulated genes which were enriched in 40 biological processes among which 21 biological processes hold their loss of function (LoF) excesses between 159 cases against 208 controls from 1000 Genomes Project. From those 21 biological processes with LoF excesses, there were 259 LoF-carried genes among which 40 genes with 56 LoF variations in 63 patients were enriched in osteoclast differentiation pathway (hsa04380) with its 3 directly regulated pathways including MAPK signaling pathway (hsa04010), calcium signaling pathway (hsa04020) and PI3K-Akt signaling pathway (hsa04151), as well as fluid shear stress and atherosclerosis pathway (hsa05418) while 12 patients carried 9 LoF variations in theNF1gene. The rare LoF variations in these pathways accounted for ∼39.6% of this CPT cohort. These findings shed light on the novel genetic mutations and molecular pathways involved in CPT, providing a new framework for understanding how the genetic variations regulate the biological processes in the pathology of CPT and indicating potential next directions to further elucidate the pathogenesis of CPT.
The draft genome of the microscopicNemertoderma westbladisheds light on the evolution of Acoelomorpha genomes
Authors: Abalde Samuel , Tellgren-Roth Christian , Heintz Julia , Pettersson Olga Vinnere , Jondelius Ulf
Published: July 2023

Background

Xenacoelomorpha is a marine phylum of microscopic worms that is an important model system for understanding the evolution of key bilaterian novelties, such as the nervous or excretory systems. Nevertheless, Xenacoelomorpha genomics has been restricted to the few species that either can be cultured in the lab or are centimetres long. Thus far, no genomes are available for Nemertodermatida, one of the phylum’s main clades and whose origin has been dated more than 400 million years ago.

Results

We present the first nemertodermatid genome sequenced from a single specimen ofNemertoderma westbladi. Although genome contiguity remains challenging (N50: 48 kbps), it is very complete (BUSCO: 81.4%, Metazoa; 91.8%, Eukaryota) and the quality of the annotation allows fine-detail analyses of genome evolution. Acoelomorph genomes seem to be conserved in terms of the percentage of repeats, number of genes, number of exons per gene and intron size. In addition, a high fraction of genes present in both protostomes and deuterostomes are absent in Acoelomorpha. Interestingly, we show that all genes related to the excretory system are present in Xenacoelomorpha butOsr, a key element in the development of these organs and whose acquisition might explain the origin of the specialised excretory system.

Conclusions

Overall, these analyses highlight the potential of the Ultra-Low Input DNA protocol and HiFi to generate high-quality genomes from single animals, even for relatively large genomes, making it a feasible option for sequencing challenging taxa, which will be an exciting resource for comparative genomics analyses.
Dynamic control of gene expression by ISGF3 and IRF1 during IFNβ and IFNγ signaling
Authors: Ravi Sundar Jose Geetha Aarathy , Fischer Katrin , Smesnik Georg , Vogt Alex , Platanitis Ekaterini , Müller Mathias , Farlik Matthias , Decker Thomas
Published: July 2023

Type I interferons (IFN-I, including IFNβ) and IFNγ produce overlapping, yet clearly distinct immunological activities. Recent data show that distinctness of global transcriptional responses to the two IFN types is not apparent when comparing their immediate effects. By analyzing nascent transcripts induced by IFN-I or IFNγ over a period of 48hrs we now show that the distinctiveness of the transcriptomes emerges over time and is based on a different employment of the ISGF3 complex as well as the second-tier transcription factor IRF1. The distinct transcriptional properties of ISGF3 and IRF1 correspond with a largely diverse nuclear protein interactome. Mechanistically, we describe specific input of ISGF3 and IRF1 into enhancer activation and the regulation of chromatin accessibility at interferon-induced genes (ISG). We further report differences between the IFN types in altering RNA polymerase II pausing at ISG 5’ ends. Our data provide insight how transcriptional regulators create immunological identities of IFN-I and IFNγ.
A Random Matrix Approach to Single Cell RNA-seq Analysis
Authors: Leviyang Sivan
Published: July 2023

Single cell RNA-seq (scRNAseq) workflows typically start with a raw expression matrix and end with the clustering of sampled cells. Viewed broadly, scRNAseq is a signal processing workflow that takes a transcriptional signal as input and outputs a cell clustering. Currently, we lack a quantitative framework through which to describe the input signal and assess the dependence of correct clustering on the signal properties. As a result, fundamental questions regarding the resolution of scRNAseq remain unanswered and experimentalists have little guidance in determining whether a hypothesized cell type will be clustered by a particular scRNAseq experiment.

In this work, we define the notion of a transcriptional signal associated with a gene module, show that the tools of random matrix theory can be used to characterize the signal as it moves through a common (PCA-based) scRNAseq workflow, and develop estimates for cell clustering based on the signal properties and, in particular, the signal strength. We give a formula - that can be computed from expression data - for the signal strength, providing a framework through which scRNAseq resolution can be investigated.
TheDrosophilacardiogenic transcription factors Myocyte enhancer factor-2 and Tinman contribute to heart lumen enlargement through direct activation of the collagen geneMultiplexin
Authors: Lovato TyAnna L. , Ryan Danielle , Bileckyj Cayleen , Johnston Christopher A. , Cripps Richard M.
Published: July 2023

During embryogenesis, the Drosophila heart forms a lumen, the posterior region of which is increased in diameter and corresponds to the heart proper. To identify the transcriptional control of this morphogenetic process, we analyzed the formation and enlargement of the heart lumen in mutants for the myogenic transcription factor geneMyocyte enhancer factor-2(Mef2). We found thatMef2contributes to both lumen formation and lumen expansion, the latter through a requirement for bothMef2and the cardiogenic genetinman(tin) to activate the collagen geneMultiplexin(Mp). To determine if Tin and MEF2 act directly upon theMpgene, we identified an enhancer whose activity recapitulates the cardiac expression ofMp. This enhancer contains binding sites for both Tin and MEF2 and is activated in tissue culture by MEF2 but not Tin. We did not observe synergistic activation of the enhancer when the factors were in combination, despite documenting a direct physical interaction between Tin and MEF2 in vitro. In vivo, the Tin sites are required for normal enhancer activity, whereas mutation of the MEF2 sites results in expanded expression of an enhancer-lacZreporter, suggesting that transcriptional repression may also contribute to regulation ofMp. Our studies underline how transcription factors must utilize combinatorial interactions to achieve organ-specific and region-specific patterns of gene expression and cell morphogenesis.
Sex peptide receptor is not required for refractoriness to remating or induction of egg laying inAedes aegypti
Authors: Amaro I. Alexandra , Wohl Margot P. , Pitcher Sylvie , Alfonso-Parra Catalina , Avila Frank W. , Paige Andrew S. , Helinski Michelle , Duvall Laura B. , Harrington Laura C. , Wolfner Mariana F. , McMeniman Conor J.
Published: July 2023

Across diverse insect taxa, the behavior and physiology of females dramatically changes after mating – processes largely triggered by the transfer of seminal proteins from their mates. In the vinegar flyDrosophila melanogaster, the seminal protein sex peptide (SP) decreases the likelihood of female flies remating and causes additional behavioral and physiological changes that promote fertility including increasing egg production. Although SP is only found in theDrosophilagenus, its receptor, sex peptide receptor (SPR), is the widely-conserved myoinhibitory peptide (MIP) receptor. To test the functional role of SPR in mediating post-mating responses in a non-Drosophiladipteran, we generated two independentSpr-knockout alleles in the yellow fever mosquitoAedes aegypti. Although SPR is needed for post-mating responses inDrosophilaand the cotton bollwormHelicoverpa armigera,SprmutantAe. aegyptishow completely normal post-mating decreases in remating propensity and increases in egg laying. In addition, injection of synthetic SP or accessory gland homogenate fromD. melanogasterinto virgin female mosquitoes did not elicit these post-mating responses. Our results indicate thatSpris not required for these canonical post-mating responses inAe. aegypti, indicating that unknown signaling pathways are likely responsible for these behavioral switches in this disease vector.
Age-Related Balance Problems in Mice Are Sharpened by the Loss of Calcitonin Gene-Related Peptide (CGRP) and a Vestibular Challenge
Authors: Rahman Shafaqat M. , Hauser Catherine , Luebke Anne E.
Published: July 2023

Aging impacts the vestibular system and contributes to imbalance. In fact, in the elderly balance deficits often precede changes in cognition. However, imbalance research is limited in assessing aging mouse models that are deficient in neuromodulators like Calcitonin Gene-Related Peptide (CGRP). We studied the loss of CGRP and its effects in the aging mouse, namely its effect on both static and dynamic imbalances. In addition, postural sway and rotarod testing were performed before and after a vestibular challenge (VC) in the 129S wildtype and the αCGRP (−/−) null mice. Four age groups were tested that correspond to young adulthood, late adulthood, middle age, and senescence in humans. Our results suggest wildtype mice experience a decline in rotarod ability with increased age, while the αCGRP (−/−) null mice perform poorly on rotarod early in life and do not improve. Our postural sway study suggests that a vestibular challenge can lead to significantly reduced CoP ellipse areas (freezing behaviors) in older mice, and this change occurs earlier in the αCGRP (−/−) null mouse. These results indicate that αCGRP is an important component of static and dynamic balance; and that the loss of αCGRP can contribute to balance complications that may compound with aging.
The gut microbiome across the cardiovascular risk spectrum
Authors: Prins Femke M. , Collij Valerie , Groot Hilde E. , Björk Johannes R. , Swarte J. Casper , Andreu-Sánchez Sergio , Jansen Bernadien H. , Fu Jingyuan , Harmsen Hermie J.M. , Zhernakova Alexandra , Lipsic Erik , van der Harst Pim , Weersma Rinse K. , Gacesa Ranko
Published: July 2023

Rationale

Despite significant progress in treatment strategies, cardiovascular disease remains a leading cause of death worldwide. Identifying new potential targets is crucial for enhancing preventive and therapeutic strategies. The gut microbiome has been associated with the development of coronary artery disease (CAD), however our understanding of the precise changes in the gut microbiome occurring during CAD development remains limited.

Objective

To investigate microbiome changes in participants without clinically manifest CAD with different cardiovascular risk levels and in patients with ST-elevation myocardial infarction (STEMI).

Methods and Results

In this cross-sectional study we characterized the gut microbiome using metagenomics of 411 fecal samples from individuals with low (n=130), intermediate (n=130) and high (n=125) cardiovascular risk based on the Framingham score, and STEMI patients (n=26). We analyzed alpha and beta diversity of the gut microbiome and differential abundance of species and functional pathways among the different groups while accounting for confounders including medication and technical covariates.

Abundances ofCollinsella stercoris, Flavonifractor plautiiandRuthenibacterium lactatiformansshowed a positive trend with cardiovascular risk, while Streptococcus thermophiluswas negatively associated. Furthermore, in the differential abundance analysis we identified eight species and 49 predicted metabolic pathways that were differently abundant among the groups. These species included species linked to inflammation. Starch biosynthesis and phenolic compound degradation pathways were enriched in the gut microbiome of STEMI patients, while pathways associated with vitamin, lipid and amino-acid biosynthesis were depleted.

Conclusions

We identified four microbial species that demonstrated a gradual trend in their abundance from low risk individuals to those with STEMI, and species and pathways that were differently abundant in STEMI patients compared to groups without clinically manifest CAD. Further investigation is warranted to gain deeper understanding of their precise role in CAD progression and potential implications, with the ultimate goal of identifying novel therapeutic targets.

Graphical abstract

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Oscillatory-Quality of sleep spindles: from properties to function
Authors: Blanco-Duque Cristina , Bond Suraya A. , Krone Lukas B. , Dufour Jean-Phillipe , Gillen Edward C.P. , Kahn Martin C. , Purple Ross J. , Bannerman David M. , Mann Edward O. , Achermann Peter , Olbrich Eckehard , Vyazovskiy Vladyslav V.
Published: July 2023

Sleep spindles are traditionally defined as 10-15Hz thalamo-cortical oscillations typical of NREM sleep. While substantial heterogeneity in the appearance or spatio-temporal dynamics of spindle events is well recognised, the physiological relevance of the underlying fundamental property - the oscillatory strength - has not been studied. Here we introduce a novel metric calledoscillatory Quality(o-Quality), which is derived by fitting an auto-regressive model to short segments of electrophysiological signals, recorded from the cortex in mice, to identify and calculate the damping of spindle oscillations. We find that theo-Qualityof spindles varies markedly across cortical layers and regions and reflects the level of synchrony within and between cortical networks. Furthermore, theo-Qualityof spindles varies as a function of sleep-wake history, determines the strength of coupling between spindles and slow waves, and influences the responsiveness to sensory stimulation during sleep. Thus, theo-Qualityemerges as a metric that, for the first time, directly links the spatio-temporal dynamics of sleep spindles with their functional role.
Uncertainties regarding cerebral palsy diagnosis: opportunities to operationalize the consensus definition
Authors: Aravamuthan Bhooma R , Fehlings Darcy L , Novak Iona , Gross Paul , Alyasiri Noor , Tilton Ann , Shevell Michael , Fahey Michael , Kruer Michael
Published: July 2023

Background and Objectives

Cerebral palsy (CP), the most common motor disability of childhood, is variably diagnosed. We hypothesized that child neurologists and neurodevelopmentalists, often on the frontlines of CP diagnosis in North America, harbor uncertainties regarding the practical application of the most recent CP consensus definition from 2006.

Methods

We conducted a cross-sectional survey of child neurologists and neurodevelopmentalists at the 2022 Child Neurology Society Annual Meeting. Attendees were provided the 2006 CP consensus definition and asked whether they had any uncertainties about the practical application of the definition across four hypothetical clinical vignettes.

Results

Of 230 attendees, 164 responded to the closing survey questions (71%). 145/164 (88%) expressed at least one uncertainty regarding the clinical application of the 2006 definition. Overwhelmingly, these areas of uncertainty focused on: 1) Age, both with regards to the minimum age of diagnosis and the maximum age of brain disturbance or motor symptom onset, (67/164, 41%), and 2) Interpretation of the term “non-progressive” (48/164, 29%). The vast majority of respondents (157/164, 96%) answered ‘Yes’ to the question: Do you think we should revise the 2006 consensus definition of CP?

Discussion

We propose that the uncertainties we identified could be addressed by operationalizing the 2006 consensus definition to support a more uniform CP diagnosis. To address the most common CP diagnostic uncertainties we identified, we propose 3 points of clarification based on the available literature: 1) Motor symptoms/signs should be present by 2 years old; 2) CP can and should be diagnosed as early as possible, even if activity limitation is not yet present, if motor symptoms/signs can be reasonably predicted to yield activity limitation (e.g. by using standardized examination instruments, Brain MRI, and a suggestive clinical history); and 3) The clinical motor disability phenotype should be non-progressive through 5 years old. We anticipate that operationalizing the 2006 definition of CP in this manner could clarify the uncertainties we identified among child neurologists and neurodevelopmentalists and reduce the diagnostic variability that currently exists.
MicroRNA-122-mediated liver detargeting enhances the tissue specificity of cardiac genome editing
Authors: Yang Luzi , Guo Congting , Liu Zhanzhao , Chen Zhan , Sun Yueshen , Hu Xiaomin , Zheng Yanjiang , Li Yifei , Gao Fei , Zhou Pingzhu , Pu William T. , Guo Yuxuan
Published: July 2023

Background

The cardiac troponin T (Tnnt2) promoter is broadly utilized for cardiac specific gene expression, particularly via adeno-associated virus (AAV)-based gene transfer. However, these vectors drive lower-level ectopic gene expression in other tissues, most notably in the liver. Whether the AAV-Tnnt2vectors remain tissue-specific in applications sensitive to low or transient gene expression, such as gene editing, remains unclear.

Methods

The tissue specificity of AAV9-Tnnt2vectors was evaluated in mice using Cre-LoxP-based fluorescence reporters and CRISPR/Cas9-mediated somatic mutagenesis. CRISPR/Cas9-triggered AAV integration into host genome was further assessed by quantitative PCR.

Results

In mice treated with AAV-Tnnt2-GFP, GFP signal was specifically observed in the heart by confocal imaging. However, when AAV-Tnnt2-Cre was administered to mice carrying LoxP-STOP-LoxP fluorescence reporters, the reporter signals were observed in up to 50% hepatic cells. Similarly, the AAV-Tnnt2-SaCas9 vector extensively edited the hepatic genome as measured by targeted amplicon-sequencing. Cas9-triggered AAV integration into the host genome was also validated in the liver. Inclusion of target sequences for microRNA-122, a highly expressed, liver-specific microRNA, in the AAV transgene’s 3’ untranslated region (3’ UTR) markedly reduced ectopic transgene expression, genome editing and AAV integration in the liver.

Conclusions

The heavily used AAV-Tnnt2system exhibits liver leakiness that severely impairs the cardiac specificity of AAV-based genetic manipulation. This problem can be mitigated via miR122-mediated liver detargeting.
Interferons are the key cytokines acting on pancreatic islets in type 1 diabetes
Authors: Coomans de Brachène Alexandra , Alvelos Maria Ines , Szymczak Florian , Zimath Priscila Laiz , Castela Angela , Marmontel de Souza Bianca , Roca Rivada Arturo , Marín-Cañas Sandra , Yi Xiaoyan , Op de Beeck Anne , Morgan Noel G. , Sonntag Sebastian , Jawurek Sayro , Title Alexandra C. , Yesildag Burcak , Pattou François , Kerr-Conte Julie , Montanya Eduard , Nacher Montserrat , Marselli Lorella , Marchetti Piero , Richardson Sarah J. , Eizirik Decio L.
Published: July 2023

The pro-inflammatory cytokines IFNα, IFNγ, IL-1β and TNFα may contribute to innate and adaptive immune responses during islet inflammation (insulitis) in type 1 diabetes (T1D). We used deep RNA-sequencing analysis to characterize the response of human pancreatic beta cells to each cytokine individually and compared the signatures obtained with those present in islets of individuals affected by T1D. IFNα and IFNγ had a much greater impact on the beta cell transcriptome when compared to IL-1β and TNFα. The IFN-induced gene signatures have a strong correlation with those observed in beta cells from T1D patients, and the level of expression of specific IFN-stimulated genes is positively correlated with proteins present in islets of these individuals, regulating beta cell responses to “danger signals” such as viral infections. These data suggest that IFNα and IFNγ are the central cytokines at the islet level in T1D, contributing to the triggering and amplification of autoimmunity.
Cranes soar on thermal updrafts behind cold fronts as they migrate across the sea
Authors: Pekarsky Sasha , Shohami David , Horvitz Nir , Bowie Rauri C. K. , Kamath Pauline L. , Markin Yuri , Getz Wayne M. , Nathan Ran
Published: July 2023

Thermal soaring conditions above the sea have long been assumed absent or too weak for terrestrial migrating birds, forcing large obligate soarers to take long detours and avoid sea crossing, and facultative soarers to cross exclusively by costly flapping flight. Thus, while atmospheric convection does develop at sea and is utilized by some seabirds, it has been largely ignored in avian migration research. Here we provide direct evidence for routine thermal soaring over open sea in the common crane, the heaviest facultative soarer known among terrestrial migrating birds. Using high-resolution biologging from 44 cranes tracked across their transcontinental migration over 4 years, we show that soaring characteristics and performance were no different over sea than over land in mid-latitudes. Sea-soaring occurred predominantly in autumn when large water-air temperature difference followed mid-latitude cyclones. Our findings challenge a fundamental paradigm in avian migration research and suggest that large soaring migrants avoid sea crossing not due to absence or weakness of thermals but due to their uncertainty and the costs of prolonged flapping. Marine cold air outbreaks, imperative to the global energy budget and climate system, may also be important for bird migration, calling for more multidisciplinary research across biological and atmospheric sciences.
Engagement of sialylated glycans with Siglec receptors on myeloid suppressor cells inhibit anti-cancer immunity via CCL2
Authors: Wieboldt Ronja , Carlini Emanuele , Lin Chia-wei , Börsch Anastasiya , Zingg Andreas , Lardinois Didier , Herzig Petra , Don Leyla , Zippelius Alfred , Läubli Heinz , Rodrigues Mantuano Natalia
Published: July 2023

Overexpression of sialic acids on glycans, called hypersialylation is a common alteration found in cancer. Hypersialylation can, for example, enhance immune evasion via interaction with sialic acid-binding immunoglobulin-like lectin (Siglec) receptors on tumor-infiltrating immune cells. Here, we tested the role of sialic acid on myeloid-derived suppressor cells (MDSCs) and their interaction with Siglec receptors. We found that MDSCs derived from the blood of lung cancer patients and tumor-bearing mice strongly express inhibitory Siglec receptors. In murine cancer models of emergency myelopoiesis, Siglec-E knockout on myeloid cells resulted in prolonged survival and increased infiltration of activated T cells. Targeting suppressive myeloid cells by blocking Siglec receptors or desialylation led to strong reduction of their suppressive potential. We further identified CCL2 as mediator involved in T cell suppression upon interaction of sialoglycans and Siglec receptors on MDSCs. Our results provide mechanistic insights how sialylated glycans inhibit anti-cancer immunity by facilitating CCL2 expression.

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