bluuebunny/crossref_metadata_2025 huggingface dataset:
Bad blood: ischemic conditions of the large bowel
Authors: Rizwan Rabia , Feuerstadt Paul
Published: October 2021

Purpose of review

Colon ischemia is the most common form of intestinal ischemic injury and is seen frequently in an elderly population. This disease is usually self-limited, and many causes have been identified. The recent literature has focused on estimates of prognosis, triaging appropriate level of care, and identification of optimal treatments. In this review, we will address our current understanding of colon ischemia including epidemiology, pathophysiology, segmental distribution, presentation, diagnosis, and management.

Recent findings

Research has recently been focused on factors associated with poor outcome. The medical comorbidities identified include chronic obstructive pulmonary disease (COPD), hepatic cirrhosis, and chronic aspirin use. Serological markers are noninvasive tools that can triage severity. Recent studies have shown procalcitonin, C-reactive protein, D-dimer, and neutrophil counts can help predict those at greatest risk for poor outcome. The timing of colonoscopy relative to symptomatic onset also can help predict severity. Early colonoscopy allows for quicker identification of ischemic stigmata, reducing the chance of misdiagnosis and potentially unnecessary and harmful treatment. The treatment of colon ischemia has classically been conservative with antimicrobials reserved for those with moderate or severe disease. Recent retrospective analysis calls into question the utility of antibiotics in the treatment of colon ischemia, although the data is not convincing enough to advise against antimicrobial treatment in patients with severe and fulminant disease.

It is an exciting time for research focused on colon ischemia. With an improved knowledge, awareness of associated risk factors and predictors of severity, clinicians now have enhanced clinical tools to diagnose and triage patients earlier in the disease. This should help institute prompt and appropriate therapies ultimately improving outcomes.
Driving Pressure Is Associated With Outcome in Pediatric Acute Respiratory Failure
Authors: van Schelven Patrick , Koopman Alette A. , Burgerhof Johannes G. M. , Markhorst Dick G. , Blokpoel Robert G. T. , Kneyber Martin C. J.
Published: October 2021

OBJECTIVES:

Driving pressure (ratio of tidal volume over respiratory system compliance) is associated with mortality in acute respiratory distress syndrome. We sought to evaluate if such association could be identified in critically ill children.

DESIGN:

We studied the association between driving pressure on day 1 of mechanical ventilation and ventilator-free days at day 28 through secondary analyses of prospectively collected physiology data.

SETTING:

Medical-surgical university hospital PICU.

PATIENTS:

Children younger than 18 years (stratified by Pediatric Mechanical Ventilation Consensus Conference clinical phenotype definitions) without evidence of spontaneous respiration.

INTERVENTIONS:

Inspiratory hold maneuvers.

MEASUREMENTS AND MAIN RESULTS:

Data of 222 patients with median age 11 months (2–51 mo) were analyzed. Sixty-five patients (29.3%) met Pediatric Mechanical Ventilation Consensus Conference criteria for restrictive and 78 patients (35.1%) for mixed lung disease, and 10.4% of all patients had acute respiratory distress syndrome. Driving pressure calculated by the ratio of tidal volume over respiratory system compliance for the whole cohort was 16 cm H2O (12–21 cm H2O) and correlated with the static airway pressure gradient (plateau pressure minus positive end-expiratory pressure) (Spearman correlation coefficient = 0.797; p < 0.001). Bland-Altman analysis showed that the dynamic pressure gradient (peak inspiratory pressure minus positive end-expiratory pressure) overestimated driving pressure (levels of agreement –2.295 to 7.268). Rematching the cohort through a double stratification procedure (obtaining subgroups of patients with matched mean levels for one variable but different mean levels for another ranking variable) showed a reduction in ventilator-free days at day 28 with increasing driving pressure in patients ventilated for a direct pulmonary indication. Competing risk regression analysis showed that increasing driving pressure remained independently associated with increased time to extubation (p < 0.001) after adjusting for Pediatric Risk of Mortality III 24-hour score, presence of direct pulmonary indication jury, and oxygenation index.

CONCLUSIONS:

Higher driving pressure was independently associated with increased time to extubation in mechanically ventilated children. Dynamic assessments of driving pressure should be cautiously interpreted.
Myocarditis Following mRNA COVID-19 Vaccine
Authors: Visclosky Timothy , Theyyunni Nik , Klekowski Nicole , Bradin Stuart
Published: October 2021

A growing number of adolescents are being diagnosed with acute myocarditis following mRNA COVID-19 vaccinations. This case describes an adolescent who presented to the emergency department with chest pain and tachycardia following the Pfizer-BioNTech COVID-19 vaccination. Point-of-care ultrasound was performed prior to the return of laboratory studies and revealed depressed left ventricular systolic function. Point-of-care ultrasound may be a tool used to rapidly diagnose or risk stratify patients with potential post–COVID-19 vaccine myocarditis.
Gram-negative bacteria as a cause of mediastinitis after cardiac surgery
Authors: Peghin Maddalena , Pompei Esmeralda , Vendramin Igor , Tascini Carlo
Published: October 2021

Purpose of review

Poststernotomy mediastinitis (PSM) remains a serious infection and is significantly associated with high morbidity, short-term and long-term mortality. Gram-negative bacteria (GNB) are an underestimated cause of PSM, and there is little information on the risk factors, prevention, diagnosis and management of GNB PSM.

Recent findings

The pathogenesis of PSM is the result of a complex and multifactorial interplay between intraoperative wound contamination, host-related and surgical host factors but GNB are probably mostly translocated from other host site infections. GNB are frequent cause of PSM (18–38% of cases) and GNB PSM have shown to more frequently polymicrobial (20–44%). GNG PSM has shown to occur earlier than Gram-positive PSM. Early diagnosis is crucial to successful treatment. The management of PSM needs a combination of culture-directed antimicrobial therapy and an early extensive surgical debridement with either immediate or delayed closure of the sternal space. Antibiotic treatment choice and duration should be based on clinical evaluation, evolution of inflammatory markers, microbiological tests and imaging studies. Mortality has shown to be significantly higher with GNB PSM compared with other causes and the inappropriateness of initial antibiotic therapy may explain the worse outcome of GNB PSM.

GNB PSM is usually undervalued in the setting of PSM and have shown to be a frequent cause of inappropriate treatment with adverse prognostic potential. There is a need for efforts to improve knowledge to prevent and adequately treat GNB PSM.
Clinical Management of End-Stage Renal Disease Patients on Dialysis Receiving Radioactive Iodine Treatment
Authors: AlSadi Rahaf , Aziz Landon C. , Bohan Michael , Dewji Shaheen , Bouhali Othmane , Djekidel Mehdi
Published: October 2021

Purpose

Radioactive iodine (RAI) is used to treat thyroid cancer patients with a clear paradigm for most patients. End-stage renal disease (ESRD) patients pose several challenges when undergoing RAI treatment, primarily due to the lack of renal clearance. We retrospectively report our experience with RAI treatment in a cohort of patients with ESRD and provide a set of recommendations on aspects such as the need for adjusted dose activity, balancing scheduling between RAI therapy and dialysis, and radiation safety precautions.

Patients and Methods

In this study, we report on 5 patients (6 cases), with ESRD on dialysis, treated with RAI for thyroid cancer. Retention measurements to determine individual biological clearance of RAI from the patient’s body before and after dialysis sessions were assessed using external exposure dose rates measured at 1 m.

Results

Delayed biological clearance of RAI, after the first hemodialysis session, resulted in a longer RAI effective half-life as a consequence of longer retention periods, consistent with observations reported in scientific literature. To achieve a much closer radiation exposure compared with a nondialysis patient, one would recommend administering ~20%–30% of the dose activity normally administered to a thyroid cancer patient based on their medical history, histopathology, and uptake with the appropriate dialysis schedule.

Conclusions

Special precautions should be taken with the administration of RAI in ESRD patients by adjusting the prescribed dose activity, dialysis sessions, and paying special attention to wastes. Pooling data from multiple centers may be useful to build a consensus and substantiated recommendations.
Diagnostic Test Accuracy of 18F-FDG PET or PET/CT for Characterization of Histologic Type of Thymic Epithelial Tumor
Authors: Kim Keunyoung , Jeong Joon-Hoon , Kim Seong-Jang
Published: October 2021

Purpose

This study investigated diagnostic accuracies of18F-FDG PET or PET/CT for characterization of histologic type of thymic epithelial tumors (TETs) through a systematic review and meta-analysis.

Patients and Methods

The PubMed, Cochrane database, and EMBASE database, from the earliest available date of indexing through August 31, 2020, were searched for studies evaluating diagnostic performance of18F-FDG PET or PET/CT for characterization of TET. We determined the sensitivities and specificities, calculated positive and negative likelihood ratios (LR+ and LR−), and constructed summary receiver operating characteristic curves.

Results

The pooled sensitivity of18F-FDG PET or PET/CT was 0.89 (95% confidence interval [CI], 0.80–0.95), and the pooled specificity was 0.77 (95% CI, 0.63–0.87) for differentiation between thymic cancer and thymoma. Likelihood ratio syntheses gave an overall positive likelihood ratio (LR+) of 3.9 and negative likelihood ratio (LR−) of 0.14. The pooled diagnostic odds ratio was 28 (95% CI, 13–63). The pooled sensitivity was 0.90 (95% CI, 0.75–0.96), and the pooled specificity was 0.81 (95% CI, 0.68–0.89) for differential diagnosis of a low-risk or high-risk TET. LR+ was 4.7 and LR− was 0.12. The pooled diagnostic odds ratio was 38 (95% CI, 12–121). In meta-regression analysis, no variable was the source of the study heterogeneity.

Conclusions

18F-FDG PET or PET/CT has excellent diagnostic performances for characterization of TET. Further large multicenter studies would be necessary to establish the diagnostic accuracy of18F-FDG PET or PET/CT for differentiation of histologic type of TET.
Subdiaphragmatic Lymph Nodes Uptake on 18F-FDG PET/CT After COVID-19 Vaccination in the Thigh
Authors: Quak Elske , Morel Adeline , Faudemer Julie , Levy Christelle , Ciappuccini Renaud
Published: October 2021

Since worldwide COVID-19 vaccination, 18F-FDG uptake in reactive axillary lymph nodes has been frequently observed in PET/CT studies. We describe a patient with breast cancer who underwent 18F-FDG PET/CT 7 days after receiving COVID-19 vaccination in the right thigh. 18F-FDG uptake was observed in nonenlarged right-sided inguinal, iliac, and para-aortic lymph nodes. As the thigh can be used as an alternate site for COVID-19 vaccine injection in case of lymphedema in both arms or for adequate axillary staging in patients with breast cancer, physicians should be aware of such 18F-FDG uptake pattern.
Vertical Comitance of Hypertropia in Congenital and Acquired Superior Oblique Palsy
Authors: Demer Joseph L.
Published: October 2021

Background:

Ivanir and Trobe have claimed that hypertropia (HT) that is greater in upgaze than downgaze, or equal to it, is characteristic of decompensated congenital superior oblique (SO) palsy and never present in ischemic, traumatic, or tumorous SO palsy. The reliability of this claim was tested in patients with SO palsy confirmed by MRI demonstration of subnormal ipsilesional SO size.

Methods:

Quasi-coronal, surface coil MRI was performed in target-controlled central gaze to identify patients with a unilateral reduction in SO cross section indicative of palsy. Nine patients gave an unequivocal history or had markedly increased vertical fusional amplitudes indicative of congenital onset (mean age 38 ± 16 years, SD). Seven patients had unequivocal acquired onset (age 47 ± 14 years and symptom duration 5.4 ± 4.8 years), including 2 with demonstrated trochlear Schwannoma and 5 with onset after severe head trauma. Fifteen patients had gradually progressive onset unequivocally not congenital yet not associated with any identifiable precipitating event (age 52 ± 20 years and symptom duration 13 ± 14 years).

Results:

Maximum SO cross section averaged 8.6 ± 3.9 mm2 in congenital palsy, not significantly different from 11.3 ± 3.5 mm2 in acquired palsy (P = 0.08) either unequivocally or progressively acquired, but significantly less than about 19 mm2 contralesionally in SO palsy (P < 10−4). Although mean central gaze HT was greater at 20.6 ± 8.0Δ in 9 cases of congenital than that in 22 acquired cases at 11.4 ± 6.8Δ (P = 0.002), HT was 8.4 ± 16.3Δ less in upgaze than downgaze in congenital SO palsy and 3.7 ± 11.2Δ less in acquired SO palsy. In congenital palsy, 33% of patients had HT greater in upgaze than downgaze while in 67% HT was greater in downgaze (by up to 42Δ). In acquired SO palsy, HT was greater in upgaze than downgaze or equal to it in 8 cases (36%, P = 0.87, X2). In acquired SO palsy, HT was greater in upgaze than downgaze in 37% and greater in downgaze than upgaze in 59% of cases. The HT was equal in upgaze and centralgaze in no congenital and 3 acquired cases of SO palsy. Trends were similar in unequivocal acquired and progressive acquired (noncongenital) SO palsy (P > 0.4).

Conclusions:

Hypertropia is not characteristically greater in upgaze than downgaze in congenital SO palsy proven by SO atrophy on MRI. In fact, average HT is greater in downgaze than upgaze in both acquired and congenital palsy, sometimes strikingly so in the latter. The finding of HT greater in upgaze than downgaze, or equal to it, does not reliably indicate that SO palsy is congenital, nor does maximum SO cross section.
Antimicrobial properties of phytohormone (gibberellins) against phytopathogens and clinical pathogens
Authors: Toner Paoirse , Nelson David , Rao Juluri R. , Ennis Madeleine , Moore John E. , Schock Bettina
Published: October 2021

The in vitro antimicrobial potential of physiologically active diterpenoid plant-derived gibberellins (gibberellic acids; GAs) was tested on microbial pathogens of significance to plant and human health. The racemic enantiomer GA3 produced varying inhibitory effects against a wide range of plant host disease causal agents (phytopathogens) comprising fungi, oomycetes and bacteria. The results showed that GA3 effected either strong growth arrest of phytopathogenic fungi or holistic biocidal effects on oomycete and phytopathogenic fungi at higher concentration (>10–50 mM) and increased hyphal extension growth when the concentration of GA3 was lowered (<10−0.1 mM). When human clinical pathogenic bacteria cohorts were challenged with gibberellin enantiomers, viz GA1, GA4, GA5, GA7, GA9 and GA13 (50 mM), employing Kirby–Bauer disc bioassay methods for assessment of their efficacies, no inhibitory effect was seen with gibberellin enantiomers, viz GA1, GA3, GA5 and GA13, while GA4 inhibited all human clinical bacterial organisms examined, with GA7 and GA9 showing limited activity. The antibiotic effects of enantiomeric diterpenoid phytohormones evinced in our preliminary study raise prospects for further studies to fully examine their potential therapeutic value for human healthcare and their compliance with cytotoxicity and other ethical considerations in the future.
SARS-COV-2 γ variant acquires spike P681H or P681R for improved viral fitness
Authors: Yang Xiang-Jiao
Published: October 2021

Severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) evolves and generates different variants through a continuously branching model. Four variants of concern have been the major pandemic drivers around the world. One important question is how they may evolve and generate subvariants, some of which may be even more virulent and drive the pandemic further. While investigating how γ (or P.1) variant has been evolving, I noticed the spike substitution P681H in a group of genomes encoding a new subvariant, which has been designated P.1.7. This subvariant has become the dominant P.1 sublineage in Brazil, Italy, Spain and Peru, supporting that P681H confers evolutionary advantage to P.1.7. In Brazil and Peru, P.1.7 was still responsible for ~30% and ~40% cases, respectively, in August 2021. However, it has been competed out by δ1 (a δ subvariant) in both countries, Italy and Spain, suggesting that P.1.7 is not as virulent as δ1. In addition, 160 P.1 genomes possess a related substitution, P681R, and 120 of them encode a new subvariant, designated P.1.8. This P.1 subvariant carries two additional spike substitutions, T470N and C1235F, located at the receptor-binding pocket and cytoplasmic tail of spike protein, respectively. More P.1.8 genomes have been identified than P.1 genomes that encode P681R but not T470N and C1235F, suggesting that these two substitutions improve virulence of P.1.8 subvariant. Some P.1 genomes carry other substitutions (such as N679K, V687L and C1250F) that affect the furin cleavage site or cytoplasmic tail of spike protein. Thus, to improve viral fitness and expand its evolutionary cage, γ variant acquires mutations to finetune the furin cleavage site and cytoplasmic tail of spike protein.
The effect of circulating zinc, selenium, copper and vitamin K1on COVID-19 outcomes: a Mendelian randomization study
Authors: Sobczyk Maria K. , Gaunt Tom R.
Published: October 2021

Background

Previous results from observational, interventional studies and in vitro experiments suggest that certain micronutrients have anti-viral and immunomodulatory activities. In particular, it has been hypothesized that zinc, selenium, copper and vitamin K1have strong potential for prophylaxis and treatment of COVID-19.

Objectives

We aimed to test whether genetically predicted Zn, Se, Cu or vitamin K1levels have a causal effect on COVID-19 related outcomes: risk of infection, hospitalization and critical illness.

Methods

We employed two-sample Mendelian Randomization (MR) analysis. Our genetic variants derived from European-ancestry GWAS reflected circulating levels of Zn, Cu, Se in red blood cells as well as Se and vitamin K1in serum/plasma. For the COVID-19 outcome GWAS, we used infection, hospitalization or critical illness. Our inverse-variance weighted (IVW) MR analysis was complemented by sensitivity analyses: more liberal selection of variants at genome-wide subsignificant threshold, MR-Egger and weighted median/mode tests.

Results

Circulating micronutrient levels show limited evidence of association with COVID-19 infection with odds ratio [OR] ranging from 0.97 (95% CI: 0.87-1.08,p-value=0.55) for zinc to 1.07 (95% CI: 1.00-1.14,p-value=0.06) – ie. no beneficial effect for copper, per 1 SD increase in exposure. Similarly minimal evidence was obtained for the hospitalization and critical illness outcomes with OR from 0.98 (95% CI: 0.87-1.09,p-value=0.66) for vitamin K1 to 1.07 (95% CI: 0.88-1.29,p-value=0.49) for copper, and from 0.93 (95% CI: 0.72-1.19,p-value=0.55) for vitamin K1to 1.21 (95% CI: 0.79-1.86,p-value=0.39) for zinc, respectively.

Conclusions

This study does not provide evidence that supplementation with zinc, selenium, copper or vitamin K1can prevent SARS-CoV-2 infection, critical illness or hospitalization for COVID-19.
Post-transcriptionally regulated genes are essential for pluripotent stem cell survival
Authors: Iwasaki Mio , Kawahara Yuka , Tabata Tsuyoshi , Nishi Yohei , Narita Megumi , Ohta Akira , Saito Hirohide , Yamamoto Takuya , Nakagawa Masato , Yamanaka Shinya , Takahashi Kazutoshi
Published: October 2021

The effects of transcription factors on the maintenance and differentiation of pluripotent stem cells (PSCs) have been well studied. However, the importance of post-transcriptional regulatory mechanisms, which cause the quantitative dissociation of mRNA and protein expression, has not been explored in detail. Here, by combining transcriptome and proteome profiling, we identified 228 post-transcriptionally regulated genes with strict upregulation of the protein level in PSCs. Among them, we found that 84 genes were vital for the survival of PSCs and HDFs, including 20 genes that were specifically necessary for the survival of PSCs. These 20 proteins were upregulated only in PSCs and not in differentiated cells derived from the three germ layers. Subcellular fractionation of the mRNA showed that the expression of most of the 20 proteins was regulated at the mRNA localization stage from the nucleus to the cytoplasm, but their translation efficiency was constant. Together, these results revealed that post-transcriptionally regulated genes have a crucial role in PSC survival.
Protease-controlled secretion and display of intercellular signals
Authors: Vlahos Alexander E. , Kang Jeewoo , Aldrete Carlos A. , Zhu Ronghui , Chong Lucy S. , Elowitz Michael B. , Gao Xiaojing J.
Published: October 2021

To program intercellular communication for biomedicine, it is crucial to regulate the secretion and surface display of signaling proteins. If such regulations are at the protein level, there are additional advantages, including compact delivery and direct interactions with endogenous signalling pathways. We created a modular, generalizable design calledRetainedEndoplasmic CleavableSecretion (RELEASE), with engineered proteins retained in the endoplasmic reticulum and displayed/secreted in response to specific proteases. The design allows functional regulation of multiple synthetic and natural proteins by synthetic protease circuits to realize diverse signal processing capabilities, including logic operation and threshold tuning. By linking RELEASE to additional novel sensing and processing circuits, we were able to achieve elevated protein secretion in response to “undruggable” oncogene KRAS mutants. RELEASE should enable the local, programmable delivery of intercellular cues for a broad variety of fields such as neurobiology, cancer immunotherapy and cell transplantation.
Crystal or Jelly? Effect of Color on the Perception of Translucent Materials with Photographs of Real-world Objects
Authors: Liao Chenxi , Sawayama Masataka , Xiao Bei
Published: October 2021

Translucent materials are ubiquitous in nature (e.g. teeth, food, wax), but our understanding of translucency perception is limited. Previous work in translucency perception has mainly used monochromatic rendered images as stimuli, which are restricted by their diversity and realism. Here, we measure translucency perception with photographs of real-world objects. Specifically, we use three behavior tasks: binary classification of “translucent” versus “opaque”, semantic attribute rating of perceptual qualities (see-throughness, glossiness, softness, glow and density), and material categorization. Two different groups of observers finish the three tasks with color or grayscale images. We find that observers’ agreements depend on the physical material properties of the objects such that translucent materials generate more inter-observer disagreements. Further, there are more disagreements among observers in the grayscale condition in comparison to that in color condition. We also discover that converting images to grayscale substantially affects the distributions of attribute ratings for some images. Furthermore, ratings of see-throughness, glossiness, and glow could predict individual observers’ binary classification of images in both grayscale and color conditions. Lastly, converting images to grayscale alters the perceived material categories for some images such that observers tend to misjudge images of food as non-food and vice versa. Our result demonstrates color is informative about material property estimation and recognition. Meanwhile, our analysis shows mid-level semantic estimation of material attributes might be closely related to high-level material recognition. We also discuss individual differences in our results and highlight the importance of such consideration in material perception.
Structural network alterations in focal and generalized epilepsy follow axes of epilepsy risk gene expression: An ENIGMA study
Authors: Larivière Sara , Royer Jessica , Rodríguez-Cruces Raúl , Caligiuri Maria Eugenia , Gambardella Antonio , Concha Luis , Keller Simon S. , Cendes Fernando , Yasuda Clarissa L. , Bonilha Leonardo , Gleichgerrcht Ezequiel , Focke Niels K. , Domin Martin , von Podewills Felix , Langner Soenke , Rummel Christian , Wiest Roland , Martin Pascal , Kotikalapudi Raviteja , O’Brien Terence J. , Sinclair Benjamin , Vivash Lucy , Desmond Patricia M. , Lui Elaine , Vaudano Anna Elisabetta , Meletti Stefano , Tondelli Manuela , Alhusaini Saud , Doherty Colin P. , Cavalleri Gianpiero L. , Delanty Norman , Kälviäinen Reetta , Jackson Graeme D. , Kowalczyk Magdalena , Mascalchi Mario , Semmelroch Mira , Thomas Rhys H. , Soltanian-Zadeh Hamid , Davoodi-Bojd Esmaeil , Zhang Junsong , Kreilkamp Barbara A. K. , Lenge Matteo , Guerrini Renzo , Hamandi Khalid , Foley Sonya , Rüber Theodor , Weber Bernd , Depondt Chantal , Absil Julie , Carr Sarah J. A. , Abela Eugenio , Richardson Mark P. , Devinsky Orrin , Severino Mariasavina , Striano Pasquale , Tortora Domenico , Hatton Sean N. , Vos Sjoerd B. , Caciagli Lorenzo , Duncan John S. , Whelan Christopher D. , Thompson Paul M. , Sisodiya Sanjay M. , Bernasconi Andrea , Labate Angelo , McDonald Carrie R. , Bernasconi Neda , Bernhardt Boris C.
Published: October 2021

Epilepsy is associated with genetic risk factors and cortico-subcortical network alterations, but associations between neurobiological mechanisms and macroscale connectomics remain unclear. This multisite ENIGMA-Epilepsy study examined whole-brain structural covariance networks in patients with epilepsy and related findings to postmortem co-expression patterns of epilepsy risk genes. Brain network analysis included 578 adults with temporal lobe epilepsy (TLE), 288 adults with idiopathic generalized epilepsy (IGE), and 1,328 healthy controls from 18 centres worldwide. Graph theoretical analysis of structural covariance networks revealed increased clustering and path length in orbitofrontal and temporal regions in TLE, suggesting a shift towards network regularization. Conversely, people with IGE showed decreased clustering and path length in fronto-temporo-parietal cortices, indicating a random network configuration. Syndrome-specific topological alterations reflected expression patterns of risk genes for hippocampal sclerosis in TLE and for generalized epilepsy in IGE. These imaging-genetic signatures could guide diagnosis, and ultimately, tailor therapeutic approaches to specific epilepsy syndromes.
Ultrasound-mediated delivery of novel tau-specific monoclonal antibody enhances brain uptake but not therapeutic efficacy
Authors: Bajracharya Rinie , Cruz Esteban , Götz Jürgen , Nisbet Rebecca M.
Published: October 2021

Tau-specific immunotherapy is an attractive therapeutic strategy for the treatment of Alzheimer’s disease and other tauopathies. However, targeting tau effectively remains a considerable challenge due to the restrictive nature of the blood-brain barrier (BBB), which excludes 99.9% of peripherally administered antibodies. We have previously shown that the delivery of tau-specific monoclonal antibody (mAb) with low-intensity scanning ultrasound in combination with intravenously injected microbubbles (SUS+MB) increases the passage of IgG antibodies into the brain. SUS+MB transiently opens tight junctions to allow paracellular transport, but also facilitates transcellular transport, particularly for larger cargoes. However, therapeutic efficacy after enhanced brain delivery has not been explored. To assess whether ultrasound-mediated delivery of tau-specific mAbs leads to an enhanced therapeutic response, K369I tau transgenic K3 mice were passively immunised once weekly for 12 weeks with a novel mAb, RNF5, in combination with SUS+MB. While none of the treatment arms improved behaviour or motor functions in these mice, we found that both RNF5 and SUS+MB treatments on their own reduced tau pathology, but, surprisingly, the combination of both (RNF5+SUS+MB) did not achieve an additive reduction in tau pathology. This was despite observing increased antibody penetration in the brain. Interestingly, a significant fraction of the antibody in the combination treatment was visualized in brain endothelial cells, suggesting that paracellular transport may not be the preferred uptake mechanism for RNF5. Taken altogether, more research is warranted to develop SUS+MB as a delivery modality for anti-tau antibodies.
Quantitative MRI reveals differences in striatal myelin in children with DLD
Authors: Krishnan Saloni , Cler Gabriel J. , Smith Harriet J. , Willis Hanna E. , Asaridou Salomi S. , Healy Máiréad P. , Papp Daniel , Watkins Kate E.
Published: October 2021

Abstract

Developmental Language Disorder (DLD) is a common neurodevelopmental disorder characterised by receptive or expressive language difficulties or both. While theoretical frameworks and empirical studies support the idea that there may be neural correlates of DLD in frontostriatal loops, findings are inconsistent across studies. Here, we use a novel semiquantitative imaging protocol – multiparameter mapping (MPM) – to investigate microstructural neural differences in children with DLD. The MPM protocol allows us to reproducibly map specific indices of tissue microstructure. In 56 typically developing children and 33 children with DLD, we derived maps of: 1) longitudinal relaxation rate R1 (1/T1); 2) the transverse relaxation rate R2* (1/T2*); and 3) Magnetization Transfer Saturation (MTsat). R1 and MTsat predominantly index myelin, while R2* is sensitive to iron content. Children with DLD showed reductions in MTsat values in the caudate nucleus bilaterally, as well as in the left ventral sensorimotor cortex and Heschl’s gyrus. They also had globally lower R1 values. No group differences were noted in R2* maps. Differences in MTsat and R1 were coincident in the caudate nucleus bilaterally. These findings support our hypothesis of corticostriatal abnormalities in DLD and indicate abnormal levels of myelin in the dorsal striatum in children with DLD.
Performance Scaling for Structural MRI Surface Parcellations: A Machine Learning Analysis in the ABCD Study
Authors: Hahn Sage , Owens Max M. , Yuan DeKang , Juliano Anthony C , Potter Alexandra , Garavan Hugh , Allgaier Nicholas
Published: October 2021

The use of pre-defined parcellations on surface-based representations of the brain as a method for data reduction is common across neuroimaging studies. In particular, prediction-based studies typically employ parcellation-driven summaries of brain measures as input to predictive algorithms, but the choice of parcellation and its influence on performance is often ignored. Here we employed pre-processed structural magnetic resonance imaging data (sMRI) from the ABCD Study® to examine the relationship between 220 parcellations and out-of-sample predictive performance across 45 phenotypic measures in a large sample of 9-10-year-old children (N=9,432). Choice of Machine Learning (ML) pipeline and use of alternative multiple parcellation-based strategies were also assessed. Relative parcellation performance was dependent on the spatial resolution of the parcellation, with larger numbers of parcels (up to ∼4000) outperforming coarser parcellations, according to a power-law scaling of between 1/4 and 1/3. Performance was further influenced by the type of parcellation, ML pipeline, and general strategy, with existing literature-based parcellations, a support vector based pipeline, and ensembling across multiple parcellations, respectively, as the highest performing. These findings highlight the choice of parcellation as an important influence on downstream predictive performance, showing in some cases that switching to a higher resolution parcellation can yield a relatively large boost to performance.
Zapline-plus: a Zapline extension for automatic and adaptive removal of frequency-specific noise artifacts in M/EEG
Authors: Klug Marius , Kloosterman Niels A.
Published: October 2021

Removing power line noise and other frequency-specific artifacts from electrophysiological data without affecting neural signals remains a challenging task. Recently, an approach was introduced that combines spectral and spatial filtering to effectively remove line noise: Zapline (de Cheveigné, 2020). This algorithm, however, requires manual selection of the noise frequency and the number of spatial components to remove during spatial filtering. Moreover, it assumes that noise frequency and spatial topography are stable over time, which is often not warranted. To overcome these issues, we introduce Zapline-plus, which allows adaptive and automatic removal of frequency-specific noise artifacts from M/EEG and LFP data. To achieve this, our extension first segments the data into periods (chunks) in which the noise is spatially stable. Then, for each chunk, it searches for peaks in the power spectrum, and finally applies Zapline. The exact noise frequency around the found target frequency is also determined separately for every chunk to allow fluctuations of the peak noise frequency over time. The number of to-be-removed components by Zapline is automatically determined using an outlier detection algorithm. Finally, the frequency spectrum after cleaning is analyzed for suboptimal cleaning and parameters are adapted accordingly if necessary before re-running the process. The software creates a detailed plot for monitoring the cleaning. We showcase the efficacy of the different features of our algorithm by applying it to four openly available data sets, two EEG sets containing both stationary and mobile task conditions, and two MEG sets containing strong line noise.
Coherent oscillations in balanced neural networks driven by endogenous fluctuations
Authors: di Volo Matteo , Segneri Marco , Goldobin Denis , Politi Antonio , Torcini Alessandro
Published: October 2021

We present a detailed analysis of the dynamical regimes observed in a balanced network of identical Quadratic Integrate-and-Fire (QIF) neurons with a sparse connectivity for homogeneous and heterogeneous in-degree distribution. Depending on the parameter values, either an asynchronous regime or periodic oscillations spontaneously emerge. Numerical simulations are compared with a mean field model based on a self-consistent Fokker-Planck equation (FPE). The FPE reproduces quite well the asynchronous dynamics in the homogeneous case by either assuming a Poissonian or renewal distribution for the incoming spike trains. An exact self consistent solution for the mean firing rate obtained in the limit of infinite in-degree allows identifying balanced regimes that can be either mean- or fluctuation-driven. A low-dimensional reduction of the FPE in terms of circular cumulants is also considered. Two cumulants suffice to reproduce the transition scenario observed in the network. The emergence of periodic collective oscillations is well captured both in the homogeneous and heterogeneous set-ups by the mean field models upon tuning either the connectivity, or the input DC current. In the heterogeneous situation we analyze also the role of structural heterogeneity.
Characterization of red fluorescent reporters for dual-color in vivo three-photon microscopy
Authors: Thornton Michael A. , Futia Gregory L. , Stockton Michael E. , Ozbay Baris N. , Kilborn Karl , Restrepo Diego , Gibson Emily A. , Hughes Ethan G.
Published: October 2021

Significance

Three-photon (3P) microscopy significantly increases the depth and resolution of in vivo imaging due to decreased scattering and nonlinear optical sectioning. Simultaneous excitation of multiple fluorescent proteins is essential to study multicellular interactions and dynamics in the intact brain.

Aim

We characterized the excitation laser pulses at a range of wavelengths for 3P microscopy, and then explored the application of tdTomato or mScarlet and EGFP for dual-color single-excitation structural 3P imaging deep in the living mouse brain.

Approach

We used frequency-resolved optical gating to measure the spectral intensity, phase, and retrieved pulse widths at a range of wavelengths. Then, we performed in vivo single wavelength-excitation 3P imaging in the 1225 - 1360 nm range deep in the mouse cerebral cortex to evaluate the performance of tdTomato or mScarlet in combination with EGFP.

Results

We find that tdTomato and mScarlet, expressed in oligodendrocytes and neurons respectively, have high signal-to-background in the 1300–1360 nm range, consistent with enhanced 3P cross sections.

Conclusions

These results suggest that a single excitation wavelength source is advantageous for multiple applications of dual-color brain imaging and highlight the importance of empirical characterization of individual fluorophores for 3P microscopy.
High-throughput Evaluation of Epilepsy-associated KCNQ2 Variants Reveals Functional and Pharmacological Heterogeneity
Authors: Vanoye Carlos G. , Desai Reshma R. , Ji Zhigang , Adusumilli Sneha , Jairam Nirvani , Ghabra Nora , Joshi Nishtha , Fitch Eryn , Helbig Katherine , McKnight Dianalee , Lindy Amanda , Zou Fanggeng , Helbig Ingo , Cooper Edward , George Alfred L.
Published: October 2021

Hundreds of KCNQ2 variants have been identified by genetic testing of children with early onset epilepsy and/or developmental disability. Voltage-clamp recording from heterologous cells has proved useful for establishing deleterious functional effects of KCNQ2 variants, but procedures adapting these assays for standardized, higher throughput data collection and reporting are lacking. In this study, we employed automated patch clamp recording to assess in parallel the functional and pharmacological properties of 79 missense and 2 in-frame deletion variants of KCNQ2. Among the variants we studied were a training set of 18 pathogenic variants previously studied by voltage-clamp recording, 24 mostly rare population variants, and 39 disease-associated variants with unclear functional effects. Variant KCNQ2 subunits were transiently expressed in a cell line stably expressing KCNQ3 to reconstitute the physiologically relevant channel complex. Variants with severe loss-of-function were also co-expressed 1:1 with WT KCNQ2 in the KCNQ3 cell line to mimic the heterozygous genotype and assess dominant-negative behavior. In total, we analyzed electrophysiological data recorded from 9,480 cells. The functional properties of WT KCNQ2/KCNQ3 channels and pharmacological responses to known blockers and activators determined by automated patch clamp recording were highly concordant with previous findings. Similarly, functional properties of 18 known pathogenic variants largely matched previously published results and the validated automated patch clamp assay. Many of the 39 previously unstudied disease-associated KCNQ2 variants exhibited prominent loss-of-function and dominant-negative effects, providing strong evidence in support of pathogenicity. All variants, exhibit response to retigabine (10 µM), although there were differences in maximal responses. Variants within the ion selectivity filter exhibited the weakest responses whereas retigabine had the strongest effect on gain-of-function variants in the voltage-sensor domain. Our study established a high throughput method to detect deleterious functional consequences of KCNQ2 variants. We demonstrated that dominant-negative loss-of-function is a common mechanism associated with missense KCNQ2 variants but this does not occur with rare population variation in this gene. Importantly, we observed genotype-dependent differences in the response of KCNQ2 variants to retigabine.
Displacement of PKA catalytic subunit from AKAP signaling islands drives pathology in Cushing’s syndrome
Authors: Omar Mitchell H. , Byrne Dominic P. , Jones Kiana N. , Lakey Tyler M. , Collins Kerrie B. , Lee Kyung-Soon , Daly Leonard A. , Forbush Katherine A. , Lau Ho-Tak , Golkowski Martin , McKnight G. Stanley , Breault David T. , Lefrançois-Martinez Anne-Marie , Martinez Antoine , Eyers Claire E. , Baird Geoffrey S. , Ong Shao-En , Smith F. Donelson , Eyers Patrick A. , Scott John D.
Published: October 2021

Mutations in the catalytic subunit of protein kinase A (PKAc) drive the stress hormone disorder adrenal Cushing’s syndrome. Here we define mechanisms of action for the PKAc-L205R and W196R variants. Both Cushing’s mutants are excluded from A kinase anchoring protein (AKAP) signaling islands and consequently diffuse throughout the cell. Kinase-dead experiments show that PKA activity is required for cortisol hypersecretion. However, kinase activation is not sufficient, as only cAMP analog drugs that displace native PKAc from AKAPs enhance cortisol release. Rescue experiments that incorporate mutant PKAc into AKAP signaling islands abolish cortisol overproduction, indicating that kinase anchoring restores normal endocrine function. Phosphoproteomics show that PKAc-L205R and W196R engage different mitogenic signaling pathways. ERK activity is elevated in adrenal-specific PKAc-W196R knock-in mice. Conversely, PKAc-L205R attenuates Hippo signaling, thereby upregulating the YAP/TAZ transcriptional co-activators. Thus, aberrant localization of each Cushing’s variant promotes the transmission of a distinct downstream pathogenic signal.
High survival following bleaching highlights the resilience of a highly disturbed region of the Great Barrier Reef
Authors: Page Cathie A , Giuliano Christine , Bay Line K , Randall Carly J
Published: October 2021

Natural bleaching events provide an opportunity to examine how local scale environmental variation influences bleaching severity and recovery. During the 2020 marine heatwave, we documented widespread and severe coral bleaching (75 – 98% of coral cover) throughout the Keppel Islands in the Southern inshore Great Barrier Reef. Acropora, Pocillopora and Porites were the most severely affected genera, while Montipora was comparatively less susceptible. Site-specific heat-exposure metrics were not correlated with Acropora bleaching severity, but recovery was faster at sites that experienced lower heat exposure. Despite severe bleaching and exposure to accumulated heat that often results in coral mortality (degree heating weeks ∼ 4 – 8), cover remained stable. Approximately 94% of fate-tracked Acropora millepora colonies survived, perhaps owing to reduced irradiance stress from high turbidity, heterotrophic feeding, and large tidal flows that can increase mass transfer. Severe bleaching followed by rapid recovery, and the continuing dominance of Acropora populations in the Keppel Islands is indicative of high resilience. These coral communities have survived an 0.8 °C increase in average temperatures over the last 150 years. However, recovery following the 2020 bleaching was driven by the easing of thermal stress, which may challenge their recovery potential under further warming.

Open Research Statement

Data are not yet provided but are being compiled. Upon acceptance data will be archived on GitHub.
Genetic and genomic architecture of species-specific cuticular hydrocarbon variation in parasitoid wasps
Authors: Buellesbach Jan , Holze Henrietta , Schrader Lukas , Liebig Jürgen , Schmitt Thomas , Gadau Juergen , Niehuis Oliver
Published: October 2021

Cuticular hydrocarbons (CHCs) serve two fundamental functions in insects: protection against desiccation and chemical signaling. CHC profiles can consist of dozens of different compounds and are considered a prime example for a complex trait. How the interaction of genes shapes CHC profiles, which are essential for insect survival, adaptation, and reproductive success, is still poorly understood. Here we investigate the genetic and genomic basis of CHC biosynthesis and variation in parasitoid wasps of the genusNasonia. Taking advantage of the wasps’ haplo-diploid sex determination and cross-species fertility, we mapped 91 quantitative trait loci (QTL) explaining variation of a total of 43 CHCs in F2hybrid males from interspecific crosses between threeNasoniaspecies. To identify candidate genes, we localized orthologs of CHC biosynthesis-related genes in theNasoniagenomes. By doing so, we discovered multiple genomic regions where the location of QTL coincides with the location of CHC biosynthesis-related candidate genes. Most conspicuously, on a region on chromosome 1 close to the centromere, multiple CHC biosynthesis-related candidate genes co-localize with several QTL explaining variation in methyl-branched alkanes. The genetic underpinnings behind this compound class are not well understood so far, despite their high potential for encoding chemical information as well as their prevalence in bothNasoniaCHC profiles and many other Hymenoptera. Our study considerably extends our knowledge on the so far little-known genetic and genomic architecture governing biosynthesis and variation of this fundamental compound class, establishing a model for methyl-branched alkane genetics in the Hymenoptera in general.
Inverse Potts model improves accuracy of phylogenetic profiling
Authors: Fukunaga Tsukasa , Iwasaki Wataru
Published: October 2021

Phylogenetic profiling is a powerful computational method for revealing the functions of function-unknown genes. Although conventional similarity evaluation measures in phylogenetic profiling showed high prediction accuracy, they have two estimation biases: an evolutionary bias and a spurious correlation bias. Existing studies have focused on the evolutionary bias, but the spurious correlation bias has not been analyzed. To eliminate the spurious correlation bias, we applied an evaluation measure based on the inverse Potts model (IPM) to phylogenetic profiling. We also proposed an evaluation measure to remove both the evolutionary and spurious correlation biases using the IPM. In an empirical dataset analysis, we demonstrated that these IPM-based evaluation measures improved the prediction performance of phylogenetic profiling. In addition, we found that the integration of several evaluation measures, including the IPM-based evaluation measures, had superior performance to a single evaluation measure. The source code is freely available at https://github.com/fukunagatsu/Ipm.