bluuebunny/crossref_metadata_2025 huggingface dataset:
Early Psychological Interventions for Somatic Symptom Disorder and Functional Somatic Syndromes: A Systematic Review and Meta-Analysis
Authors: Berezowski Lukas , Ludwig Lea , Martin Alexandra , Löwe Bernd , Shedden-Mora Meike C.
Published: September 2021

Objective

Psychological treatments for somatic symptom disorder and functional somatic syndromes (SSD/FSS) achieve moderate effects only, potentially because of the high chronicity in these patients. Therefore, we aimed to evaluate whether early treatment, that is, treatment in populations at risk or with recent onset, improves outcome.

Methods

We conducted a systematic review and meta-analysis of (cluster-)randomized controlled trials evaluating early psychological interventions in the prevention and treatment of SSD/FSS in adults compared with inactive control conditions, standard care, or placebo. Individuals at risk for SSD/FSS, suffering from subthreshold symptoms or new onsets of SSD/FSS, or presenting with SSD/FSS for the first time were included.

Results

We identified 30 eligible studies, mostly examining pain-related conditions. Interventions were diverse, ranging from bibliotherapy to cognitive-behavioral therapy. We found positive effects on depression post-treatment (Hedges’ g = 0.12 [95% confidence interval = 0.03–0.2], k = 5) as well as on somatic symptom severity (g = 0.25 [0.096–0.41], k = 17) and health care utilization (g = 0.31 [0.18–0.44], k = 3) at follow-up. However, because of a high risk of bias, sensitivity to corrections for meta-bias, and missing outcome data, findings should be interpreted cautiously.

Conclusions

Our review shows that targeting SSD/FSS at an early stage represents a conceptual and practical challenge. Readily accessible interventions addressing transsymptomatic processes of SSD/FSS development and consolidation are highly needed. Future studies are needed to evaluate individuals with diverse symptoms, examine symptom history thoroughly, use placebo controls, and report outcomes completely to determine the efficacy of early psychological interventions for SSD/FSS.

PROSPERO Registration:
CRD42020140122.
Upfront Use of 177Lu-Labeled PSMA Radioligand Therapy and Treatment Response Assessment in Treatment-Naive Prostate Cancer
Authors: Malik Dharmender , Sen Ishita B. , Thakral Parul , Das Subha Shankar , Manda Divya , CB Virupakshappa
Published: September 2021

Prostatic malignancy is the most common type of nonskin cancer and associated with significant morbidity and mortality. Early androgen deprivation therapy (ADT) is the treatment of choice in metastatic prostate cancer, whereas ADT delays progression of disease, but it is associated with significant adverse effects and frequently impairs the quality of life. Therefore, there is growing interest in treatments to postpone ADT while achieving a good progression-free survival. We present a case of oligometastatic prostate cancer, who was treated upfront with 177Lu-labeled PSMA radioligand therapy and demonstrated excellent response to a single dose of 177Lu-PSMA-617.
Muscle Involvement Caused by Chronic Active Epstein-Barr Virus Infection on 18F-FDG PET/CT in a Pediatric Patient
Authors: Yang Xu , Lu Xia , Kan Ying , Wang Wei , Yang Jigang
Published: September 2021

A 7-year-old girl with chronic active EBV (CAEBV) infection-associated hemophagocytic lymphohistiocytosis presented with fever. 18F-FDG PET/CT revealed heterogeneous FDG uptake in multiple muscle groups without significant abnormal activity elsewhere. On repeat FDG PET/CT scan 1 year later after therapy, the abnormal activity in muscles disappeared. Skeletal muscle involvement by CAEBV infection should be included as differential diagnosis for increased muscle activity on FDG PET/CT study.
68Ga-FAPI PET/CT Imaging of Baastrup Disease in a Patient With Esophageal Cancer
Authors: Yang Xiao , Liu Yuhong , Chen Jinping , Chen Yue , Liu Huipan
Published: September 2021

68Ga-FAPI is a novel PET agent that has been shown to be promising for imaging tumors. Meanwhile, FAPI uptake in nonmalignant diseases has also been reported. Herein, we presented 68Ga-FAPI PET/CT findings of Baastrup disease in a patient with esophageal cancer.
Dual-Time-Point 18F-Fluorocholine PET/CT Improves Characterization of Thyroid Nodules in Patients Referred for Primary Hyperparathyroidism
Authors: Bani Jacob , Morland David , Hubelé Fabrice , Ignat Mihaela , Latge Adrien , Bourahla Khalil , Zalzali Mohamad , Vix Michel , Taïeb David , Imperiale Alessio
Published: September 2021

Purpose

Thyroid nodules frequently coexist with primary hyperparathyroidism (pHPT). Because of the increasing use of 18F-fluorocholine (18F-FCH) PET/CT in patients with pHPT, evaluation of its clinical utility for thyroid nodules characterization in this population is of paramount importance. Herein, we investigate the value of dual-point 18F-FCH PET/CT in the diagnosis of thyroid cancer in patients referred for pHPT imaging who have thyroid nodules.

Patients and Methods

All pHPT patients who underwent a dual-time point 18F-FCH PET/CT (at 5 and 60 minutes postinjection) between July 2019 and December 2020 were analyzed. Only those with a thyroid nodule greater than 10-mm and pathological analysis (criterion standard) were included. Nodule-to-thyroid SUVmax ratio was calculated at the 2 study points, as well as the 18F-FCH washout index (WO%).

Results

Twenty-seven patients (32 nodules) were included in this study. The final diagnoses were as follows: 27 benign nodules including 2 NIFTPs (noninvasive follicular thyroid neoplasm with papillary-like nuclear features) and 5 cancers of follicular origin. Early uptake ratio was significantly higher in malignant lesions than in benign nodules (P = 0.0008). Thyroid cancers were also characterized by a marked 18F-FCH washout index (WO% benign vs cancer: 2.9% ± 4.1% vs 45.5% ± 13.4%, P = 0.0001). Using a WO% threshold of 22.1%, 25/27 benign nodules and 5/5 malignant lesions were accurately classified (sensitivity of 100%, specificity of 92.6%, positive predictive value of 71.4%, and negative predictive value of 100%). The false-positive findings were related to the 2 NIFTPs that share similarities with thyroid cancer.

Conclusions

Our preliminary results suggest to perform a dual-time-point PET/CT acquisition protocol in pHPT patients with uncharacterized centimeter thyroid nodules. However, the real impact of these promising results should be assessed by prospective studies on a larger cohort of patients.
Inhalation of 2% Hydrogen Improves Survival Rate and Attenuates Shedding of Vascular Endothelial Glycocalyx in Rats with Heat Stroke
Authors: Truong Sang Kien , Katoh Takasumi , Mimuro Soichiro , Sato Tsunehisa , Kobayashi Kensuke , Nakajima Yoshiki
Published: September 2021

Heat stroke is characterized by excessive oxidative stress and inflammatory responses, both of which are implicated in vascular endothelial glycocalyx shedding and heat-stroke mortality. Although molecular hydrogen has antioxidation and anti-inflammatory potency, its effect on the vascular endothelial glycocalyx in heat stroke has not been examined. Therefore, the aim of this study was to investigate the influence of hydrogen inhalation on the survival and thickness of the vascular endothelial glycocalyx of rats subjected to heat stroke. Altogether, 98 Wistar rats were assigned to the experiments. A heat-controlled chamber set at 40°C temperature and 60% humidity was used to induce heat stroke. After preparation, the anesthetized rats that underwent the heating process were subjected to an hour of stabilization in which 0%, 2%, or 4% hydrogen gas was inhaled and maintained until the experiment ended. In addition to survival rate assessments, blood samples and left ventricles were collected to evaluate the thickness of the vascular endothelial glycocalyx and relevant biomarkers. The results showed that 2% hydrogen gas significantly improved survival in the heat-stroked rats and partially preserved the thickness of the endothelial glycocalyx. In addition, serum levels of endotoxin, syndecan-1, malondialdehyde, and tumor necrosis factor-α decreased, whereas superoxide dismutase levels increased, indicating that inhalation of 2% hydrogen attenuated the damage to the vascular endothelial glycocalyx through its antioxidative and anti-inflammatory effects.
Coluthur Gopalan. 28 November 1918—3 October 2019
Authors: Ramachandran Prema , Seshadri Malini , Gopalan Sarath
Published: September 2021

Gopalan was a brilliant medical student. The Bengal famine of 1942 made him decide to devote his career to ‘the investigation and mitigation of the nutrition-related problems of Indians, especially those of the disadvantaged sections’. He was the first Indian to win a Nuffield Foundation research scholarship to study in England in 1946. In less than three years he had earned a PhD as well as a DSc in nutrition. He returned to India and joined the Nutrition Research Laboratory in Coonoor. His studies over the next decade showed that, contrary to the global belief, both kwashiorkor and marasmus were manifestations of protein energy malnutrition. His research studies on improving the nutritional status of pregnant women and children with food supplementation led to the initiation of India's Integrated Child Development Scheme and Mid-day Meal programmes. India's National Anaemia Prophylaxis Programme and Massive Dose Vitamin A Supplementation Programme were also initiated on the basis of the studies he led.

As Director General of the Indian Council of Medical Research he created institutions to undertake research in the areas of neglected tropical diseases and medical statistics. He initiated the National Talent Search Scheme to ensure adequate human resources for medical research. After he retired, he set up the Nutrition Foundation of India, to continue with policy and operational research studies on the triple burden of malnutrition. He initiated the setting up of the Nutrition Society of India and the Federation of Asian Nutrition Societies to improve networking among nutrition scientists. In reply to a query on his major contributions, he said: ‘I helped to get Nutrition Science in India the recognition it deserved, and I built institutions that will serve the people of India long after my lifetime.’
A Bayesian method for synthesizing multiple diagnostic outcomes of COVID-19 tests
Authors: Cao Lirong , Zhao Shi , Li Qi , Ling Lowell , Wu William K. K. , Zhang Lin , Lou Jingzhi , Chong Marc K. C. , Chen Zigui , Wong Eliza L. Y. , Zee Benny C. Y. , Chan Matthew T. V. , Chan Paul K. S. , Wang Maggie H.
Published: September 2021

The novel coronavirus disease 2019 (COVID-19) has spread worldwide and threatened human life. Diagnosis is crucial to contain the spread of SARS-CoV-2 infections and save lives. Diagnostic tests for COVID-19 have varying sensitivity and specificity, and the false-negative results would have substantial consequences to patient treatment and pandemic control. To detect all suspected infections, multiple testing is widely used. However, it may be challenging to build an assertion when the testing results are inconsistent. Considering the situation where there is more than one diagnostic outcome for each subject, we proposed a Bayesian probabilistic framework based on the sensitivity and specificity of each diagnostic method to synthesize a posterior probability of being infected by SARS-CoV-2. We demonstrated that the synthesized posterior outcome outperformed each individual testing outcome. A user-friendly web application was developed to implement our analytic framework with free access via
http://www2.ccrb.cuhk.edu.hk/statgene/COVID_19/
. The web application enables the real-time display of the integrated outcome incorporating two or more tests and calculated based on Bayesian posterior probability. A simulation-based assessment demonstrated higher accuracy and precision of the Bayesian probabilistic model compared with a single-test outcome. The online tool developed in this study can assist physicians in making clinical evaluations by effectively integrating multiple COVID-19 tests.
The limits of convergence: the roles of phylogeny and dietary ecology in shaping non-avian amniote crania
Authors: Melstrom Keegan M. , Angielczyk Kenneth D. , Ritterbush Kathleen A. , Irmis Randall B.
Published: September 2021

Cranial morphology is remarkably varied in living amniotes and the diversity of shapes is thought to correspond with feeding ecology, a relationship repeatedly demonstrated at smaller phylogenetic scales, but one that remains untested across amniote phylogeny. Using a combination of morphometric methods, we investigate the links between phylogenetic relationships, diet and skull shape in an expansive dataset of extant toothed amniotes: mammals, lepidosaurs and crocodylians. We find that both phylogeny and dietary ecology have statistically significant effects on cranial shape. The three major clades largely partition morphospace with limited overlap. Dietary generalists often occupy clade-specific central regions of morphospace. Some parallel changes in cranial shape occur in clades with distinct evolutionary histories but similar diets. However, members of a given clade often present distinct cranial shape solutions for a given diet, and the vast majority of species retain the unique aspects of their ancestral skull plan, underscoring the limits of morphological convergence due to ecology in amniotes. These data demonstrate that certain cranial shapes may provide functional advantages suited to particular dietary ecologies, but accounting for both phylogenetic history and ecology can provide a more nuanced approach to inferring the ecology and functional morphology of cryptic or extinct amniotes.
Effect of Ag alloying and trace precipitation on corrosion resistance of Ti-Ta-Ag ternary alloy
Authors: Zhang Jun-Min , Zhao Zong-Yan , Chen Qing-Hua , Chen Xing-Hu , Li Yin-He
Published: September 2021

This work systematically analysed the electrochemical and corrosion behaviour of Ti-Ta-Ag ternary alloy samples in Hank's solution. For the samples with 1.5% and 3% Ag content, the sintering temperature increased from 750 to 950°C, and the corresponding corrosion resistance increased by 100 times due to the increased alloying of Ag; meanwhile for the sample with 4.5% Ag content, the sintering temperature increased from 750 to 950°C, and the corresponding corrosion resistance decreased by six times due to the increased precipitation of Ag. These tests prove that the Ag alloying is beneficial to the enhancement of the corrosion resistance of Ti-Ta-Ag ternary alloy, but the Ag trace precipitation has the opposite effect. A series of electrochemical characterizations and density functional theory calculations explain the mechanism of the above phenomenon. Ag alloying can promote the formation of uniform, complete, dense, stable and thick passivation layer on the surface of Ti-Ta-Ag ternary alloy, which makes Ti-Ta-Ag ternary alloy uniformly corroded without pitting. In addition, Ag alloying can effectively reduce the contact resistance of the solid–liquid interface. However, the trace precipitation of Ag plays the opposite role to the above effect.
Estimating the reproducibility of social learning research published between 1955 and 2018
Authors: Minocher Riana , Atmaca Silke , Bavero Claudia , McElreath Richard , Beheim Bret
Published: September 2021

Reproducibility is integral to science, but difficult to achieve. Previous research has quantified low rates of data availability and results reproducibility across the biological and behavioural sciences. Here, we surveyed 560 empirical publications, published between 1955 and 2018 in the social learning literature, a research topic that spans animal behaviour, behavioural ecology, cultural evolution and evolutionary psychology. Data were recoverable online or through direct data requests for 30% of this sample. Data recovery declines exponentially with time since publication, halving every 6 years, and up to every 9 years for human experimental data. When data for a publication can be recovered, we estimate a high probability of subsequent data usability (87%), analytical clarity (97%) and agreement of published results with reproduced findings (96%). This corresponds to an overall rate of recovering data and reproducing results of 23%, largely driven by the unavailability or incompleteness of data. We thus outline clear measures to improve the reproducibility of research on the ecology and evolution of social behaviour.
Mechanical and permeation response characteristics of basalt fibre reinforced tailings to different reinforcement technologies: an experimental study
Authors: Liu Jianzhong , Yang Han , Zhang Dongming , Wang Yun , Xiao Weijing , Ye Chen , Zheng Binbin , Yang Yushun
Published: September 2021

Tailings dam is a man-made hazard with high potential energy; dam failure would cause great losses to human lives and properties. However, the limitations of conventional reinforcement methods like geosynthetic make it easy to slide along the weak structural plane. In this paper, we innovatively added basalt fibre (BF) with different lengths (l) and contents (ω) into tailings to study its mechanical and permeation characteristics. The results indicate that BF can improve the shear strength (τ), cohesion (c) and compression index (Cc) of tailings, but it has little effect on internal friction angle (φ). Whenlis constant,τ,candCcare positively correlated withω. One notable phenomenon is thatτandcdo not constantly increase withlwhenωis constant, but obtain the maximum under the optimal length of 6 mm. Moreover, whenω> 0.6%, permeability coefficient (k) is greater than that of the original tailings and the sensitivity ofc,φ,τ,Cc,kto fibre content is greater than that of length. The research results facilitate the understanding of BF reinforced tailings, and could serve as references for improving the safety of tailings dam and other artificial soil slopes or soil structures.
Border collision bifurcations of chaotic attractors in one-dimensional maps with multiple discontinuities
Authors: Avrutin Viktor , Panchuk Anastasiia , Sushko Iryna
Published: September 2021

In one-dimensional piecewise smooth maps with multiple borders, chaotic attractors may undergo border collision bifurcations, leading to a sudden change in their structure. We describe two types of such border collision bifurcations and explain the mechanisms causing the changes in the geometrical structure of the attractors, in particular, in the number of their bands (connected components).
Why do some primate mothers carry their infant's corpse? A cross-species comparative study
Authors: Fernández-Fueyo Elisa , Sugiyama Yukimaru , Matsui Takeshi , Carter Alecia J.
Published: September 2021

Non-human primates respond to the death of a conspecific in diverse ways, some of which may present phylogenetic continuity with human thanatological responses. Of these responses, infant corpse carrying by mothers (ICC) is the most frequently reported. Despite its prevalence, quantitative analyses of this behaviour are scarce and inconclusive. We compiled a database of 409 published cases across 50 different primate species of mothers' responses to their infants' deaths and used Bayesian phylogenetic regressions with an information-theoretic approach to test hypotheses proposed to explain between- and within-species variation in ICC. We found that ICC was more likely when the infant's death was non-traumatic (e.g. illness) versus traumatic (e.g. infanticide), and when the mother was younger. These results support the death detection hypothesis, which proposes that ICC occurs when there are fewer contextual or sensory cues indicating death. Such an interpretation suggests that primates are able to attain an awareness of death. In addition, when carried, infant age affected ICC duration, with longer ICC observed for younger infants. This result suggests that ICC is a by-product of strong selection on maternal behaviour. The findings are discussed in the context of the evolution of emotion, and implications for evolutionary thanatology are proposed.
Maternal care in Mid-Cretaceous lagonomegopid spiders
Authors: Guo Xiangbo , Selden Paul A. , Ren Dong
Published: September 2021

Maternal care benefits the survival and fitness of offspring, often at a cost to the mother's future reproduction, and has evolved repeatedly throughout the animal kingdom. In extant spider species, this behaviour is very common and has different levels and diverse forms. However, evidence of maternal care in fossil spiders is quite rare. In this study, we describe four Mid-Cretaceous (approx. 99 Ma) amber specimens from northern Myanmar with an adult female, part of an egg sac and some spiderlings of the extinct family Lagonomegopidae preserved, which suggest that adult lagonomegopid females probably built and then guarded egg sacs in their retreats or nests, and the hatched spiderlings may have stayed together with their mother for some time. The new fossils represent early evidence of maternal care in fossil spiders, and enhance our understanding of the evolution of this behaviour.
Associations between metabolic traits and growth rate in brown trout (
Salmo trutta
) depend on thermal regime
Authors: Archer Louise C. , Hutton Stephen A. , Harman Luke , Russell Poole W. , Gargan Patrick , McGinnity Philip , Reed Thomas E.
Published: September 2021

Metabolism defines the energetic cost of life, yet we still know relatively little about why intraspecific variation in metabolic rate arises and persists. Spatio-temporal variation in selection potentially maintains differences, but relationships between metabolic traits (standard metabolic rate (SMR), maximum metabolic rate (MMR), and aerobic scope) and fitness across contexts are unresolved. We show that associations between SMR, MMR, and growth rate (a key fitness-related trait) vary depending on the thermal regime (a potential selective agent) in offspring of wild-sampled brown trout from two populations reared for approximately 15 months in either a cool or warm (+1.8°C) regime. SMR was positively related to growth in the cool, but negatively related in the warm regime. The opposite patterns were found for MMR and growth associations (positive in warm, negative in the cool regime). Mean SMR, but not MMR, was lower in warm regimes within both populations (i.e. basal metabolic costs were reduced at higher temperatures), consistent with an adaptive acclimation response that optimizes growth. Metabolic phenotypes thus exhibited a thermally sensitive metabolic ‘floor’ and a less flexible metabolic ‘ceiling’. Our findings suggest a role for growth-related fluctuating selection in shaping patterns of metabolic variation that is likely important in adapting to climate change.
High viral SARS-CoV-2 load in placenta of patients with hypertensive disorders after COVID-19 during pregnancy
Authors: Fabre M , Calvo P , Ruiz-Martinez S , Peran M , Oros D , Medel Martinez A , Strunk M , Benito R , Schoorlemmer J , Paules C
Published: September 2021

Introduction

Studies described an increased frequency of hypertensive disorders of pregnancy after a COVID-19 episode. There is limited evidence about SARS-CoV-2 viral load in placenta. This study aimed to investigate the relationship between SARS-CoV-2 viral load in placenta and clinical development of HDP after COVID-19 throughout different periods of gestation.

Methods

This was a case-control study in women with and without gestational hypertensive disorders (HDP) after SARS-CoV-2 infection diagnosed by RT-PCR during pregnancy. Patients were matched by gestational age at the moment of COVID-19 diagnosis. We performed an analysis of SARS-CoV-2 RNA levels in placenta.

Results

A total of 28 women were enrolled. Sixteen patients were diagnosed with COVID-19 during the third trimester and the remaining twelve patients in the others trimesters. Ten placentas (35.7%) were positive for SARS-CoV-2, nine of them (90%) belonged to the HDP group versus one (10%) in control group (p=0.009). Those cases with the highest loads of viral RNA developed severe-preeclampsia.

Conclusion

The presence of SARS-CoV-2 was more frequent in placentas of patients with HDP after COVID-19. There seems to be a relationship between high viral load in the placenta and the development of hypertensive disorders. We found SARS-CoV-2 viral load in placenta after birth in mothers infected at the first half of pregnancy, but with negative nasopharyngeal RT-PCR at delivery. Our data suggest that SARS-CoV-2 infection during pregnancy could trigger gestational hypertensive disorders through placenta-related mechanisms.
A novel RAB11-containing adaptor complex anchoring myosin-5 to secretory vesicles
Authors: Pinar Mario , Alonso Ana , de los Ríos Vivian , Bravo-Plaza Ignacio , Gandara Álvaro , Arias-Palomo Ernesto , Á. Peñalva Miguel
Published: September 2021

Hyphal fungi grow rapidly by apical extension, providing a notorious example of polarized growth. The continuous supply of secretory vesicles necessary to meet the demands of the extending tip and the long intracellular distances existing between the tip and the basal septum, often localized > 100 µm away from the former, impose the need of efficient networks of intracellular traffic involving exquisite cooperation between microtubule- and actin-mediated transport. In Aspergillus nidulans kinesin-1 conveys secretory vesicles to the hyphal tip, where they are transferred to myosin-5, which focuses them at the growing apex, thereby determining cell shape. This relay mechanism and the central role played by myosin-5 in hyphal morphogenesis suggested that the mechanisms anchoring secretory vesicles to this motor should involve specific adaptor(s) ensuring the robustness of actomyosin-dependent transport.

Secretory vesicles are charged with RAB11, a regulatory GTPase that determines the Golgi to post-Golgi identity transition. By using a combination of shotgun proteomics, GST-RAB pull-down assays, in vitro reconstitution experiments, targeted reverse genetics and multidimensional fluorescence microscopy with endogenously tagged proteins we show that RAB11, the master regulator of fungal exocytosis, mediates myosin-5 engagement both by contacting the motor and by recruiting UDS1, a homologue of an as yet uncharacterized Schizosaccharomyces protein ‘upregulated during mitosis’, which we demonstrate to be a novel RAB11 effector. Analytical ultracentrifugation determined that UDS1 is an elongated dimer and negative-stain electron microscopy showed that, in agreement, UDS1 is rod-shaped. UDS1 does not contact myosin-5 directly, but rather recruits the coiled-coil HMSV, which bridges RAB11/UDS1 to myosin-5. An HMSV-scaffolded complex containing UDS1 and myosin-5 is present in cells, and a RAB11-UDS1-HMSV complex can be reconstituted in vitro in a RAB nucleotide state-dependent manner. In the absence of UDS1/HMSV the steady state levels of myosin-5 at the apical vesicle supply center diminish markedly, such that microtubule-dependent transport spreading vesicles across the apical dome predominates over apex-focused actin-mediated transport. As a consequence, RAB11 and chitin-synthase B (a cargo of the RAB11 pathway) are not focused at the apex, being distributed instead across the apical dome. Therefore, the RAB11 effector UDS1/HMSV cooperates with the GTPase to adapt secretory vesicles to myosin-5, which is required for the apical targeting of RAB11 cargoes and thus for the normal morphology of the hyphae.
Germline Missense Variants in CDC20 Result in Aberrant Mitotic Progression and Familial Cancer
Authors: Chen Owen J. , Castellsagué Ester , Moustafa-Kamal Mohamed , Nadaf Javad , Rivera Barbara , Fahiminiya Somayyeh , Wang Yilin , Gamache Isabelle , Pacifico Caterina , Jiang Lai , Carrot-Zhang Jian , Witkowski Leora , Berghuis Albert M. , Schoenberger Stefan , Schneider Dominik , Bens Susanne , Siebert Reiner , Stewart Colin J. R. , Zhang Ziguo , Chao William C. , Greenwood Celia M.T. , Barford David , Tischkowitz Marc , Majewski Jacek , Foulkes William D. , Teodoro Jose G.
Published: September 2021

CDC20 is a co-activator of the anaphase promoting complex/cyclosome (APC/C) and is essential for mitotic progression. APC/CCDC20 is inhibited by the spindle assembly checkpoint (SAC), which prevents premature separation of sister chromatids and aneuploidy in daughter cells. Although overexpression of CDC20 is common in many cancers, oncogenic mutations have never been identified in humans. Using whole exome sequencing, we identified heterozygous missense CDC20 variants (L151R and N331K) that segregate with cancer in two families. Characterization of these mutants showed they retain APC/C activation activity but show reduced binding to BUBR1, a component of the SAC. Expression of L151R and N331K promoted mitotic slippage in HeLa cells and primary skin fibroblasts derived from carriers. CRISPR/Cas9 was used to generate mice carrying N331K. Homozygous mice carrying N331K were non-viable, however, heterozygotes displayed accelerated oncogenicity in Myc-driven cancers. These findings highlight an unappreciated role for CDC20 variants as tumor promoting genes in humans.
A cell-based platform for oxidative stress monitoring in motor neurons using genetically encoded biosensors of H2O2
Authors: Ustyantseva Elizaveta I. , Zakian Suren M. , Medvedev Sergey P.
Published: September 2021

Background

Oxidative stress plays an important role in the development of neurodegenerative diseases: it either can be the initiator or part of a pathological cascade leading to the neuron’s death. Although a lot of methods are known for oxidative stress study, most of them operate on non-native cellular substrates or interfere with the cell functioning. Genetically encoded (GE) biosensors of oxidative stress demonstrated their general functionality and overall safety in various live systems. However, there is still insufficient data regarding their use for research of disease-related phenotypes in relevant model systems, such as human cells.

Methods

We applied CRISPR/Cas9 genome editing to introduce mutations (c.272A>C and c.382G>C) in the associated with amyotrophic lateral sclerosis SOD1 gene of induced pluripotent stem cells (iPSC) obtained from a healthy individual. Using CRISPR/Cas9, we modified these mutant iPSC lines, as well as the parental iPSC line, and a patient-specific SOD1D91A/D91A iPSC line with ratiometric GE biosensors of cytoplasmic (Cyto-roGFP2-Orp1) and mitochondrial (Mito-roGFP2-Orp1) H2O2. The biosensors sequences along with a specific transactivator for doxycycline-controllable expression were inserted in the “safe harbor” AAVS1 (adeno-associated virus site 1) locus. We differentiated these transgenic iPSCs into motor neurons and investigated the functionality of the biosensors in such a system. We measured relative oxidation in the cultured motor neurons and its dependence on culture conditions, age, and genotype, as well as kinetics of H2O2 elimination in real-time.

Results

We developed a cell-based platform consisting of isogenic iPSC lines with different genotypes associated with amyotrophic lateral sclerosis. The iPSC lines were modified with GE biosensors of cytoplasmic and mitochondrial H2O2. We provide proof-of-principle data showing that this approach may be suitable for monitoring oxidative stress in cell models of various neurodegenerative diseases as the biosensors reflect the redox state of neurons.

Conclusion

We found that the GE biosensors inserted in the AAVS1 locus remain functional in motor neurons and reflect pathological features of mutant motor neurons, although the readout largely depends on the severity of the mutation.
The RNA-binding protein DRBD18 regulates processing and export of the mRNA encoding Trypanosoma brucei RNA-binding protein 10
Authors: Tshitenge Tania Bishola , Liu Bin , Clayton Christine
Published: September 2021

The parasite Trypanosoma brucei grows as bloodstream forms in mammalian hosts, and as procyclic forms in tsetse flies. Trypanosome protein coding genes are arranged in polycistronic transcription units, so gene expression regulation depends heavily on post-transcriptional mechanisms. The essential RNA-binding protein RBP10 is expressed only in mammalian-infective forms, where it targets procyclic-specific mRNAs for destruction. We show that developmental regulation of RBP10 expression is mediated by the exceptionally long 7.3 Kb 3’-UTR of its mRNA. Different regulatory sequences that can independently enhance mRNA stability and translation in bloodstream forms, or destabilize and repress translation in procyclic forms, are scattered throughout the 3’-UTR. The RNA-binding protein DRBD18 is implicated in the export of a subset of mRNAs from the nucleus in procyclic forms. We confirmed that in bloodstream forms, DRBD18 copurifies the outer ring of the nuclear pore, mRNA export proteins and exon junction complex proteins. Loss of DRBD18 in bloodstream forms caused accumulation of several shortened RBP10 mRNA isoforms, with loss of longer species, but RNAi targeting the essential export factor MEX67 did not cause such changes, demonstrating specificity. Long RBP10 mRNAs accumulated in the nucleus, while shorter ones reached the cytoplasm. We suggest that DRBD18 binds to processing signals in the RBP10 3’-UTR, simultaneously preventing their use and recruiting mRNA export factors. DRBD18 depletion caused truncation of the 3’-UTRs of more than 100 other mRNAs, suggesting that it has an important role in regulating use of alternative processing sites.
Constitutive loss of DNMT3A causes morbid obesity through misregulation of adipogenesis
Authors: Tovy Ayala , Reyes Jaime M. , Zhang Linda , Huang Yung-Hsin , Rosas Carina , Daquinag Alexes C. , Guzman Anna G. , Ramabadran Raghav , Chen Chun-Wei , Gu Tianpeng , Gupta Sinjini , Ortinau Laura , Park Dongsu , Cox Aaron R. , Rau Rachel E , Hartig Sean M. , Kolonin Mikhail G , Goodell Margaret A.
Published: September 2021

DNA Methyltransferase 3A (DNMT3A) is an important facilitator of differentiation of both embryonic and hematopoietic stem cells. Heterozygous germline mutations in DNMT3A lead to Tatton-Brown-Rahman Syndrome (TBRS), characterized by obesity and excessive height. While DNMT3A is known to impact feeding behavior via the hypothalamus, here we investigated a role in adipocyte progenitors utilizing heterozygous knockout mice that recapitulate cardinal TBRS phenotypes. These mice become morbidly obese due to adipocyte enlargement and tissue expansion. Adipose tissue in these mice exhibited defects in preadipocyte maturation and precocious activation of inflammatory gene networks, including interleukin-6 signaling. Adipocyte progenitor cell lines lacking DNMT3A exhibited aberrant differentiation. Furthermore, mice in which Dnmt3a was specifically ablated in adipocyte progenitors showed enlarged fat depots and increased progenitor numbers, partly recapitulating the TBRS obesity phenotypes. Loss of DNMT3A led to constitutive DNA hypomethylation, such that the DNA methylation landscape of young adipocyte progenitors resemble that of older wild-type mice. Together, our results demonstrate that DNMT3A coordinates both the central and local control of energy storage required to maintain normal weight and prevent inflammatory obesity.
Secretin channel-interactors prevent antibiotic influx during type IV pili assembly in Pseudomonas aeruginosa
Authors: Kwon Oh Hyun , Sher Joel W , Kim Bi-o , Cho You-Hee , Cho Hongbaek
Published: September 2021

Type IV pili (T4P) are important virulence factors involved in host attachment and other aspects of bacterial pathogenesis. In Gram-negative bacteria, the T4P filament is polymerized from pilin subunits at the platform complex in the inner membrane (IM) and exits the outer membrane (OM) through the OM secretin channel. Although essential for T4P assembly and function, the OM secretin complexes can potentially impair the permeability barrier function of the OM and allow the entry of antibiotics and other toxic molecules. The mechanism by which Gram-negative bacteria prevent secretin-mediated OM leakage is currently not well understood. Here, we report a discovery of SlkA and SlkB (PA5122 and PA5123) that prevent permeation of several classes of antibiotics through the secretin channel of Pseudomonas aeruginosa type IV pili. We found these periplasmic proteins interact with the OM secretin complex and prevent toxic molecules from entering through the channel when there is a problem in the assembly of the T4P IM subcomplexes or when docking between the OM and IM complexes is defective. Thus, our results indicate that the secretin channel-interacting proteins play an important role in maintaining the OM permeability barrier, suggesting they may be attractive targets for potentiators that sensitize Gram-negative pathogens to antibiotics that are normally ineffective at penetrating the OM.
Axial multi-layer perceptron architecture for automatic segmentation of choroid plexus in multiple sclerosis
Authors: Schmidt-Mengin Marius , Ricigliano Vito A.G. , Bodini Benedetta , Morena Emanuele , Colombi Annalisa , Hamzaoui Mariem , Yazdan Panah Arya , Stankoff Bruno , Colliot Olivier
Published: September 2021

Choroid plexuses (CP) are structures of the brain ventricles which produce most of the cerebrospinal fluid (CSF). Several postmortem and in vivo studies have pointed towards their role in the inflammatory processes in multiple sclerosis (MS). Automatic segmentation of CP from MRI thus has high value for studying their characteristics in large cohorts of patients. To the best of our knowledge, the only freely available tool for CP segmentation is FreeSurfer but its accuracy for this specific structure is poor. In this paper, we propose to automatically segment CP from non-contrast enhanced T1-weighted MRI. To that end, we introduce a new model called “Axial-MLP” based on an assembly of Axial multi-layer perceptrons (MLPs). This is inspired by recent works which showed that the self-attention layers of Transformers can be replaced with MLPs. This approach is systematically compared with a standard 3D U-Net, nnU-Net, Freesurfer and FastSurfer. For our experiments, we make use of a dataset of 141 subjects (44 controls and 97 patients with MS). We show that all the tested deep learning (DL) methods outperform FreeSurfer (Dice around 0.7 for DL vs 0.33 for FreeSurfer). Axial-MLP is competitive with U-Nets even though it is slightly less accurate. The conclusions of our paper are two-fold: 1) the studied deep learning methods could be useful tools to study CP in large cohorts of MS patients; 2) Axial-MLP is a potentially viable alternative to convolutional neural networks for such tasks, although it could benefit from further improvements.
Selective Modulator of Nuclear Receptor PPARγ with Reduced Adipogenic Potential Ameliorates Experimental Nephrotic Syndrome
Authors: Burton Claire , Rask Galen , Waller Amanda P , Webb Amy , Galdino-Pitta Marina R , Amato Angelica A. , Cianciolo Rachel , Becknell Brian , Kerlin Bryce A , Neves Francisco A. R. , Fornoni Alessia , Agrawal Shipra
Published: September 2021

Background

Glomerular disease, often manifesting as nephrotic syndrome (NS) with high proteinuria, can be refractory to standard treatment and is typically associated with hypoalbuminemia, hypercholesterolemia and hypercoagulopathy. We hypothesized that the nuclear receptor PPARγ can be selectively modulated using a novel partial agonist, GQ-16, to gain therapeutic advantage over traditional PPARγ agonists (e.g. thiazolidinediones) for the treatment of glomerular disease.

Methods

Nephropathy was induced with puromycin amino-nucleoside (PAN) in Wistar rats and treated with Pioglitazone (Pio) or GQ-16. Plasma, serum, and urine chemistries were performed, and kidneys, glomeruli, liver, and white adipose tissue (WAT) were harvested. Lipid accumulation and adipogenic gene expression were measured in adipocytes.

Results

PAN-induced proteinuria was significantly reduced with Pio to 64% of PAN-value. It was reduced robustly with GQ-16 to 81% of PAN, which was comparable to controls. While both GQ-16 and Pio restored glomerularNphs1and hepaticPcsk9expression and reduced hypercholesterolemia, GQ-16 also restored glomerularNrf2, and reduced hypoalbuminemia and hypercoagulopathy. Furthermore, RNA-seq analysis identified both common and distinct restored glomerular genes downstream of Pio and GQ-16. Pio but not GQ-16 significantly inducedaP2(fatty acid binding protein) in adipocytes and in WAT. Pio induced more lipid accumulation than GQ-16 in differentiated adipocytes. Both, Pio and GQ-16 induced insulin sensitizing adipokines in WAT with varying degrees.

Conclusions

Selective modulation of PPARγ by a partial agonist, GQ-16, is more advantageous than pioglitazone in reducing proteinuria and NS associated co-morbidities, while reducing the adipogenic side-effects conferred by traditional PPARγ full agonists.

Translational Statement

The authors have previously reported that type-II diabetes drugs, thiazolidinediones (PPARγ agonists), also provide beneficial effects in reducing podocyte and glomerular injury. However, these drugs are associated with adverse effects such as weight gain, and their effects on glomerular disease-associated features are largely unexplored. Their current findings demonstrate that PPARγ can be selectively modulated by its partial agonist, GQ-16, which reduces proteinuria and improves nephrotic syndrome (NS) with reduced side-effects typically conferred by thiazolidinediones. These findings not only deepen our molecular understanding of the role of PPARγ in glomerular disease and underscore the potential for partial agonists of PPARγ, such as GQ-16 as a treatment modality for NS, but also lend the possibility of its potential benefits in diabetic nephropathy.
Development of a novel, pan-variant aerosol intervention for COVID-19
Authors: Shoemaker Robert H. , Panettieri Reynold A. , Libutti Steven K. , Hochster Howard S. , Watts Norman R. , Wingfield Paul T. , Starkl Philipp , Pimenov Lisabeth , Gawish Riem , Hladik Anastasiya , Knapp Sylvia , Boring Daniel , White Jonathan M. , Lawrence Quentin , Boone Jeremy , Marshall Jason D. , Matthews Rebecca L. , Cholewa Brian D. , Richig Jeffrey W. , Chen Ben T. , McCormick David L. , Gugensberger Romana , Höller Sonja , Penninger Josef M. , Wirnsberger Gerald
Published: September 2021

To develop a universal strategy to block SARS-CoV-2 cellular entry and infection represents a central aim for effective COVID-19 therapy. The growing impact of emerging variants of concern increases the urgency for development of effective interventions. Since ACE2 is the critical SARS-CoV-2 receptor and all tested variants bind to ACE2, some even at much increased affinity (see accompanying paper), we hypothesized that aerosol administration of clinical grade soluble human recombinant ACE2 (APN01) will neutralize SARS-CoV-2 in the airways, limit spread of infection in the lung and mitigate lung damage caused by deregulated signaling in the renin-angiotensin (RAS) and Kinin pathways. Here we show that intranasal administration of APN01 in a mouse model of SARS-CoV-2 infection dramatically reduced weight loss and prevented animal death. As a prerequisite to a clinical trial, we evaluated both virus binding activity and enzymatic activity for cleavage of Ang II following aerosolization. We report successful aerosolization for APN01, retaining viral binding as well as catalytic RAS activity. Dose range-finding and IND-enabling repeat-dose aerosol toxicology testing were conducted in dogs. Twice daily aerosol administration for two weeks at the maximum feasible concentration revealed no notable toxicities. Based on these results, a Phase I clinical trial in healthy volunteers can now be initiated, with subsequent Phase II testing in individuals with SARS-CoV-2 infection. This strategy could be used to develop a viable and rapidly actionable therapy to prevent and treat COVID-19, against all current and future SARS-CoV-2 variants.

One Sentence Summary

Preclinical development and evaluation of aerosolized soluble recombinant human ACE2 (APN01) administered as a COVID-19 intervention is reported.
Controls on the isotopic composition of microbial methane
Authors: Gropp Jonathan , Jin Qusheng , Halevy Itay
Published: September 2021

Microbial methane production (methanogenesis) is responsible for more than half of the annual emission of this major greenhouse gas to the atmosphere. Though the stable isotopic composition of methane is often used to characterize its sources and sinks, strictly empirical descriptions of the isotopic signature of methanogenesis currently limit such attempts. We developed a biochemical-isotopic model of methanogenesis by CO2 reduction, which predicts carbon and hydrogen isotopic fractionations, and clumped isotopologue distributions, as functions of the cell’s environment. We mechanistically explain multiple-isotopic patterns in laboratory and natural settings and show that such patterns constrain the in-situ energetics of methanogenesis. Combining our model with environmental data, we infer that in almost all marine environments and gas deposits, energy-limited methanogenesis operates close to chemical and isotopic equilibrium.
Evolutionary dynamics of pseudoautosomal region 1 in humans and great apes
Authors: Bergman Juraj , Schierup Mikkel Heide
Published: September 2021

The pseudoautosomal region 1 (PAR1) is a 2.7 Mb telomeric region of human sex chromosomes. As the largest point of contact between the X and Y, PAR1 has a crucial role in ensuring proper segregation of sex chromosomes during male meiosis, exposing it to extreme recombination and associated mutational processes. We investigate PAR1 evolution using population genomic datasets of extant humans, eight populations of great apes and two archaic human genome sequences. We find that the PAR1 sequence is closer to nucleotide equilibrium than autosomal telomeric sequences. We detect a difference between long-term substitution patterns and extant diversity in PAR1 that is mainly driven by the conflict between strong mutation and recombination-associated fixation bias at CpG sites. Additionally, we detect excess C→G mutations in PAR1 of all great ape species, specific to the mutagenic effect of male recombination. Analysis of differences between frequencies of alleles segregating in females and males provided no evidence for sexually antagonistic selection in this region. Furthermore, despite recent evidence for Y chromosome introgression from humans into Neanderthals, we find that the Neanderthal PAR1 retained similarity to the Denisovan sequence, as is the case for the X chromosome and the autosomes. Lastly, we study repeat content and double-strand break hotspot regions in PAR1 and find that they may play roles in ensuring the obligate X-Y recombination event during male meiosis. Our study provides an unprecedented quantification of population genetic forces and insight into evolutionary processes governing PAR1 biology.