bluuebunny/crossref_metadata_2025 huggingface dataset:
A three-gene cluster in Trichoderma reesei reveals a potential role of dmm2 in DNA repair and cellulase production
Authors: Cai Wanchuan , Chen Yumeng , Zhang Lei , Fang Xu , Wang Wei
Published: March 2022

Background

The ascomycete Trichoderma reesei is one of the most efficient industrial producers of cellulase. Gene targeting by homologous recombination is a key technique for improving strains and constructing mutants. In T. reesei, tku70 (homologous to human KU70) was deleted to block non-homologous end-joining, which led to 95% of transformants exhibiting homologous recombination.

Results

Two genes located in close proximity to tku70 were identified: the ferrochelatase gene hem8 (tre78582, homologous to Aspergillus niger hemH and Cryptococcus neoformans HEM15) and a putative DNA methylation modulator-2 gene dmm2 (tre108087, homologous to Neurospora crassa dmm-2). Genome-wide surveys of 324 sequenced fungal genomes revealed that the homologues of the three genes of interest are encoded in tandem in most Sordariomycetes. The expression of this three-gene cluster is regulated by blue light. The roles of these three genes were analyzed via deletion and complementation tests. The gene hem8 was originally described as a novel and highly distinct auxotrophic marker in T. reesei and we found that the product protein, HEM8, catalyzes the final step in heme biosynthesis from highly photoreactive porphyrins. The lethal phenotype of the hem8 deletion could be overcome by hematin supplementation. We also studied the functions of tku70 and dmm2 in DNA repair using mutagen sensitivity experiments. We found that the Δtku70 strain showed increased sensitivity to bleomycin, which induces DNA double-strand breaks, and that the Δdmm2 strain was sensitive to bleomycin, camptothecin (an inhibitor of type I topoisomerases), and hydroxyurea (a deoxynucleotide synthesis inhibitor). The double-mutant Δtku70&dmm2 showed higher sensitivity to hydroxyurea, camptothecin, and bleomycin than either of the single mutants. Knockout of dmm2 significantly increased cellulase production.

Conclusions

Our data show, for the first time, that ferrochelatase encoded by hem8 catalyzes the final step in heme biosynthesis from highly photoreactive porphyrins and that dmm2 encodes a putative DNA methylation modulator-2 protein related to DNA repair and cellulase expression in T. reesei. Our data provide important insights into the roles of this three-gene cluster in T. reesei and other Sordariomycetes and show that the DNA methylation modulator DMM2 affects cellulase gene expression in T. reesei.
An 8-gene machine learning model improves clinical prediction of severe dengue progression
Authors: Liu Yiran E. , Saul Sirle , Rao Aditya Manohar , Robinson Makeda Lucretia , Agudelo Rojas Olga Lucia , Sanz Ana Maria , Verghese Michelle , Solis Daniel , Sibai Mamdouh , Huang Chun Hong , Sahoo Malaya Kumar , Gelvez Rosa Margarita , Bueno Nathalia , Estupiñan Cardenas Maria Isabel , Villar Centeno Luis Angel , Rojas Garrido Elsa Marina , Rosso Fernando , Donato Michele , Pinsky Benjamin A. , Einav Shirit , Khatri Purvesh
Published: March 2022

Background

Each year 3–6 million people develop life-threatening severe dengue (SD). Clinical warning signs for SD manifest late in the disease course and are nonspecific, leading to missed cases and excess hospital burden. Better SD prognostics are urgently needed.

Methods

We integrated 11 public datasets profiling the blood transcriptome of 365 dengue patients of all ages and from seven countries, encompassing biological, clinical, and technical heterogeneity. We performed an iterative multi-cohort analysis to identify differentially expressed genes (DEGs) between non-severe patients and SD progressors. Using only these DEGs, we trained an XGBoost machine learning model on public data to predict progression to SD. All model parameters were “locked” prior to validation in an independent, prospectively enrolled cohort of 377 dengue patients in Colombia. We measured expression of the DEGs in whole blood samples collected upon presentation, prior to SD progression. We then compared the accuracy of the locked XGBoost model and clinical warning signs in predicting SD.

Results

We identified eight SD-associated DEGs in the public datasets and built an 8-gene XGBoost model that accurately predicted SD progression in the independent validation cohort with 86.4% (95% CI 68.2–100) sensitivity and 79.7% (95% CI 75.5–83.9) specificity. Given the 5.8% proportion of SD cases in this cohort, the 8-gene model had a positive and negative predictive value (PPV and NPV) of 20.9% (95% CI 16.7–25.6) and 99.0% (95% CI 97.7–100.0), respectively. Compared to clinical warning signs at presentation, which had 77.3% (95% CI 58.3–94.1) sensitivity and 39.7% (95% CI 34.7–44.9) specificity, the 8-gene model led to an 80% reduction in the number needed to predict (NNP) from 25.4 to 5.0. Importantly, the 8-gene model accurately predicted subsequent SD in the first three days post-fever onset and up to three days prior to SD progression.

Conclusions

The 8-gene XGBoost model, trained on heterogeneous public datasets, accurately predicted progression to SD in a large, independent, prospective cohort, including during the early febrile stage when SD prediction remains clinically difficult. The model has potential to be translated to a point-of-care prognostic assay to reduce dengue morbidity and mortality without overwhelming limited healthcare resources.
Asymptomatic foot and ankle structural injuries: a 3D imaging and finite element analysis of elite fencers
Authors: Lu Congfei , Fan Yuxuan , Yu Genyu , Chen Hua , Sinclair Jonathan , Fan Yifang
Published: March 2022

Background

Fencing is a highly asymmetrical combat sport, that imposes high mechanical demands over repeated exposures on the musculoskeletal structures, a primary cause of injuries in fencers. However, there are limited epidemiological studies on the structural injuries of the foot and ankle in fencers. This study aimed to investigate foot and ankle structural injuries, and explore how metatarsophalangeal joint structural changes may affect the mechanisms of foot and ankle injuries in asymptomatic fencers.

Methods

3D images of foot and ankle morphology using computed tomography were obtained from ten elite fencers. We then constructed finite element models of the first metatarsophalangeal joint in the foot of their trail legs. The validated models were used to simulate stress distribution changes from different ankle joint angles during lunging.

Results

The findings showed that stress distribution changes at the medial and lateral sesamoid may have caused sesamoid fractures, and that habitual and concentrated stress on the metatarsal bones might have flattened the sesamoid groove. This process may damage the integrity of the first metatarsophalangeal joint, and consequently affect the efficiency of the windlass mechanism in fencers. During lunging, different ankle joint angles of the trail foot increased the total stress difference of the medial and lateral foot, and thus influenced the lunging quality and its stability.

Conclusions

Our findings revealed that the asymmetric nature of fencing might have caused asymptomatic foot and ankle structural injuries, and finite element analysis results indicated that this might increase the incidence of the serious injuries if unattended. Regular computed tomography examination should be introduced to monitor elite fencers’ lower limb alterations, permitting unique angle adjustments in the trail foot without sacrificing technical or physiologic properties based on the exam results and reduce the lower limb injury risk.
Transcriptome resequencing data for rock pigeon (Columba livia)
Authors: Kharrati-Koopaee Hamed , Esmailizadeh Ali , Sabahi Fatemeh
Published: March 2022

Objective

How do birds navigate their way? It is one of the interesting question about homing pigeons, however the genetic of navigation has reminded as a puzzle. Optic lobe, olfactory bulb, hippocampus and cere were collected for RNA sampling. The generated RNA-seq represent RNA resequencing data for racing homer (homing) pigeon and other rock pigeon breeds. The obtained data set can provide new insight about hippocampus role and GSR contribution to pigeon magnetoreception.

Data description

To investigate the navigation ability of rock pigeon breeds, 60 whole transcriptome sequence data sets related to homing pigeon, Shiraz tumblers, feral pigeons and Persian high flyers were obtained. RNA extraction was performed from three brain regions (optic lobe, olfactory bulb, hippocampus) and cere. Paired-end 150 bp short reads (Library size 350 bp) were sequenced by Illumina Hiseq 2000. In this way, about 342.1 Gbp and 130.3 Gb data were provided. The whole transcriptome data sets have been deposited at the NCBI SRA database (PRJNA532674). The submitted data set may play critical role to describe the mechanism of navigation ability of rock pigeon breeds.
Efficacy of SGLT2 inhibitors as additional treatment in Japanese type 2 diabetic patients: second or third choice?
Authors: Fujiwara Makoto , Shimizu Masaru , Maejima Yuko , Shimomura Kenju
Published: March 2022

Objectives

Due to the increase of type 2 diabetes (T2D), the number of patients in treatment with multiple anti-diabetic agents is increased. According to the recent recommendation of treatment guidelines, sodium-glucose cotransporter 2 (SGLT2) inhibitors would be used as additional treatment to the currently administered anti-diabetic drugs for poorly controlled T2D patients. Here, we assessed the efficacy of SGLT2 inhibitors added to the current treatment with metformin, dipeptidyl peptidase-4 (DPP4) inhibitors, or both in Japanese T2D patients.

Results

Japanese T2D subjects with poor glucose control, who were treated with metformin (n = 10), DPP4 inhibitors (n = 11), or both (n = 28) and who were in need of additional treatment, were recruited. HbA1c levels before and 6 months after addition of SGLT2 inhibitor treatment were used to compare the effectiveness. The HbA1c levels after addition of SGLT2 inhibitors significantly decreased in all groups. The change in HbA1c levels (delta HbA1c) showed no significant difference between the three groups. The present data indicated that addition of SGLT2 inhibitors to metformin and/or DPP4 inhibitors is equally effective in the treatment of Japanese T2D patients.
Epigenome-wide DNA methylation profiling of conditioned pain modulation in individuals with non-specific chronic low back pain
Authors: Goodin Burel R. , Overstreet Demario S. , Penn Terence M. , Bakshi Rahm , Quinn Tammie L. , Sims Andrew , Ptacek Travis , Jackson Pamela , Long D. Leann , Aroke Edwin N.
Published: March 2022

Background

The pathoanatomic cause of chronic low back pain (cLBP) cannot be identified for up to 90% of individuals. However, dysfunctional processing of endogenous nociceptive input, measured as conditioned pain modulation (CPM), has been associated with cLBP and may involve changes in neuronal gene expression. Epigenetic-induced changes such as DNA methylation (DNAm) have been associated with cLBP.

Methods

In the present study, the relationship between CPM and DNAm changes in a sample of community-dwelling adults with nonspecific cLBP (n = 48) and pain-free controls (PFC; n = 50) was examined using reduced representation bisulfite sequencing. Gene ontology (GO) term enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were applied to identify key pathways involved in efficient versus deficient CPM.

Results

Based on CPM efficiency, we identified 6006 and 18,305 differentially methylated CpG sites (DMCs) with q values < 0.01 among individuals with cLBP and PFCs, respectively. Most of the DMCs were hypomethylated and annotated to genes of relevance to pain, including OPRM1, ADRB2, CACNA2D3, GNA12, LPL, NAXD, and ASPHD1. In both cLBP and PFC groups, the DMCs annotated genes enriched many GO terms relevant to pain processing, including transcription regulation by RNA polymerase II, nervous system development, generation of neurons, neuron differentiation, and neurogenesis. Both groups also enriched the pathways involved in Rap1-signaling, cancer, and dopaminergic neurogenesis. However, MAPK-Ras signaling pathways were enriched in the cLBP, not the PFC group.

Conclusions

This is the first study to investigate the genome-scale DNA methylation profiles of CPM phenotype in adults with cLBP and PFCs. Based on CPM efficiency, fewer DMC enrichment pathways were unique to the cLBP than the PFCs group. Our results suggest that epigenetically induced modification of neuronal development/differentiation pathways may affect CPM efficiency, suggesting novel potential therapeutic targets for central sensitization. However, CPM efficiency and the experience of nonspecific cLBP may be independent. Further mechanistic studies are required to confirm the relationship between CPM, central sensitization, and nonspecific cLBP.
Combining plasma phospho-tau and accessible measures to evaluate progression to Alzheimer’s dementia in mild cognitive impairment patients
Authors: Pichet Binette Alexa , Palmqvist Sebastian , Bali Divya , Farrar Gill , Buckley Christopher J. , Wolk David A. , Zetterberg Henrik , Blennow Kaj , Janelidze Shorena , Hansson Oskar
Published: March 2022

Background

Up to now, there are no clinically available minimally invasive biomarkers to accurately identify mild cognitive impairment (MCI) patients who are at greater risk to progress to Alzheimer’s disease (AD) dementia. The recent advent of blood-based markers opens the door for more accessible biomarkers. We aimed to identify which combinations of AD related plasma biomarkers and other easily accessible assessments best predict progression to AD dementia in patients with mild cognitive impairment (MCI).

Methods

We included patients with amnestic MCI (n = 110) followed prospectively over 3 years to assess clinical status. Baseline plasma biomarkers (amyloid-β 42/40, phosphorylated tau217 [p-tau217], neurofilament light and glial fibrillary acidic protein), hippocampal volume, APOE genotype, and cognitive tests were available. Logistic regressions with conversion to amyloid-positive AD dementia within 3 years as outcome was used to evaluate the performance of different biomarkers measured at baseline, used alone or in combination. The first analyses included only the plasma biomarkers to determine the ones most related to AD dementia conversion. Second, hippocampal volume, APOE genotype and a brief cognitive composite score (mPACC) were combined with the best plasma biomarker.

Results

Of all plasma biomarker combinations, p-tau217 alone had the best performance for discriminating progression to AD dementia vs all other combinations (AUC 0.84, 95% CI 0.75–0.93). Next, combining p-tau217 with hippocampal volume, cognition, and APOE genotype provided the best discrimination between MCI progressors vs. non-progressors (AUC 0.89, 0.82–0.95). Across the few best models combining different markers, p-tau217 and cognition were consistently the main contributors. The most parsimonious model including p-tau217 and cognition had a similar model fit, but a slightly lower AUC (0.87, 0.79–0.95, p = 0.07).

Conclusion

We identified that combining plasma p-tau217 and a brief cognitive composite score was strongly related to greater risk of progression to AD dementia in MCI patients, suggesting that these measures could be key components of future prognostic algorithms for early AD.

Trial registration

NCT01028053, registered December 9, 2009.
MRI in female pelvis: an ESUR/ESR survey
Authors: Nougaret Stephanie , Lakhman Yulia , Gourgou Sophie , Kubik-Huch Rahel , Derchi Lorenzo , Sala Evis , Forstner Rosemarie ,   the European Society of Radiology (ESR) and the European Society of Urogenital Radiology (ESUR)
Published: March 2022

Objectives

While magnetic resonance imaging (MRI) is considered the gold standard for the imaging of female pelvis, there is an ongoing debate about the most appropriate indications and optimal imaging protocols. The European Society of Urogenital Radiology (ESUR) launched a survey to evaluate the current utilization of female pelvic MRI in clinical practice.

Methods

The ESUR female imaging subgroup developed an online survey that was then approved by the ESR board and circulated among the ESR members. The questions in the survey encompassed training and experience, indications for imaging and MR imaging protocols, reporting styles and preferences. The results of the survey were tabulated, and subgroups were compared using χ2 test.

Results

A total of 5900 ESR members with an interest in both MRI and female pelvic imaging were invited to participate; 840 (14.23%) members completed the survey. Approximately 50% of respondents were academic radiologists (50.6%) and nearly 60% women (59.69%). One third of the respondents were subspecialized in Gynecological imaging. Nearly half of the survey participants were aware of the presence of ESUR guidelines for imaging of the female pelvis (47.1%). The adoption of the ESUR recommendations was higher among subspecialized and/or academic and/or senior and/or European radiologists compared to all others. The current ESUR recommendations about female pelvic MRI protocols were generally followed. However wide variations in practice were identified with respect to the use of contrast media.

Conclusion

Female pelvic MRI protocol was generally following the ESUR recommendations, especially among subspecialized and academic radiologists. However, the fact that they are followed by only half of the participants highlights the need for wider awareness of these recommendations.
The utility of splenic imaging parameters in cardiac magnetic resonance for the diagnosis of immunoglobulin light-chain amyloidosis
Authors: Lama Niki , Briasoulis Alexandros , Karavasilis Efstratios , Stamatelopoulos Kimon , Chasouraki Angeliki , Alexopoulou Efthymia , Spiliopoulos Stavros , Theodorakakou Foteini , Dimopoulos Meletios Athanasios , Kastritis Efstathios , Kelekis Nikolaos L.
Published: March 2022

Objectives

Cardiac magnetic resonance (CMR) imaging is a key test in the diagnosis of cardiac amyloidosis (CA). Extracardiac involvement is common in light chain (AL) amyloidosis and MRI findings may assist in its diagnosis. We sought to investigate the utility of splenic CMR parameters for the diagnosis of CA.

Methods

Thirty-four patients with AL amyloidosis and 32 patients with severe left ventricular hypertrophy in the setting of aortic stenosis (LVH-AS) who completed 3T cardiac MRI at the time of their diagnosis of AL or LVH-AS were assessed with T1, T2 (modified Look-Locker inversion recovery), extracellular volume (ECV) mapping, and late gadolinium enhancement (LGE) imaging of the heart and spleen.

Results

Age, left ventricular mass index, wall thickness, ejection fraction, and splenic dimensions did not differ significantly between groups. All AL patients had cardiac involvement. T1 and T2 spleen mapping did not differ significantly between groups but AL patients had higher median ECV in the spleen than in LVH-AS (AL 46.9%, LVH-AS: 31%, p < 0.001), and significantly lower short tau inversion recovery ratio (AL: 1.7, LVH-AS: 2.7, p < 0.001) both with very good diagnostic performance to diagnose AL. We identified 16 AL patients with spleen involvement and 16 without. Spleen ECV and “normalized” spleen ratio, defined as the ratio of spleen LGE to muscle values exhibited strong correlation and had excellent diagnostic performance to discriminate those with spleen involvement.

Conclusion

Our findings show that spleen CMR parameters can identify spleen involvement in AL patients and differentiate them from those without AL amyloidosis.
Impact of defacing on automated brain atrophy estimation
Authors: Rubbert Christian , Wolf Luisa , Turowski Bernd , Hedderich Dennis M. , Gaser Christian , Dahnke Robert , Caspers Julian ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: March 2022

Background

Defacing has become mandatory for anonymization of brain MRI scans; however, concerns regarding data integrity were raised. Thus, we systematically evaluated the effect of different defacing procedures on automated brain atrophy estimation.

Methods

In total, 268 Alzheimer’s disease patients were included from ADNI, which included unaccelerated (n = 154), within-session unaccelerated repeat (n = 67) and accelerated 3D T1 imaging (n = 114).

Atrophy maps were computed using the open-source software veganbagel for every original, unmodified scan and after defacing using afni_refacer, fsl_deface, mri_deface, mri_reface, PyDeface or spm_deface, and the root-mean-square error (RMSE) between z-scores was calculated.

RMSE values derived from unaccelerated and unaccelerated repeat imaging served as a benchmark. Outliers were defined as RMSE > 75th percentile and by using Grubbs’s test.

Results

Benchmark RMSE was 0.28 ± 0.1 (range 0.12–0.58, 75th percentile 0.33).

Outliers were found for unaccelerated and accelerated T1 imaging using the 75th percentile cutoff: afni_refacer (unaccelerated: 18, accelerated: 16), fsl_deface (unaccelerated: 4, accelerated: 18), mri_deface (unaccelerated: 0, accelerated: 15), mri_reface (unaccelerated: 0, accelerated: 2) and spm_deface (unaccelerated: 0, accelerated: 7). PyDeface performed best with no outliers (unaccelerated mean RMSE 0.08 ± 0.05, accelerated mean RMSE 0.07 ± 0.05).

The following outliers were found according to Grubbs’s test: afni_refacer (unaccelerated: 16, accelerated: 13), fsl_deface (unaccelerated: 10, accelerated: 21), mri_deface (unaccelerated: 7, accelerated: 20), mri_reface (unaccelerated: 7, accelerated: 6), PyDeface (unaccelerated: 5, accelerated: 8) and spm_deface (unaccelerated: 10, accelerated: 12).

Conclusion

Most defacing approaches have an impact on atrophy estimation, especially in accelerated 3D T1 imaging. Only PyDeface showed good results with negligible impact on atrophy estimation.
Structural failure in bridging stentgrafts for branched endovascular aneurysm repair: a case–control study
Authors: Hauck Sven R. , Kupferthaler Alexander , Freund Martin C. , Pichler Peter , Stelzmüller Marie-Elisabeth , Burghuber Christopher , Ehrlich Marek , Teufelsbauer Harald , Loewe Christian , Funovics Martin A.
Published: March 2022

Objective

To present a case series of spontaneous structural failure of bridging stentgrafts (BSGs) after branched endovascular aortic repair (bEVAR), as well as their failure types and their detection. While bEVAR is a safe and effective procedure, one main limitation is the reintervention rate associated with the BSGs. Structural failure of BSGs, defined as fabric disruption, stent fracture with leak or complete separation is a major cause for reinterventions and difficult to detect in computed tomography angiography (CTA).

Methods

From a multicenter bEVAR complication database, structural BSG failures were identified. Patient and BSG characteristics, detection mode, failure type, treatment and outcome were recorded and compared with bEVAR patients with intact BSGs.

Results

Twenty-three BSG failures were detected in 12 patients with only 43% directly identified in CTA, after a mean of 21.4 months after implantation. The BSGs were Advanta (n = 4), E-Ventus (n = 16) and BeGraft (n = 3) in 10 renal, 9 superior mesenteric, and 4 celiac branches. Religning with another BSG was successful in 20/22 cases, one BSG failure necessitated renal branch embolization (organ loss), and one mesenteric bypass surgery. Two reintervention-related mortalities occurred.

Conclusion

Structural failure of BSGs is a serious limitation for bEVAR, which can result in high reintervention rates and serious complications. BSG failure typically occurs in single-layer types and events are clustered in patients. The necessary reinterventions carry serious morbidity and mortality. Since the use as BSG in bEVAR is off-label with all current BSG manufacturers, caution is advised regarding patient-informed consent.
Contamination of CT scanner surfaces with SARS-CoV-2 and infective potential after examination of invasively ventilated, non-invasively ventilated and non-ventilated patients with positive throat swabs: prospective investigation using real-time reverse-transcription PCR and viral cell culture
Authors: Göhler Friedemann , Corman Victor M. , Bleicker Tobias , Stroux Andrea , Dewey Marc , Diekhoff Torsten
Published: March 2022

Background

During the current severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) pandemic, computed tomography (CT) has become widely used in patients with suspected or known coronavirus disease 2019 (COVID-19). This prospective observational study in 28 invasively ventilated and 18 non-invasively ventilated patients with confirmed SARS-CoV-2 contamination aims at investigating SARS-CoV-2 contamination of CT scanner surfaces and its infectiousness.

Methods

Swab sampling of the CT table and gantry before and after CT examinations was performed. Additionally, the CT ventilation system air grid was wiped off after each examination. Real-time reverse-transcription polymerase chain reaction (RT-PCR) for SARS-CoV-2 RNA (ribonucleic acid) and viral cell culture were performed in the virology core lab.

Results

After examination of non-invasively ventilated or non-ventilated patients, SARS-CoV-2 RNA was found in 11.1% (4/36) on patient near surfaces (CT table and gantry) and in 16.7% (3/18) on the CT air grid respectively after examination of invasively ventilated patients in 5.4% (3/56) on CT table and gantry and 7.1% (2/28) on the CT air grid. Surface contamination was more common in non-invasively ventilated or non-ventilated patients with a high viral load who were actively coughing. RT-PCR cycle threshold (Ct) was high (35.96–39.31) in all positive samples and no positive viral cell culture was found.

Conclusion

Our study suggests that CT scanner surface contamination with SARS-CoV-2 is considerable and more common after examination of non-invasively ventilated or non-ventilated patients compared to invasively ventilated patients. However, no viral cell culture positivity was found, hence the infectious potential seems low.
A transgenic mouse embryonic stem cell line for puromycin selection of V0V interneurons from heterogenous induced cultures
Authors: Pardieck Jennifer , Harb Manwal , Sakiyama-Elbert Shelly E.
Published: March 2022

Background

Spinal interneurons (INs) relay sensory and motor control information between the brain and body. When this relay circuitry is disrupted from injury or disease, it is devastating to patients due to the lack of native recovery in central nervous system (CNS) tissues. Obtaining a purified population of INs is necessary to better understand their role in normal function and as potential therapies in CNS. The ventral V0 (V0V) INs are excitatory neurons involved in locomotor circuits and are thus of interest for understanding normal and pathological spinal cord function. To achieve scalable amounts of V0V INs, they can be derived from pluripotent sources, such as mouse embryonic stem cells (mESCs), but the resultant culture is heterogenous, obscuring the specific role of V0V INs. This study generated a transgenic mESC line to enrich V0V INs from induced cultures to allow for a scalable, enriched population for future in vitro and in vivo studies.

Methods

The transgenic Evx1-PAC mESC line was created by CRISPR-Cas9-mediated insertion of puromycin-N-acetyltransferase (PAC) into the locus of V0V IN marker Evx1. Evx1 and PAC mRNA expression were measured by qPCR. Viability staining helped establish the selection protocol for V0V INs derived from Evx1-PAC mESCs inductions. Immunostaining was used to examine composition of selected inductions. Cultures were maintained up to 30 days to examine maturation by expression of mature/synaptic markers, determined by immunostaining, and functional activity in co-cultures with selected motor neurons (MNs) and V2a INs on microelectrode arrays (MEAs).

Results

V0V IN inductions were best selected with 4 µg/mL puromycin on day 10 to 11 and showed reduction of other IN populations and elimination of proliferative cells. Long-term selected cultures were highly neuronal, expressing neuronal nuclear marker NeuN, dendritic marker MAP2, pre-synaptic marker Bassoon, and glutamatergic marker VGLUT2, with some cholinergic VAChT-expressing cells. Functional studies on MEAs showed that co-cultures with MNs or MNs plus V2a INs created neuronal networks with synchronized bursting.

Conclusions

Evx1-PAC mESCs can be used to purify V0V IN cultures for largely glutamatergic neurons that can be used in network formation studies or for rodent models requiring transplanted V0V INs.
Transformer-based molecular optimization beyond matched molecular pairs
Authors: He Jiazhen , Nittinger Eva , Tyrchan Christian , Czechtizky Werngard , Patronov Atanas , Bjerrum Esben Jannik , Engkvist Ola
Published: March 2022

Molecular optimization aims to improve the drug profile of a starting molecule. It is a fundamental problem in drug discovery but challenging due to (i) the requirement of simultaneous optimization of multiple properties and (ii) the large chemical space to explore. Recently, deep learning methods have been proposed to solve this task by mimicking the chemist’s intuition in terms of matched molecular pairs (MMPs). Although MMPs is a widely used strategy by medicinal chemists, it offers limited capability in terms of exploring the space of structural modifications, therefore does not cover the complete space of solutions. Often more general transformations beyond the nature of MMPs are feasible and/or necessary, e.g. simultaneous modifications of the starting molecule at different places including the core scaffold. This study aims to provide a general methodology that offers more general structural modifications beyond MMPs. In particular, the same Transformer architecture is trained on different datasets. These datasets consist of a set of molecular pairs which reflect different types of transformations. Beyond MMP transformation, datasets reflecting general structural changes are constructed from ChEMBL based on two approaches: Tanimoto similarity (allows for multiple modifications) and scaffold matching (allows for multiple modifications but keep the scaffold constant) respectively. We investigate how the model behavior can be altered by tailoring the dataset while using the same model architecture. Our results show that the models trained on differently prepared datasets transform a given starting molecule in a way that it reflects the nature of the dataset used for training the model. These models could complement each other and unlock the capability for the chemists to pursue different options for improving a starting molecule.
Clinical feasibility and impact of data-driven respiratory motion compensation studied in 200 whole-body 18F-FDG PET/CT scans
Authors: Dias André H. , Schleyer Paul , Vendelbo Mikkel H. , Hjorthaug Karin , Gormsen Lars C. , Munk Ole L.
Published: March 2022

Background

This study examines the clinical feasibility and impact of implementing a fully automated whole-body PET protocol with data-driven respiratory gating in patients with a broad range of oncological and non-oncological pathologies 592 FDG PET/CT patients were prospectively included. 200 patients with lesions in the torso were selected for further analysis, and ungated (UG), belt gated (BG) and data-driven gating (DDG) images were reconstructed. All images were reconstructed using the same data and without prolonged acquisition time for gated images. Images were quantitatively analysed for lesion uptake and metabolic volume, complemented by a qualitative analysis of visual lesion detection. In addition, the impact of gating on treatment response evaluation was evaluated in 23 patients with malignant lymphoma.

Results

Placement of the belt needed for BG was associated with problems in 27% of the BG scans, whereas no issues were reported using DDG imaging. For lesion quantification, DDG and BG images had significantly greater SUV values and smaller volumes than UG. The physicians reported notable image blurring in 44% of the UG images that was problematic for clinical evaluation in 4.5% of cases.

Conclusion

Respiratory motion compensation using DDG is readily integrated into clinical routine and produce images with more accurate and significantly greater SUV values and smaller metabolic volumes. In our broad cohort of patients, the physicians overwhelmingly preferred gated over ungated images, with a slight preference for DDG images. However, even in patients with malignant disease in the torso, no additional diagnostic information was obtained by the gated images that could not be derived from the ungated images.
DNA in extracellular vesicles: from evolution to its current application in health and disease
Authors: Ghanam Jamal , Chetty Venkatesh Kumar , Barthel Lennart , Reinhardt Dirk , Hoyer Peter-Friedrich , Thakur Basant Kumar
Published: March 2022

Extracellular vesicle (EV) secretion is a highly conserved evolutionary trait in all organisms in the three domains of life. The packaging and release of EVs appears to be a bulk-flow process which takes place mainly under extreme conditions. EVs participate in horizontal gene transfer, which supports the survival of prokaryotic and eukaryotic microbes. In higher eukaryotes, almost all cells secrete a heterogeneous population of EVs loaded with various biomolecules. EV secretion is typically higher in cancer microenvironments, promoting tumor progression and metastasis. EVs are now recognized as additional mediators of autocrine and paracrine communication in health and disease. In this context, proteins and RNAs have been studied the most, but extracellular vesicle DNA (EV-DNA) has started to gain in importance in the last few years. In this review, we summarize new findings related to the loading mechanism(s), localization, and post-shedding function of EV-DNA. We also discuss the feasibility of using EV-DNA as a biomarker when performing a liquid biopsy, at the same time emphasizing the lack of data from clinical trials in this regard. Finally, we outline the potential of EV-DNA uptake and its interaction with the host genome as a promising tool for understanding the mechanisms of cancer evolution.
Recommendation method for fusion of knowledge graph convolutional network
Authors: Jiang Xiaolin , Fu Yu , Dong Changchun
Published: March 2022

In the application of internet of vehicles system, it is particularly important to obtain real-time and effective vehicle information and provide personalized functional services for vehicle operation. This algorithm combines knowledge graph technology with convolutional network and presents a new algorithm model, that is, when calculating the representation of a given entity in the knowledge graph, the information of the neighboring entity is combined with the deviation. Through the integration of neighbor entity information, the local neighborhood structure can be better captured and stored in each entity, and the weight of different neighbor entities depends on the relationship between them and the specific user, which can better reflect the user's personalized interests, in order to fully demonstrate the characteristics of the entity. Compared with the traditional coordinated filtering technology SVD model, this model has improved accuracy and F1 value.
On the interference arising from random spatial fields of interferers utilizing multiple subcarriers
Authors: Zheng Ce , Egan Malcolm , Clavier Laurent , Peters Gareth W. , Gorce Jean-Marie
Published: March 2022

Effective symbol detection, channel estimation and decoding of channel codes require an accurate characterization of the noise probability distribution. In many systems, notably the internet of things, noise is largely in the form of interference, arising from a massive number of simultaneous transmissions from uncoordinated devices. Obtaining the probability distribution of the interference is a challenging problem due to the use of non-orthogonal multiple access schemes over several subcarriers (leading to multivariate statistical models) and the heavy-tailed nature of the interference due to the random locations of devices. In this paper, we derive a novel tractable characterization of the interference probability distribution based on an application of Sklar’s theorem to develop a combination of $$\alpha$$
α
-stable and t-copula dependence models. We demonstrate that this formulation produces an accurate statistical modeling framework that admits efficient parameter estimation methods. As an illustration of the utility of our models, we develop a simple-to-implement nonlinear receiver when a binary signal is transmitted over all subcarriers by the desired transmitter, which is effective in a range of scenarios and can significantly outperform existing approaches.
Heart failure in childhood cancer survivors—a systematic review protocol
Authors: Berg Tove , Böhmer Jens , Nwaru Bright I. , Karason Kristjan , Jarfelt Marianne
Published: March 2022

Background

Over the past decades, the survival rate for childhood cancer has greatly improved. However, the risk of late cardiac complications after cancer treatment remains high. Previous studies have shown that the risk for heart failure among childhood cancer survivors is significantly higher than that observed in varying control populations. The aim of this systematic review is to identify, critically appraise, and synthesize existing population-based studies reporting on the frequency of heart failure, both the incidence and prevalence, that may develop after treatment for childhood cancer.

Method

The following databases will be searched from their inception date until May 17, 2021: MEDLINE, Embase, Scopus, CINAHL, CAB International, AMED, Global Health, PsycINFO, Web of Science, and Google Scholar. Population-based studies reporting on the incidence and/or prevalence of heart failure after the treatment of any type of childhood cancer will be included. The screening of articles, data extraction, and quality assessment will be performed independently by two reviewers. The quality and risk of bias in the included studies will be assessed by using the Effective Public Health Practice Project tool. A narrative synthesis of the extracted data will be carried out, and for studies that are sufficiently homogenous, a meta-analysis using random-effects models will be performed.

Discussion

This systematic review will provide a clearer picture of the epidemiology of heart failure after the treatment of childhood cancer. The collected data will be of value for future childhood cancer treatment protocols and will offer guidance for posttreatment cardiac surveillance among survivors.

Systematic review registration

PROSPERO CRD42021247622. Registered on April 28, 2021. This protocol follows the structure of the recommendation of the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P).
Examining the association between work stress, life stress and obesity among working adult population in Canada: findings from a nationally representative data
Authors: Geda Nigatu Regassa , Feng Cindy Xin , Yu Yamei
Published: March 2022

Background

Obesity is a priority public health concern in Canada and other parts of the world. The study primarily aims at assessing the role of  self-perceived work and life stress on obesity among working adults in Canada.

Methods

The study was conducted based on a total of 104,636 Canadian adults aged 18 and above, extracted from the 2017–2018 Canadian Community Health Survey (CCHS) data. We used a mixed-effect logistic regression model to determine the possible association between two stress variables and obesity, controlling for other variables in the model. The random effect term accounts for the correlation among the observations from the same health region.

Results

A total of 63,815 adult respondents (aged 18 and above) who were working during the 12 months prior to the survey were studied. Of those, 18.7% were obese based on their self-reported BMI > =30.0 kg/m2. More than two-thirds of the respondents reported that their stress level is a bit stressful to extremely stressful. The results of multivariable mixed-effect logistic regression showed that the odds of obesity were 1.432 times (95% CI: 1.248–1.644) among those who reported extremely work-related stress, compared to those who had no work-related stress. Perceived life stress was not significantly associated with obesity risk among working adult population, after adjusting other factors.

Conclusion

The study concluded that obesity among Canadian adults is 18.7% of the working adult population being obese. Given the reported high prevalence of stress and its effect on obesity, the findings suggested improving social support systems, individual/group counseling, and health education focusing on work environments to prevent and manage stressors and drivers to make significant program impacts.
Purposes of internet use among Iranian university students: exploring its relationship with social networking site (SNS) addiction
Authors: Hashemi Yasaman , Zarani Fariba , Heidari Mahmood , Borhani Khatereh
Published: March 2022

Background

Higher education students are heavy users of the internet for a wide variety of reasons, including Social Networking Sites (SNSs). This study investigated various purposes of internet use among undergraduate university students, and how different categories of such activities are related to SNS addiction.

Methods

The sample set from 420 SNS users (280 females), a survey questionnaire was used to collect the information, including demographic information, purposes for internet usage (social, entertainment, academic, and economic purposes), and SNS addiction. Descriptive statistics, correlation, and a path diagram to estimate the regression coefficients were used to examine the data.

Results

Findings revealed that the most common purposes for using the internet were online social networking and information seeking, followed by listening to music or watching movies, learning, relaxing, using email for educational needs, and reading socio-political news. In the comparison between categories of purposes for internet usage, the most prevalent group of purposes were academic and informative, recreational, social, and economic categories respectively. Moreover, the most significant influences belonged to the social group [positively], the academic and informative group (negatively), and the recreational group (positively) on SNS addiction respectively. The economic group of purposes did not have a significant influence on SNS addiction.

Conclusion

This study has important implications for education and health providers, particularly in universities; we recommend that they try to improve students’ mental health and academic performance by providing opportunities for them to improve their IT literacy and skills.
Liver X receptor-agonist treatment rescues degeneration in a Drosophila model of hereditary spastic paraplegia
Authors: Byrne Dwayne J. , Garcia-Pardo M. Elena , Cole Nelson B. , Batnasan Belguun , Heneghan Sophia , Sohail Anood , Blackstone Craig , O’Sullivan Niamh C.
Published: March 2022

Hereditary spastic paraplegias (HSPs) are a group of inherited, progressive neurodegenerative conditions characterised by prominent lower-limb spasticity and weakness, caused by a length-dependent degeneration of the longest corticospinal upper motor neurons. While more than 80 spastic paraplegia genes (SPGs) have been identified, many cases arise from mutations in genes encoding proteins which generate and maintain tubular endoplasmic reticulum (ER) membrane organisation. The ER-shaping proteins are essential for the health and survival of long motor neurons, however the mechanisms by which mutations in these genes cause the axonopathy observed in HSP have not been elucidated. To further develop our understanding of the ER-shaping proteins, this study outlines the generation of novel in vivo and in vitro models, using CRISPR/Cas9-mediated gene editing to knockout the ER-shaping protein ADP-ribosylation factor-like 6 interacting protein 1 (ARL6IP1), mutations in which give rise to the HSP subtype SPG61. Loss of Arl6IP1 in Drosophila results in progressive locomotor deficits, emulating a key aspect of HSP in patients. ARL6IP1 interacts with ER-shaping proteins and is required for regulating the organisation of ER tubules, particularly within long motor neuron axons. Unexpectedly, we identified physical and functional interactions between ARL6IP1 and the phospholipid transporter oxysterol-binding protein-related protein 8 in both human and Drosophila model systems, pointing to a conserved role for ARL6IP1 in lipid homeostasis. Furthermore, loss of Arl6IP1 from Drosophila neurons results in a cell non-autonomous accumulation of lipid droplets in axonal glia. Importantly, treatment with lipid regulating liver X receptor-agonists blocked lipid droplet accumulation, restored axonal ER organisation, and improved locomotor function in Arl6IP1 knockout Drosophila. Our findings indicate that disrupted lipid homeostasis contributes to neurodegeneration in HSP, identifying a potential novel therapeutic avenue for the treatment of this disorder.
Trends in dispensing of individual prescription opioid formulations, Canada 2005–2020
Authors: Jones Wayne , Kaoser Ridhwana , Rudoler David , Fischer Benedikt
Published: March 2022

Background

Canada has experienced a distinctly bifurcated pattern of (strong) opioid utilization post-2000, with multifold increases rendering it one of the world’s highest opioid consumption rates, followed by subsequent substantive declines since 2011/2012. Several interventions to control especially high-risk opioid use have been implemented post-2010 at different levels, yet with their effects assessed mostly for overall opioid utilization. Little knowledge exists for over-time patterns of individual opioid formulations.

Methods

Raw information on community-based prescription opioid dispensing for years 2005–2020 were obtained from a large national database based on a stratified sample of 6500 retail pharmacies across Canada (IQVIA/Compuscript), These data were converted into Defined-Daily-Doses/1000 population/day (DDD/1000/day) for individual (strong and weak) opioid formulations—specifically: fentanyl, hydromorphone, hydrocodone, morphine, oxycodone, codeine—per standard methods. Descriptive data on individual opioid dispensing were computed, and segmented regression (or ‘broken-stick’) analysis was applied to the overtime dispensing towards assessing potentially significant ‘breakpoints’ interrupting linear utilization trends. Akaike information criterion (AIC) values were computed to assess the resulting models’ quality-of-fit.

Results

Five of the six opioid formulations featured a lower dispensing level in 2020 compared with 2005, but mostly with peak values in years between, contributing to the overall inversion pattern. For five of the six opioid formulations, a three-segmented model emerged as the best fit for the dispensing observed; only hydrocodone presented a linear (downward) dispensing trend. Among the five interrupted trend models for individual formulations, four (fentanyl, morphine, oxycodone, codeine but not hydromorphone) indicated their initial breakpoint during 2011–2014 introducing a downward dispensing trend. Inconsistently, morphine also featured a recent breakpoint (2018) towards a dispensing increase.

Conclusions

While all opioids showed marked declines, we found heterogeneous patterns of dispensing for individual opioid formulations. While we cannot estimate direct causal effects, opioid control interventions appear to have had differential impacts on dispensing of individual formulations. The earliest breakpoint occurred towards substantive decreases for oxycodone dispensing in 2011; subsequently, there were increases in dispensing of hydromorphone and fentanyl likely due to substitution effects, followed by across-the-board declines post-2015/2016. Recent ‘safer opioid’ distribution programs to reduce illicit/toxic opioid exposure linked with high levels of poisoning fatalities seem to fuel resurgences in select opioid (e.g., morphine) dispensing.