bluuebunny/crossref_metadata_2025 huggingface dataset:
Bromodomain inhibition overcomes treatment resistance in distinct molecular subtypes of melanoma
Authors: Dar Altaf A. , Bezrookove Vladimir , Nosrati Mehdi , Ice Ryan , Patino John M. , Vaquero Edith M. , Parrett Brian , Leong Stanley P. , Kim Kevin B. , Debs Robert J. , Soroceanu Liliana , Miller James R. , Desprez Pierre-Yves , Cleaver James E. , Salomonis Nathan , McAllister Sean , Kashani-Sabet Mohammed
Published: August 2022

Therapy of
BRAF
-mutant melanoma with selective inhibitors of BRAF (BRAFi) and MEK (MEKi) represents a major clinical advance but acquired resistance to therapy has emerged as a key obstacle. To date, no clinical approaches successfully resensitize to BRAF/MEK inhibition. Here, we develop a therapeutic strategy for melanoma using bromosporine, a bromodomain inhibitor. Bromosporine (bromo) monotherapy produced significant anti-tumor effects against established melanoma cell lines and patient-derived xenografts (PDXs). Combinatorial therapy involving bromosporine and cobimetinib (bromo/cobi) showed synergistic anti-tumor effects in multiple BRAFi-resistant PDX models. The bromo/cobi combination was superior in vivo to standard BRAFi/MEKi therapy in the treatment-naive
BRAF
-mutant setting and to MEKi alone in the setting of immunotherapy-resistant
NRAS
- and
NF1
-mutant melanoma. RNA sequencing of xenografts treated with bromo/cobi revealed profound down-regulation of genes critical to cell division and mitotic progression. Bromo/cobi treatment resulted in marked DNA damage and cell-cycle arrest, resulting in induction of apoptosis. These studies introduce bromodomain inhibition, alone or combined with agents targeting the mitogen activated protein kinase pathway, as a rational therapeutic approach for melanoma refractory to standard targeted or immunotherapeutic approaches.
Structure of a cholinergic cell membrane
Authors: Unwin Nigel
Published: August 2022

Cell membranes are complex assemblies of proteins and lipids making transient or long-term associations that have yet to be characterized at a molecular level. Here, cryo-electron microscopy is applied to determine how phospholipids and cholesterol arrange between neighboring proteins (nicotinic acetylcholine receptors) of
Torpedo
cholinergic membrane. The lipids exhibit distinct properties in the two leaflets of the bilayer, influenced by the protein surfaces and by differences in cholesterol concentration. In the outer leaflet, the lipids show no consistent motif away from the protein surfaces, in keeping with their assumed fluidity. In the inner leaflet, where the cholesterol concentration is higher, the lipids organize into extensive close-packed linear arrays. These arrays are built from the sterol groups of cholesterol and the initial saturated portions of the phospholipid hydrocarbon chains. Together, they create an ordered ∼7 Å-thick “skin” within the hydrophobic core of the bilayer. The packing of lipids in the arrays appears to bear a close relationship to the linear cholesterol arrays that form crystalline monolayers at the air-water interface.
Double-port homodyne detection in a squeezed-state interferometry with a binary-outcome data processing
Authors: Zhou Likun , Liu Pan , Jin Guang-Ri
Published: August 2022

Performing homodyne detection at a single output port of a squeezed-state light interferometer and then separating the measurement quadrature into two intervals can realize super-resolving and super-sensitive phase measurements, which is equivalent to a binary-outcome measurement. Obviously, the single-port homodyne detection may lose almost part of the phase information, reducing the estimation precision. Here, we propose a data-processing technique over the double-port homodyne detection, where the two-dimensional measurement quadrature (p
1, p
2) has been divided into two regions. With such a binary-outcome measurement, we estimate the phase shift accumulated in the interferometer by inverting the output signal. By analyzing the full width at half maximum of the signal and the phase sensitivity, we show that both the resolution and the achievable sensitivity are better than that of the previous binary-outcome scheme.
Post-treatment stability after 5 years of retention with vacuum-formed and bonded retainers—a randomized controlled trial
Authors: Krämer Anke , Sjöström Mats , Apelthun Catharina , Hallman Mats , Feldmann Ingalill
Published: August 2022

Background

Retention after orthodontic treatment is still a challenge and more evidence about post-treatment stability and patients’ perceptions of different retention strategies is needed.

Objectives

This trial compares removable vacuum-formed retainers (VFR) with bonded cuspid-to-cuspid retainers (CTC) after 5 years of retention.

Trial design

A single centre two-arm parallel-group randomized controlled trial.

Methods

This trial included 104 adolescent patients, randomized into two groups (computer-generated), using sequentially numbered, opaque, and sealed envelopes. All patients were treated with fixed appliances in both jaws with and without tooth extractions. Patients in the intervention group received a VFR in the mandible (n = 52), and patients in the active comparator group received a CTC (n = 52). Both groups had a VFR in the maxilla. Dental casts at debond (T1), after 6 months (T2), after 18 months (T3), and after 5 years (T4) were digitized and analysed regarding Little’s Irregularity Index (LII), overbite, overjet, arch length, and intercanine and intermolar width. The patients completed questionnaires at T1, T2, T3, and T4.

Results

Post-treatment changes between T1 and T4 in both jaws were overall small. In the maxilla, LII increased significantly (median difference: 0.3 mm), equally in both groups. In the mandible, LII increased significantly in the group VFR/VFR (median difference: 0.6 mm) compared to group VFR/CTC (median difference: 0.1 mm). In both groups, overjet was stable, overbite increased, and arch lengths decreased continuously. Intercanine widths and intermolar width in the mandible remained stable, but intermolar width in the maxilla decreased significantly. No differences were found between groups. Regardless of retention strategy, patients were very satisfied with the treatment outcome and their retention appliances after 5 years.

Limitations

It was not possible to perform blinded assessments of digital models at follow-up.

Conclusions

Post-treatment changes in both jaws were small. Anterior alignment in the mandible was more stable with a bonded CTC retainer compared to a removable VFR after 5 years of retention. Patients were equally satisfied with fixed and removable retention appliances.

Trial registration

ClinicalTrials.gov (NCT03070444).
Epigenome-wide Association Study Analysis of Calorie Restriction in Humans, CALERIETM Trial Analysis
Authors: Ramaker Megan E , Corcoran David L , Apsley Abner T , Kobor Michael S , Kraus Virginia B , Kraus William E , Lin David T S , Orenduff Melissa C , Pieper Carl F , Waziry Reem , Huffman Kim M , Belsky Daniel W
Published: August 2022

Calorie restriction (CR) increases healthy life span and is accompanied by slowing or reversal of aging-associated DNA methylation (DNAm) changes in animal models. In the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIETM) human trial, we evaluated associations of CR and changes in whole-blood DNAm. CALERIETM randomized 220 healthy, nonobese adults in a 2:1 allocation to 2 years of CR or ad libitum (AL) diet. The average CR in the treatment group through 24 months of follow-up was 12%. Whole blood (baseline, 12, and 24 months) DNAm profiles were measured. Epigenome-wide association study (EWAS) analysis tested CR-induced changes from baseline to 12 and 24 months in the n = 197 participants with available DNAm data. CR treatment was not associated with epigenome-wide significant (false discovery rate [FDR] < 0.05) DNAm changes at the individual-CpG-site level. Secondary analysis of sets of CpG sites identified in published EWAS revealed that CR induced DNAm changes opposite to those associated with higher body mass index and cigarette smoking (p < .003 at 12- and 24-month follow-ups). In contrast, CR altered DNAm at chronological-age-associated CpG sites in the direction of older age (p < .003 at 12- and 24-month follow-ups). Although individual CpG site DNAm changes in response to CR were not identified, analyses of sets CpGs identified in prior EWAS revealed CR-induced changes to blood DNAm. Altered CpG sets were enriched for insulin production, glucose tolerance, inflammation, and DNA-binding and DNA-regulation pathways, several of which are known to be modified by CR. DNAm changes may contribute to CR effects on aging.
A bioinformatic-assisted workflow for genome-wide identification of ncRNAs
Authors: Schmal Matthias , Girod Crystal , Yaver Debbie , Mach Robert L , Mach-Aigner Astrid R
Published: August 2022

With the upcoming of affordable Next-Generation Sequencing technologies, the number of known non-protein coding RNAs increased drastically in recent years. Different types of non-coding RNAs (ncRNAs) emerged as key players in the regulation of gene expression on the RNA–RNA, RNA–DNA as well as RNA–protein level, ranging from involvement in chromatin remodeling and transcription regulation to post-transcriptional modifications. Prediction of ncRNAs involves the use of several bioinformatics tools and can be a daunting task for researchers. This led to the development of analysis pipelines such as UClncR and lncpipe. However, these pipelines are limited to datasets from human, mouse, zebrafish or fruit fly and are not able to analyze RNA sequencing data from other organisms. In this study, we developed the analysis pipeline Pinc (Pipeline for prediction of ncRNA) as an enhanced tool to predict ncRNAs based on sequencing data by removing transcripts that show protein-coding potential. Additionally, a feature for differential expression analysis of annotated genes as well as for identification of novel ncRNAs is implemented. Pinc uses Nextflow as a framework and is built with robust and well-established analysis tools. This will allow researchers to utilize sequencing data from every organism in order to reliably identify ncRNAs.
Magnetic resonance spectroscopy outperforms perfusion in distinguishing between pseudoprogression and disease progression in patients with glioblastoma
Authors: El-Abtah Mohamed E , Talati Pratik , Fu Melanie , Chun Benjamin , Clark Patrick , Peters Anna , Ranasinghe Anthony , He Julian , Rapalino Otto , Batchelor Tracy T , Gilberto Gonzalez R , Curry William T , Dietrich Jorg , Gerstner Elizabeth R , Ratai Eva-Maria
Published: August 2022

Background

There is a need to establish biomarkers that distinguish between pseudoprogression (PsP) and true tumor progression in patients with glioblastoma (GBM) treated with chemoradiation.

Methods

We analyzed magnetic resonance spectroscopic imaging (MRSI) and dynamic susceptibility contrast (DSC) MR perfusion data in patients with GBM with PsP or disease progression after chemoradiation. MRSI metabolites of interest included intratumoral choline (Cho), myo-inositol (mI), glutamate + glutamine (Glx), lactate (Lac), and creatine on the contralateral hemisphere (c-Cr). Student T-tests and area under the ROC curve analyses were used to detect group differences in metabolic ratios and their ability to predict clinical status, respectively.

Results

28 subjects (63 ± 9 years, 19 men) were evaluated. Subjects with true progression (n = 20) had decreased enhancing region mI/c-Cr (P = .011), a marker for more aggressive tumors, compared to those with PsP, which predicted tumor progression (AUC: 0.84 [0.76, 0.92]). Those with true progression had elevated Lac/Glx (P = .0009), a proxy of the Warburg effect, compared to those with PsP which predicted tumor progression (AUC: 0.84 [0.75, 0.92]). Cho/c-Cr did not distinguish between PsP and true tumor progression. Despite rCBV (AUC: 0.70 [0.60, 0.80]) and rCBF (AUC: 0.75 [0.65, 0.84]) being individually predictive of tumor response, they added no additional predictive value when combined with MRSI metabolic markers.

Conclusions

Incorporating enhancing lesion MRSI measures of mI/c-Cr and Lac/Glx into brain tumor imaging protocols can distinguish between PsP and true progression and inform patient management decisions.
A Comparison of Use Topography and Nicotine Pharmacokinetics Among Loose and Portioned Smokeless Tobacco Users
Authors: Nighbor Tyler , Meredith Steven , Salazar Esther , Cartagena Casandra , Koszowski Bartosz , Pickworth Wallace B , Hull Lynn C
Published: August 2022

Introduction

Moist snuff smokeless tobacco (ST) products are available in the United States in both “loose” and “portioned” (ie, pouched) formats, but no published study to date has clinically evaluated the associations between ST format, use behavior, and nicotine exposure.

Aims and Methods

Participants used their usual brand of ST (loose ST [n = 30] or portioned ST [n = 20]) during an experimental visit wherein use behavior and plasma nicotine pharmacokinetic parameters were measured following single use (first hour of the session) and ad libitum use (remaining 7 h of the session). Participants’ ST products were chemically characterized prior to use for pH and nicotine content.

Results

The average amount per use (2.99 vs. 1.52 g; p = .005) and total amount used (11.45 vs. 5.4 g; p = .002) were significantly higher among the loose ST group. Maximum plasma nicotine concentration (Cmax; 33.4 vs. 19.1 ng/ml) and area under the nicotine concentration versus time curve (AUC) were significantly higher for the loose ST group for the first hour (1474.8 vs. 807.2 min* ng/ml; p = .003) and throughout the 8-hour session (15827.9 vs. 8155.3 min* ng/ml; p < .001). Significant associations were observed between free nicotine content and first use Cmax (rs = .488, loose ST group) and AUC0–1 h (rs = 0.448, loose ST group; rs = .441, portioned ST group).

Conclusions

The loose ST group used more product and had a greater average deposition time per use than the portioned ST group. Nicotine exposure was more strongly associated with free nicotine content than total nicotine content.

Implications

To our knowledge, the current investigation was the first study to date to clinically evaluate the associations between usual-brand smokeless format, use behavior, and nicotine exposure. We observed meaningful differences in use behavior and subsequent nicotine exposure between loose and portioned ST users. Further, we observed that nicotine exposure was more strongly associated with free nicotine content than total nicotine content.
Dampened sensory representations for expected input across the ventral visual stream
Authors: Richter David , Heilbron Micha , de Lange Floris P
Published: August 2022

Expectations, derived from previous experience, can help in making perception faster, more reliable and informative. A key neural signature of perceptual expectations is expectation suppression, an attenuated neural response to expected compared with unexpected stimuli. While expectation suppression has been reported using a variety of paradigms and recording methods, it remains unclear what neural modulation underlies this response attenuation. Sharpening models propose that neural populations tuned away from an expected stimulus are particularly suppressed by expectations, thereby resulting in an attenuated, but sharper population response. In contrast, dampening models suggest that neural populations tuned toward the expected stimulus are most suppressed, thus resulting in a dampened, less redundant population response. Empirical support is divided, with some studies favoring sharpening, while others support dampening. A key limitation of previous neuroimaging studies is the ability to draw inferences about neural-level modulations based on population (e.g. voxel) level signals. Indeed, recent simulations of repetition suppression showed that opposite neural modulations can lead to comparable population-level modulations. Forward models provide one solution to this inference limitation. Here, we used forward models to implement sharpening and dampening models, mapping neural modulations to voxel-level data. We show that a feature-specific gain modulation, suppressing neurons tuned toward the expected stimulus, best explains the empirical fMRI data. Thus, our results support the dampening account of expectation suppression, suggesting that expectations reduce redundancy in sensory cortex, and thereby promote updating of internal models on the basis of surprising information.
Retinal degeneration induced in a mouse model of ischemia–reperfusion injury and its management by pemafibrate treatment
Authors: Lee Deokho , Nakai Ayaka , Miwa Yukihiro , Tomita Yohei , Kunimi Hiromitsu , Chen Junhan , Ikeda Shin‐Ichi , Tsubota Kazuo , Negishi Kazuno , Kurihara Toshihide
Published: August 2022

Retinal ischemia–reperfusion (I/R) injury is a common cause of visual impairment. To date, no effective treatment is available for retinal I/R injury. In addition, the precise pathological mechanisms still need to be established. Recently, pemafibrate, a peroxisome proliferator‐activated receptor α (PPARα) modulator, was shown to be a promising drug for retinal ischemia. However, the role of pemafibrate in preventing retinal I/R injury has not been documented. Here, we investigated how retinal degeneration occurs in a mouse model of retinal I/R injury by elevation of intraocular pressure and examined whether pemafibrate could be beneficial against retinal degeneration. Adult mice were orally administered pemafibrate (0.5 mg/kg/day) for 4 days, followed by retinal I/R injury. The mice were continuously administered pemafibrate once every day until the end of the experiments. Retinal functional changes were measured using electroretinography. Retina, liver, and serum samples were used for western blotting, quantitative PCR, immunohistochemistry, or enzyme linked immunosorbent assay. Retinal degeneration induced by retinal inflammation was prevented by pemafibrate administration. Pemafibrate administration increased the hepatic PPARα target gene expression and serum levels of fibroblast growth factor 21, a neuroprotective molecule in the eye. The expression of hypoxia‐response and pro‐and anti‐apoptotic/inflammatory genes increased in the retina following retinal I/R injury; however, these changes were modulated by pemafibrate administration. In conclusion, pemafibrate is a promising preventive drug for ischemic retinopathies.
Comparative efficacy and safety of oral nifedipine with other antihypertensive medications in the management of hypertensive disorders of pregnancy: a systematic review and meta-analysis of randomized controlled trials
Authors: George Rosemol , Thomas Christy , Joy Chippy Anna , Varghese Bincy , Undela Krishna , Adela Ramu
Published: August 2022

Background:

Hypertensive disorders of pregnancy are the most frequently occurring medical condition during pregnancy, resulting in fetal and/or maternal morbidity and mortality. This meta-analysis compared the efficacy and safety of nifedipine with other antihypertensive medications used in hypertensive disorders of pregnancy.

Methodology:

A comprehensive search was performed using PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), and Google Scholar. The meta-analysis was carried out using Review Manager Software, and the pooled effect estimate was generated as standardized mean difference and odds ratio with 95% confidence interval and two-sided P-value.

Results:

The meta-analysis was comprised of 22 randomized control trials with 2595 participants. It was found that meantime and number of doses required to achieve target blood pressure were lower in the nifedipine group (P < 0.05). Even though it is statistically insignificant, fetal APGAR (Appearance, Pulse, Grimace, Activity, and Respiration) scores less than seven favors nifedipine intervention. Furthermore, none of the fetal or maternal secondary outcomes were found significant.

Conclusion:

Nifedipine was found to be more effective than other antihypertensive medications to reduce blood pressure, particularly in patients with severe hypertension. However, future clinical studies, including real-world data are necessary to establish the safety profile of nifedipine concerning the fetal outcomes in hypertensive pregnant women.
Descending projections from the insular cortex to the trigeminal spinal subnucleus caudalis facilitate excitatory outputs to the parabrachial nucleus in rats
Authors: Nakaya Yuka , Yamamoto Kiyofumi , Kobayashi Masayuki
Published: August 2022

Nociceptive information from the orofacial area projects to the trigeminal spinal subnucleus caudalis (Sp5C) and is then conveyed to several nuclei, including the parabrachial nucleus (PBN). The insular cortex (IC) receives orofacial nociceptive information and sends corticofugal projections to the Sp5C. The Sp5C consists of glutamatergic and GABAergic/glycinergic interneurons that induce excitatory postsynaptic currents and inhibitory postsynaptic currents, respectively, in projection neurons. Therefore, quantification of glutamatergic IC inputs in combination with identifying postsynaptic neuronal subtypes is critical to elucidate IC roles in the regulation of Sp5C activities. We investigated features of synaptic transmission from the IC to glutamatergic and GABAergic/glycinergic Sp5C neurons of laminae I/II using vesicular GABA transporter-Venus transgenic rats that received an injection of adeno-associated virus-channelrhodopsin-2-mCherry into the IC. Selective stimulation of IC axon terminals in Sp5C slice preparations induced monosynaptic excitatory postsynaptic currents in both excitatory glutamatergic and inhibitory GABAergic/glycinergic Sp5C neurons with a comparable amplitude. Paired whole-cell patch-clamp recordings showed that unitary inhibitory postsynaptic currents from inhibitory neurons influencing excitatory neurons, including neurons projecting to the PBN, exhibited a high failure rate and were suppressed by both bicuculline and strychnine, suggesting that excitatory neurons in the Sp5C receive both GABAergic and glycinergic inhibition with low impact. Moreover, selective stimulation of IC axons increased the firing rate at the threshold responses. Finally, we demonstrated that selective stimulation of IC axons in the Sp5C by a chemogenetic approach decreased the thresholds of both mechanical and thermal nociception. Thus, IC projection to the Sp5C is likely to facilitate rather than suppress excitatory outputs from the Sp5C.
GLI1-Rearranged Enteric Tumor
Authors: Jessurun José , Orr Christine , McNulty Samantha N. , Hagen Catherine E. , Alnajar Hussein , Wilkes David , Kudman Sarah , Al Assaad Majd , Dorsaint Princesca , Ohara Kentaro , He Feng , Chiu Kenrry , Yin Yong Mei , Xiang Jenny Zhaoying , Qin Lihui , Sboner Andrea , Elemento Olivier , Yantiss Rhonda K. , Graham Rondell P. , Poizat Flora , Mosquera Juan Miguel
Published: August 2022

GLI1 encodes a transcription factor that targets cell cycle regulators affecting stem cell proliferation. GLI1 gene fusions were initially described in pericytomas with a t[7;12] translocation and more recently in gastric plexiform fibromyxomas and gastroblastomas. This study describes the clinicopathologic, immunohistochemical, and molecular features of three intestinal-based neoplasms harboring GLI1 gene fusions. We studied three unique mesenchymal small bowel tumors. Paraffin embedded tumor tissues from these cases and 62 additional tumor samples that included a plexiform fibromyxoma were sequenced using a targeted RNAseq method to detect fusion events. The study patients included two women and one man who were 52, 80, and 22 years of age at the time of diagnosis. The tumors involved the submucosa and muscularis propria of the duodenum, jejunum, and ileum. All 3 tumors contained a proliferation of monotonous oval or spindle cells with scattered, somewhat dilated vessels. Two cases showed epithelioid structures such as glands, tubules, or nests. Immunohistochemical analysis revealed cytokeratin expression in the epithelioid components of both tumors displaying these features, and variable numbers of mesenchymal cells. Diffuse CD56 positivity was seen in the mesenchymal component of 2 tumors and desmin and smooth muscle actin staining in the other tumor. Immunostains for S-100 protein, DOG-1, and CD117 were negative in all cases. GLI1 fusions with different partner genes were detected in all tumors, and in the plexiform fibromyxoma, used as a control. Validation by fluorescence in situ hybridization was performed. None of the tumors have recurred or metastasize after surgery. We describe novel GLI1 fusions in 3 mesenchymal neoplasms of the small intestine, including 2 with biphenotypic features. Thus far, all cases have pursued indolent clinical courses. We propose the term “GLI1-rearranged enteric tumor” to encompass this group of unique neoplasms of the small intestine that harbor GLI1 gene fusions and expand the spectrum of gastrointestinal neoplasms with these alterations.
Endoscopic Endonasal Optic Nerve Decompression in a Patient With Invasive Fungal Sinusitis Invasion Into the Orbital Apex: Intraoperative Video and Literature Review
Authors: Lee Il Hwan , Yoon Wan-Soo , Kim Dong-Hyun , Son Soo Ah
Published: August 2022

Invasive fungal sinusitis (IFS) is rare but potentially fatal in immunocompromised patients. Orbital extension of IFS can cause visual loss or ophthalmoplegia, and the rate of recovery of visual acuity can be low even after treatment with antifungal agents and sinus surgery. In this case, optic nerve decompression with the endoscopic endonasal approach was successful for the treatment of visual loss in a patient with IFS with orbital apex extension. The authors describe the recovery of visual acuity after optic nerve decompression in a patient with IFS who had exhibited visual loss caused by invasion into the orbital apex. The authors also provide an intraoperative video and literature review.
Orbital Reconstruction in Le Fort III Fractures
Authors: Wang Yang , Li Zhengkang , Chen Huifang , Deng Yuan
Published: August 2022

Background:

Few quantitative results are reported about the surgical effect of orbital reconstruction in Le Fort III fractures. The authors’ team proposed an ordered surgery method which was effective for Le Fort III fractures. The aim of this study was to evaluate the effectiveness of this method with quantitative outcomes.

Methods:

A retrospective study was conducted of all patients who were diagnosed with Le Fort III fractures and underwent orbital and facial fractures repair from January 2015 to June 2019. Surgical reconstruction was performed with an ordered surgery method. Orbital volumes were used to evaluate the effectiveness of orbital reconstruction.

Results:

Fifteen patients (21 eyes) with Le Fort III fractures were included in this study. Preoperative and postoperative orbital volume changes were statistically significant (P<0.01). For unilateral fractures, orbital volumes were different in 2 eyes (P<0.01). For bilateral fractures, orbital volumes were almost the same in 2 eyes (P=0.34). For the affected eye in unilateral fractures group and eyes in bilateral fractures group, after surgery, orbital volume were almost the same (P=0.35).

Conclusions:

This study showed effectiveness and safety of the ordered surgery in the treatment of Le Fort III fractures, which would result in significant decrease in orbital volumes.
Prkra Mutation Alters Long Noncoding RNA Expression During Embryonic External Ear Development
Authors: Liu Wei , Jin Shengyang , Lin Lin , Yang Qinghua , Jiang Haiyue
Published: August 2022

Point mutations in the Prkra gene result in abnormalities in mouse external ear development; however, the regulatory mechanisms underlying this phenotype are unclear. This study evaluated long noncoding RNA (lncRNA) expression profiles in the outer ear tissues of embryos at E15.5 and E17.5 from the Prkra little ear mouse model using transcriptome sequencing. Differentially expressed lncRNAs between the experimental and control groups were identified and evaluated by gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses. The results revealed various lncRNAs that contribute to the external ear development in Prkra mutant mice, some of which were involved in multiple developmental signaling pathways. There were expression changes in some key regulatory lncRNAs after point mutations in the Prkra gene, some of which were involved in multiple developmental signaling pathways, such as the Hippo, MAPK, and ErbB signaling pathways. These results provide insight into the regulatory mechanism underlying external ear embryonic development and reveal candidate lncRNAs.
Long-term Dependency in Older Adults After Surgery or Stereotactic Body Radiation Therapy for Stage I Non–Small Cell Lung Cancer
Authors: Hirpara Dhruvin H. , Kidane Biniam , Louie Alexander V. , Zuk Victoria , Darling Gail , Rousseau Mathieu , Chesney Tyler , Coburn Natalie , Hallet Julie ,   for the REcovery After Surgical Therapy for Older adults REsearch—Cancer (RESTORE-C) Group
Published: August 2022

Objective:

To examine long-term healthcare dependency outcomes of stereotactic body radiation therapy (SBRT) to surgery for older adults with stage I non–small cell lung cancer (NSCLC).

Background:

SBRT is an emerging alternative to surgery in patients with early-stage lung cancer. There remains a paucity of prospective studies comparing these modalities, especially with respect to long-term dependency outcomes in older adults with lung cancer.

Methods:

Adults 70 years old and above with stage I NSCLC treated with surgery or SBRT from January 2010 to December 2017 were analyzed using 1:1 propensity score matching. Homecare use, days at home, and time spent alive and at home were compared. E-value methods assessed residual confounding.

Results:

A total of 1129 and 2570 patients underwent SBRT and surgery, respectively. In all, 1016 per group were matched. SBRT was associated with a higher overall risk of homecare utilization [hazard ratio (HR)=1.75, 95% confidence interval (CI): 1.37–2.23] than surgery up to 5 years following treatment. While the hazards of death or nursing home admission were lower in the first 3 months after SBRT (HR=0.55, 95% CI: 0.36–0.85), they became consistently higher beyond this period and remained high up to 5 years compared with surgery (HR=2.13; 95% CI: 1.85–2.45). The above findings persisted in stratified analyses for frail patients and those with no pretreatment homecare. E-values indicated it was unlikely that the observed estimates could be explained by unmeasured confounders.

Conclusions:

Surgery offers robust long-term dependency outcomes compared with SBRT. These are important patient-centered endpoints which may be used for counseling and shared decision-making in older adults with stage I NSCLC.
Estimation of local time-varying reproduction numbers in noisy surveillance data
Authors: Li Wenrui , Bulekova Katia , Gregor Brian , White Laura F. , Kolaczyk Eric D.
Published: August 2022

A valuable metric in understanding local infectious disease dynamics is the local time-varying reproduction number, i.e. the expected number of secondary local cases caused by each infected individual. Accurate estimation of this quantity requires distinguishing cases arising from local transmission from those imported from elsewhere. Realistically, we can expect identification of cases as local or imported to be imperfect. We study the propagation of such errors in estimation of the local time-varying reproduction number. In addition, we propose a Bayesian framework for estimation of the true local time-varying reproduction number when identification errors exist. And we illustrate the practical performance of our estimator through simulation studies and with outbreaks of COVID-19 in Hong Kong and Victoria, Australia.

This article is part of the theme issue ‘Technical challenges of modelling real-life epidemics and examples of overcoming these’.
Statistical analysis of number of genes and chromosome lengths of different microbial species
Authors: Ng Wenfa
Published: August 2022

Genome architecture concerns the organisation of genes on a chromosome, and has important implications to the fidelity in which genes are encoded on the chromosome, and how the information is read by DNA polymerase and RNA polymerase. This facet of genomics did receive attention in the early epoch of genomics, but it has received less attention in contemporary genomics as attention shifts to structural and functional genomics with the goal of annotating the function of each gene in the genome. This work sought to uncover relationships between number of genes and chromosome length in a variety of bacteria and archaea species as a preamble to understanding the prevalence and importance of repetitive sequences in the genome of prokaryotic species. Aggregate results with the ensemble of prokaryotic species profiled revealed a positive linear correlation between number of genes and chromosome length. Upon dissection into the Bacteria and Archaea domains, the linear relationship described above still stands for Bacteria but starts to break down in Archaea. This suggests that repetitive sequences are more important to Archaea species, which generally have a smaller genome (1.8 to 2.8 Mbp) and fewer genes (1500 to 2400) compared to bacterial species. In comparison, the bacterial genome is larger (4 to 5.6 Mbp), and encodes more genes (3600 to 5100). Overall, the results highlight that bacterial genome are efficiently encoded with few repetitive sequences. This, however, is not true for archaeal genome, which provides another line of evidence supporting the notion that archaea are ancestral eukaryotic cells, which like the archaea also houses large repetitive sequences.

Graphical abstract

Short description

Statistical analysis across an ensemble of 59 microbial species revealed a strong linear correlation between number of genes and chromosome length. This suggests that prokaryotic genomes are highly compact with genes, and do not carry significant amounts of repeats unlike the case in eukaryotic organisms. The result holds significant implications for our understanding of genome evolution and compaction in prokaryotic organisms, and what drove their accession as foundational species of many ecosystems.

Subject areas

genomics, molecular biology, evolutionary biology, bioinformatics, systems biology,
Criminal mutilation homicides in Japan: Corpse dismemberment and disposal pattern types, and offender characteristics
Authors: Zaitsu Wataru
Published: August 2022

This study examined the offender characteristics of criminal mutilation homicides in Japan for offender profiling. The current sample (N = 108) showed that the most typical offender was a male, in his 30s (age that observed most often), one‐person, and acquainted with the victim. This study highlighted that the cases of mutilation homicide differed in comparison with the regular homicide group in terms of the victim–offender (VO) relationship and the number of offenders. Furthermore, the multiple correspondence analysis classified mutilation homicides into four behavioral pattern types based on two dimensions (level of “efforts of corpse dismemberment” and “efforts of corpse disposal”). In the first type “high evidence destruction effort (n = 29)”, having the greatest efforts to destroy evidence, all offenders were men. The rates of no VO relationship and serial murders were higher. In the second type “convenient disposal (n = 32)”, likely to abandon victim body in home and trash, the rate of female offenders who assaulted family members was statistically significantly higher among the four types. In the third type “high geographic distance (n = 23)”, traveling long distances for corpse disposal, the percentage of cases by co‐offenders was likely to be higher than in the other types. Lastly, the offenders in “low evidence destruction effort (n = 24)” were likely to kill other acquaintances and have the least efforts for corpse dismemberment and disposal. From these results, the criminal profilers can estimate mutilation homicide offenders on the basis of efforts of corpse dismemberment and disposal.
soundscape_IR: A source separation toolbox for exploring acoustic diversity in soundscapes
Authors: Sun Yi‐Jen , Yen Shih‐Ching , Lin Tzu‐Hao
Published: August 2022

Soundscapes contain rich acoustic information associated with animal behaviours, environmental characteristics and human activities, providing opportunities for predicting biodiversity changes and associated drivers. However, assessing the diversity of animal vocalizations remains challenging due to the interference of environmental and anthropogenic noise. A tool for separating sound sources and delineating changes in acoustic signals is crucial for an effective assessment of acoustic diversity.

We present soundscape_IR, an open‐source Python toolbox dedicated to soundscape information retrieval in which nonnegative matrix factorization is applied. This toolbox provides algorithms for supervised and unsupervised source separation (SS). It also enables the use of a snapshot recording for model training and subsequently applying adaptive and semi‐supervised SS when target species produce sounds with varying features and when unseen sound sources are encountered.

Our results demonstrated that SS could enhance the vocalizations of target species, characterize the complexity of vocal repertoires and investigate the spatio‐temporal divergence of soundscapes. In tropical forest soundscapes, the application of SS effectively detected the rutting vocalizations of sika deer and revealed a graded structure in their acoustic characteristics. In subtropical estuarine soundscapes, SS automated the process of identifying distinct biotic and abiotic sounds, and the result uncovered divergent sound compositions between inshore and offshore waters.

Implementation of SS in soundscape analysis offers a promising method for streamlining the assessment of acoustic diversity in diverse environments. Future application of SS will open new directions to acoustically quantify ecological interactions across individual, species and ecosystem levels.
The longitudinal trajectory of emotion regulation and associated neural activity in patients with bipolar disorder: A prospective fMRI study
Authors: Kjærstad Hanne Lie , de Siqueira Rotenberg Luisa , Knudsen Gitte Moos , Vinberg Maj , Kessing Lars Vedel , Macoveanu Julian , Lafer Beny , Miskowiak Kamilla Woznica
Published: August 2022

Objectives

Impaired emotion regulation is a key feature of bipolar disorder (BD) that presents during acute mood episodes and in remission. The neural correlates of voluntary emotion regulation seem to involve deficient prefrontal top‐down regulation already at BD illness onset. However, the trajectory of aberrant neuronal activity during emotion regulation in BD is unclear.

Methods

We investigated neural activity during emotion regulation in response to aversive pictures from the International Affective Picture System in patients with recently diagnosed BD (n = 43) in full or partial remission and in healthy controls (HC) (n = 38) longitudinally at baseline and 16 months later.

Results

Patients with BD exhibited stable hypo‐activity in the left dorsomedial prefrontal cortex (DMPFC) and right dorsolateral prefrontal cortex (DLPFC) and impaired emotion regulation compared to HC over the 16 months follow‐up time. More DLPFC hypo‐activity during emotion regulation correlated with less successful down‐regulation (r = 0.16, p = 0.045), more subsyndromal depression (r = −0.18, p = 0.02) and more functional impairment (r = −0.24, p = 0.002), while more DMPFC hypo‐activity correlated with less efficient emotion regulation (r = 0.16, p = 0.048). Finally, more DMPFC hypo‐activity during emotion regulation at baseline was associated with an increased likelihood of subsequent relapse during the 16 months follow‐up time (β = −2.26, 95% CI [0.01; 0.99], p = 0.048).

Conclusion

The stable DLPFC and DMPFC hypo‐activity during emotion regulation represents a neuronal trait‐marker of persistent emotion regulation difficulties in BD. Hypo‐activity in the DMPFC may contribute to greater risk of relapse.
Long‐term changes in milk component immunoglobulins reflect milk oral immunotherapy outcomes in Finnish children
Authors: Kauppila Tiina Kaisa , Hinkkanen Victoria , Savinko Terhi , Karisola Piia , Kukkonen Anna Kaarina , Paassilta Marita , Pelkonen Anna S. , Mäkelä Mika J.
Published: August 2022

Background

Milk oral immunotherapy (OIT) may increase the amount of milk protein that can be ingested without triggering an allergic reaction. It is important to understand why some patients benefit from the treatment while others do not.

Objective

The aim was to define the differences in the milk allergen component‐specific (casein, α‐lactalbumin, ß‐lactoglobulin) immunoglobulin (sIg [sIgE, sIgG4, and sIgA]) levels relative to the long‐term outcomes of milk OIT.

Methods

In this long‐term, open‐label follow‐up study, 286 children started milk OIT between 2005 and 2015. Follow‐up data were collected at two points: the post‐buildup phase and long term (range 1–11 years, median 6 years). Comparisons of sIg levels were made among three outcome groups of self‐reported long‐term milk consumption (high‐milk dose, low‐milk dose, and avoidance).

Results

A total of 168 (59%) of the 286 patients on OIT participated. Most patients (57%) were in the high‐dose group; here, 80% of these patients had a baseline casein sIgE value less than 28 kUA/L, they had the lowest casein sIgE levels at all time (p < .001), their casein sIgG4/IgE levels increased, and long‐term casein sIgA was highest compared with the low‐dose and avoidance groups (p = .02). Low‐milk dose group had the highest casein sIgG4/IgE levels in long term (p = .002).

Conclusion

The baseline Ig profiles and responses to milk OIT differed depending on long‐term milk consumption. Lower casein sIgE levels were associated with better outcome. Milk casein sIgA differed in the long term among high‐milk consumers.
SHARPIN promotes cell proliferation of cholangiocarcinoma and inhibits ferroptosis via p53/SLC7A11/GPX4 signaling
Authors: Zeng Chong , Lin Jie , Zhang Ketao , Ou Huohui , Shen Ke , Liu Qingbo , Wei Zibo , Dong Xinhuai , Zeng Xiaokang , Zeng Liming , Wang Weidong , Yao Jie
Published: August 2022

SHARPIN is a tumor‐associated gene involved in the growth and proliferation of many tumor types. A function of SHARPIN in cholangiocarcinoma (CCA) is so far unclear. Here, we studied the role and function of SHARPIN in CCA and revealed its relevant molecular mechanism. The expression of SHARPIN was analyzed in cholangiocarcinoma tissues from patients using immunohistochemistry, quantitative PCR, and western blot analysis. Expression of SHARPIN was suppressed/overexpressed by siRNA silencing or lentiviral overexpression vector, and the effect on cell proliferation was determined by the CCK‐8 assay and flow cytometry. Accumulation of reactive oxygen species was measured with MitoTracker, and JC‐1 staining showed mitochondrial fission/fusion and mitochondrial membrane potential changes as a result of the silencing or overexpression. The ferroptosis marker solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase 4 (GPX4), and the antioxidant enzymes superoxide dismutase 1 (SOD‐1) and SOD‐2 were analyzed by western blot. The results showed that SHARPIN expression was increased in CCA tissue, and this was involved in cell proliferation. SHARPIN silencing resulted in accumulated reactive oxygen species, reduced mitochondrial fission, and a reduced mitochondrial membrane potential. Silencing of SHARPIN inhibited the ubiquitination and degradation of p53, and downregulated levels of SLC7A11, GPX4, SOD‐1, and SOD‐2, all of which contributed to excessive oxidative stress that leads to ferroptosis. Overexpression of SHARPIN would reverse the above process. The collected data suggest that in CCA, SHARPIN‐mediated cell ferroptosis via the p53/SLC7A11/GPX4 signaling pathway is inhibited. Targeting SHARPIN might be a promising approach for the treatment of CCA.
Measuring respiratory syncytial virus infection severity in hospitalized children using the Pediatric Respiratory Syncytial Virus Electronic Severity and Outcome Rating System (PRESORS)
Authors: Vandendijck Yannick , Scott Jane , Heerwegh Dirk , Van Der Elst Wim , Witek James , Sinha Rekha , Fennema Hein
Published: August 2022

Background

The Pediatric Respiratory Syncytial Virus Electronic Severity and Outcome Rating System (PRESORS) was developed to assess the severity of respiratory syncytial virus (RSV) infection in children. Because young children cannot report how they feel or function, ratings are based on observations by the child's caregiver (Observer‐Reported Outcome questionnaire [ObsRO]) and clinician (Clinician‐Reported Outcome questionnaire [ClinRO]). This prospective study aimed to evaluate the psychometric properties of the PRESORS.

Methods

The PRESORS version 6 ObsRO and ClinRO were evaluated in children with RSV infection requiring hospitalization in centers in the United States, Argentina, and Chile. Assessments were performed from days 1 to 7 by the child's caregiver and clinician. To assess inter‐rater reliability, two clinicians independently performed the ClinRO near in time.

Results

A total of 124 children aged ≤36 months were enrolled (mean age, 8 months). Factor analysis demonstrated that RSV severity consists of two dimensions, respiratory signs and illness behavior, and that these dimensions were consistent over time. The inter‐rater reliability for the ClinRO was 0.66 (95% confidence interval [CI], 0.55–0.75) but improved to 0.79 (95% CI, 0.71–0.86) after removing one outlying site, suggesting that quantifying RSV severity is not trivial, even using qualified raters, but that an adequate inter‐rater reliability is achievable with the PRESORS through adequate training. ClinRO and ObsRO displayed acceptable internal consistency and acceptable convergent validity with the Respiratory Syncytial Virus Network Scale, global impression scores, and key hospital characteristics.

Conclusions

The PRESORS is relevant and appropriate for assessing the severity of RSV infection in infants requiring hospitalization.