bluuebunny/crossref_metadata_2025 huggingface dataset:
Millimetre wave channel modeling based on grey genetic optimization model
Authors: Geng Suiyan , Wen Yang , Zhao Xiongwen , Zhang Lei , Chen Suhong
Published: March 2021

In this paper, grey genetic optimization model (GGOM) is proposed for predicting insufficient channel parameters without increasing the amount of measurement data. Based on the millimetre wave 28 GHz indoor measurement data for both LOS and NLOS scenarios, the GGOM model is compared with traditional back propagation (BP) and grey model (GM) to analyse channel parameters like delay spread, excess delay and azimuth spread. Results show that the fitness of GGOM is better than the grey model in improving the stability of system. It works well with insufficient data (size less than 30) in most cases as it is set regardless of the specific scene and measurement data. This is verified by QuaDRiGa platform by generating uniformly distributed and interpolated data between the experimental measurement data. GGOM fits best with the measurement data compared with other prediction methods in channel characterization. Moreover, the mean absolute percentage error (MAPE) for GGOM is the least compared with GM and BP methods. The proposed GGOM model has good performance in modeling insufficient data of propagation channel, practically.
Shell nouns as register-specific discourse devices
Authors: Fang Alex Chengyu , Dong Min
Published: March 2021

This article provides a corpus-based investigation into shell nouns. Shell nouns perform a variety of referential functions and express speaker stance. The investigation was motivated by the fact that past research in this area has been primarily based on written texts. Very little is known about the use of shell nouns in speech. The study used the ICE-GB corpus of contemporary British English and investigated cataphoric shell nouns complemented by appositivethat-clauses across fine-grained spoken and written registers. It has revealed that the deployment of shell nouns is governed by the principle of register formality definable in terms of contextual configurations of the Field-Tenor-Mode complex rather than the mode of production. Additionally, the study has uncovered the frequent use of a small core set of shell nouns common across speech and writing. Hence it argues that shell nouns are part and parcel of spoken and written discourse and that they pertain more to grammar than to lexis.
“You turn your back and there’s somebody moving in”
Authors: Hopper Paul J.
Published: March 2021

Anacrustic Coordination (AC) is a type of biclausal conjunction such that an initial clause or phrase sets up a
state of affairs and is followed by and and a strongly focused second clause, for example three years
it’s been sitting here and I haven’t done it. AC figures in a number of kinds of interaction. One is the
topic/comment conditional, as in call it up and there’s something that actually says your number. It is a
possibility for enhancing certain illocutionary acts such as threats and warnings: I’m gonna take that and I’m gonna dig
it into you. It is a basis for syntactic mirativity, the coding of surprise and unexpectedness (DeLancey 1997): you turn your back and there’s somebody moving in. AC raises questions
about the nature of constructions and of Construction Grammar.
The grammar of proposals for joint activities
Authors: Thompson Sandra A. , Fox Barbara A. , Raymond Chase Wesley
Published: March 2021

The action of proposing has been studied from various perspectives in research on talk-in-interaction, both in mundane as well as in institutional talk. Aiming to exemplify Interactional Linguistics as a drawing together of insights from Linguistics and Conversation Analysis, we explore the grammar of proposals and the stances displayed by participants in making proposals in the context of joint activities, where a future or hypothetical activity is being put forth as something the speaker and recipient(s) might do together. Close examination of interactions among American English-speaking adults reveals four recurrent grammatical formats for issuing proposals:Let’s, Why don’t we, Modal Declaratives, and Modal Interrogatives. We argue that these four formats for doing proposing within a joint activity are used in socially distinct environments, contributing to a growing understanding of the fit between entrenched linguistic patterns and the social work they have evolved to do.
Formation and immunomodulatory function of meningeal B cell aggregates in progressive CNS autoimmunity
Authors: Mitsdoerffer Meike , Di Liberto Giovanni , Dötsch Sarah , Sie Christopher , Wagner Ingrid , Pfaller Monika , Kreutzfeldt Mario , Fräßle Simon , Aly Lilian , Knier Benjamin , Busch Dirk H , Merkler Doron , Korn Thomas
Published: March 2021

Meningeal B lymphocyte aggregates have been described in autopsy material of patients with chronic multiple sclerosis. The presence of meningeal B cell aggregates has been correlated with worse disease. However, the functional role of these meningeal B cell aggregates is not understood. Here, we use a mouse model of multiple sclerosis, the spontaneous opticospinal encephalomyelitis model, which is built on the double transgenic expression of myelin oligodendrocyte glycoprotein-specific T-cell and B-cell receptors, to show that the formation of meningeal B cell aggregates is dependent on the expression of α4 integrins by antigen-specific T cells. T cell-conditional genetic ablation of α4 integrins in opticospinal encephalomyelitis mice impaired the formation of meningeal B cell aggregates, and surprisingly, led to a higher disease incidence as compared to opticospinal encephalomyelitis mice with α4 integrin-sufficient T cells. B cell-conditional ablation of α4 integrins in opticospinal encephalomyelitis mice resulted in the entire abrogation of the formation of meningeal B cell aggregates, and opticospinal encephalomyelitis mice with α4 integrin-deficient B cells suffered from a higher disease burden than regular opticospinal encephalomyelitis mice. While anti-CD20 antibody-mediated systemic depletion of B cells in opticospinal encephalomyelitis mice after onset of disease failed to efficiently decrease meningeal B cell aggregates without significantly modulating disease progression, treatment with anti-CD19 chimeric antigen receptor-T cells eliminated meningeal B cell aggregates and exacerbated clinical disease in opticospinal encephalomyelitis mice. Since about 20% of B cells in organized meningeal B cell aggregates produced either IL-10 or IL-35, we propose that meningeal B cell aggregates might also have an immunoregulatory function as to the immunopathology in adjacent spinal cord white matter. The immunoregulatory function of meningeal B cell aggregates needs to be considered when designing highly efficient therapies directed against meningeal B cell aggregates for clinical application in multiple sclerosis.
Bioinformatics tools developed to support BioCompute Objects
Authors: Patel Janisha A , Dean Dennis A , King Charles Hadley , Xiao Nan , Koc Soner , Minina Ekaterina , Golikov Anton , Brooks Phillip , Kahsay Robel , Navelkar Rahi , Ray Manisha , Roberson Dave , Armstrong Chris , Mazumder Raja , Keeney Jonathon
Published: March 2021

Developments in high-throughput sequencing (HTS) result in an exponential increase in the amount of data generated by sequencing experiments, an increase in the complexity of bioinformatics analysis reporting and an increase in the types of data generated. These increases in volume, diversity and complexity of the data generated and their analysis expose the necessity of a structured and standardized reporting template. BioCompute Objects (BCOs) provide the requisite support for communication of HTS data analysis that includes support for workflow, as well as data, curation, accessibility and reproducibility of communication. BCOs standardize how researchers report provenance and the established verification and validation protocols used in workflows while also being robust enough to convey content integration or curation in knowledge bases. BCOs that encapsulate tools, platforms, datasets and workflows are FAIR (findable, accessible, interoperable and reusable) compliant. Providing operational workflow and data information facilitates interoperability between platforms and incorporation of future dataset within an HTS analysis for use within industrial, academic and regulatory settings. Cloud-based platforms, including High-performance Integrated Virtual Environment (HIVE), Cancer Genomics Cloud (CGC) and Galaxy, support BCO generation for users. Given the 100K+ userbase between these platforms, BioCompute can be leveraged for workflow documentation. In this paper, we report the availability of platform-dependent and platform-independent BCO tools: HIVE BCO App, CGC BCO App, Galaxy BCO API Extension and BCO Portal. Community engagement was utilized to evaluate tool efficacy. We demonstrate that these tools further advance BCO creation from text editing approaches used in earlier releases of the standard. Moreover, we demonstrate that integrating BCO generation within existing analysis platforms greatly streamlines BCO creation while capturing granular workflow details. We also demonstrate that the BCO tools described in the paper provide an approach to solve the long-standing challenge of standardizing workflow descriptions that are both human and machine readable while accommodating manual and automated curation with evidence tagging.

Database URL:  https://www.biocomputeobject.org/resources
Cardiovascular events in patients with chronic myeloid leukaemia treated with tyrosine kinase inhibitors in Taiwan: a nationwide population-based study
Authors: Yang Yu Chien , Huang Ru Yu , Tsai Hui Jen , Li Po Chih , Yang Yi Hsin , Hsieh Kun Pin
Published: March 2021

Aims

New-generation breakpoint cluster region-Abelson tyrosine kinase inhibitors (TKIs) have a higher incidence of cardiovascular events than imatinib in patients with chronic myeloid leukaemia (CML). However, this knowledge is insufficiently proven. Hence, this study aimed to explore the association between cardiovascular events and TKIs in patients with CML.

Methods and results

This retrospective population-based cohort study enrolled first-time users of imatinib, dasatinib, and nilotinib between 1 January 2007 and 31 December 2016. Arterial thromboembolic events (ATEs) were the primary outcome, while other cardiovascular-related events were the secondary outcomes. The event rates were estimated using Kaplan–Meier estimates, and the hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox regression. Additionally, the competing risk was adjusted using the Fine and Gray competing risk model. We included 1207 patients. Nilotinib had a significantly higher ATE risk (subdistribution HR = 4.92, 95% CI = 1.68–14.36) than imatinib. Conversely, no difference was found for other cardiovascular-related events. Risks of ATE and other cardiovascular-related events were similar between dasatinib and imatinib and between nilotinib and dasatinib. The risk of ATE hospitalization consistently increased throughout the main analyses and sensitivity analyses.

Conclusion

Nilotinib-treated patients had a significantly higher risk of developing ATE than imatinib-treated patients. However, the risks of ATE and other cardiovascular-related events were not significantly different between dasatinib and imatinib.
Comparative Study on the Thermal Performance of Three Aedes aegypti (Diptera: Culicidae) Populations From Argentina
Authors: De Majo María Sol , Zanotti Gabriela , Gimenez Javier O , Campos Raúl E , Fischer Sylvia
Published: March 2021

The distribution of Aedes aegypti (L.) (Diptera: Culicidae) is expanding towards colder regions, which could be aided by an adaptation of the immature stages to the local thermal conditions. This study aimed to assess the developmental success at different temperatures in three populations of Ae. aegypti located across a climate gradient in Argentina. Survival to the adult stage, development time, and wing length at 14, 18.5 and 24°C were compared among three populations of Argentina: Resistencia in the subtropical region, and Buenos Aires and San Bernardo in the temperate region. Survival was similar between populations and equal to or higher than 69%, and increased at higher temperatures within the studied range. Development times were similar between populations. A negative effect of temperature was observed and the reduction of development time at increasing temperatures was stronger for males than for females. Wing lengths were negatively affected by increasing temperatures, and the reduction of wing length was stronger for females than for males. Also, the reduction of wing lengths with temperature was stronger for San Bernardo and Resistencia than for Buenos Aires, and differences between sexes were larger for Resistencia than for Buenos Aires or San Bernardo. Although the results do not evidence differences in survival and development time between temperate and tropical populations, the three populations have a higher tolerance to low temperatures than the populations from other regions.
Ethical Issues in Private Practice: A Phenomenological Investigation of Music Therapy Business Owners
Authors: Wilhelm Kyle , Wilhelm Lindsey
Published: March 2021

As a music therapy private practice is both a business and a healthcare service, it should adhere to ethical standards from both disciplines. However, this topic has rarely been examined in the music therapy literature. The purpose of this phenomenological study was to explore ethical dilemmas experienced by music therapy business owners (MTBOs) in their private practice and how MTBOs avoid or address ethical dilemmas. Utilizing convenience and snowball sampling techniques, 21 MTBOs in the United States were interviewed using semi-structured interviews. To answer the two areas of inquiry, we identified three themes and 12 subthemes: (1) Ethical issues related to client welfare, (2) Ethical issues related to business relationships and operation, and (3) Strategies to address or avoid ethical dilemmas. MTBOs also shared how they ensure ethical behavior in themselves, with their employees or independent contractors, and when interacting with professionals outside the private practice. These findings provide a better understanding of MTBOs’ lived experiences of ethics in their private practice and may benefit other music therapists who are in private practice or are wanting to go into private practice. Limitations and recommendations for further research are provided.
A programmable pAgo nuclease with universal guide and target specificity from the mesophilic bacterium Kurthia massiliensis
Authors: Kropocheva Ekaterina , Kuzmenko Anton , Aravin Alexei A , Esyunina Daria , Kulbachinskiy Andrey
Published: March 2021

Argonaute proteins are programmable nucleases that are found in both eukaryotes and prokaryotes and provide defense against invading genetic elements. Although some prokaryotic argonautes (pAgos) were shown to recognize RNA targets in vitro, the majority of studied pAgos have strict specificity toward DNA, which limits their practical use in RNA-centric applications. Here, we describe a unique pAgo nuclease, KmAgo, from the mesophilic bacterium Kurthia massiliensis that can be programmed with either DNA or RNA guides and can precisely cleave both DNA and RNA targets. KmAgo binds 16–20 nt long 5′-phosphorylated guide molecules with no strict specificity for their sequence and is active in a wide range of temperatures. In bacterial cells, KmAgo is loaded with small DNAs with no obvious sequence preferences suggesting that it can uniformly target genomic sequences. Mismatches between the guide and target sequences greatly affect the efficiency and precision of target cleavage, depending on the mismatch position and the nature of the reacting nucleic acids. Target RNA cleavage by KmAgo depends on the formation of secondary structure indicating that KmAgo can be used for structural probing of RNA. These properties of KmAgo open the way for its use for highly specific nucleic acid detection and cleavage.
Structural and functional studies of SF1B Pif1 from Thermus oshimai reveal dimerization-induced helicase inhibition
Authors: Dai Yang-Xue , Chen Wei-Fei , Liu Na-Nv , Teng Fang-Yuan , Guo Hai-Lei , Hou Xi-Miao , Dou Shuo-Xing , Rety Stephane , Xi Xu-Guang
Published: March 2021

Pif1 is an SF1B helicase that is evolutionarily conserved from bacteria to humans and plays multiple roles in maintaining genome stability in both nucleus and mitochondria. Though highly conserved, Pif1 family harbors a large mechanistic diversity. Here, we report crystal structures of Thermus oshimai Pif1 (ToPif1) alone and complexed with partial duplex or single-stranded DNA. In the apo state and in complex with a partial duplex DNA, ToPif1 is monomeric with its domain 2B/loop3 adopting a closed and an open conformation, respectively. When complexed with a single-stranded DNA, ToPif1 forms a stable dimer with domain 2B/loop3 shifting to a more open conformation. Single-molecule and biochemical assays show that domain 2B/loop3 switches repetitively between the closed and open conformations when a ToPif1 monomer unwinds DNA and, in contrast with other typical dimeric SF1A helicases, dimerization has an inhibitory effect on its helicase activity. This mechanism is not general for all Pif1 helicases but illustrates the diversity of regulation mechanisms among different helicases. It also raises the possibility that although dimerization results in activation for SF1A helicases, it may lead to inhibition for some of the other uncharacterized SF1B helicases, an interesting subject warranting further studies.
Transcriptome screening followed by integrated physicochemical and structural analyses for investigating RNA-mediated berberine activity
Authors: Satpathi Sagar , Endoh Tamaki , Podbevšek Peter , Plavec Janez , Sugimoto Naoki
Published: March 2021

Non-coding RNAs are regarded as promising targets for the discovery of innovative drugs due to their abundance in the genome and their involvement in many biological processes. Phytochemicals (PCs) are the primary source of ligand-based drugs due to their broad spectrum of biological activities. Since many PCs are heterocyclic and have chemical groups potentially involved in the interaction with nucleic acids, detailed interaction analysis between PCs and RNA is crucial to explore the effect of PCs on RNA functions. In this study, an integrated approach for investigating interactions between PCs and RNAs were demonstrated to verify the RNA-mediated PCs functions by using berberine (BRB) as a model PC. RNA screening of a transcriptome library followed by sequence refinement found minimal RNA motif consisting of a cytosine bulge with U-A and G-U neighbouring base pairs for interaction with BRB. NMR-based structure determination and physicochemical analyses using chemical analogues of BRB demonstrated the importance of electrostatic and stacking interactions for sequence selective interaction and RNA stabilization. The selective interaction with a relatively small RNA motif based on a chemical structure of a planer heterocyclic highlights the biological activities of various PCs mediated by the interactions with particular functional RNAs. In addition, the systematic and quantitative investigations demonstrated in this study could be useful for the development of therapeutic chemicals targeting functional RNAs, based on the PCs, in the future.
Do We Nurture Our Young? Qualitative Conceptual Analysis of Worst and Best Mentorship Experiences Among Neonatal Advanced Practice Providers
Authors: Morris April L. , Bosque Elena M.
Published: March 2021

Background:

There is increasing demand for neonatal advanced practice providers (APPs) and a shortage of neonatal nurse practitioners (NNPs). In many neonatal intensive care units, neonatal physician assistants are trained and hired, as well as new graduate NNPs. Neonatal APPs are utilized as mentors in a regional neonatology program in the Pacific Northwest. As part of a long-term goal to develop an educational program for neonatal APP mentors, an initial survey was administered.

Purpose:

The purpose of this survey was to raise personal insight and identify themes about 51 neonatal APP mentors' recollections of one's own worst and best mentorship experiences.

Methods:

The design used in this content analysis of survey responses included a phenomenological, qualitative approach. The participants received an online survey consisting of 2 questions asking them to describe their worst and best mentorship experiences. The blinded results were analyzed via content analysis by 2 coinvestigators.

Results:

Consistent themes about worst experiences include “Eat our young,” “I am better than you,” “Thrown under bus,” and “Unwanted.” Consistent themes about best experiences include “Validation,” “Empowerment,” “Positivity,” and “Inclusion.”

Implications for Practice:

Recommendations for successful neonatal APP mentorship based upon the recurrent themes include use of consistent, engaged, trained, and supported mentors, provision of on-time constructive feedback, avoidance of public criticism, private and public praise, focus on the learner, preparation for tasks, and semiautonomy, with adequate support.

Implications for Research:

Absenteeism, recruitment, retention, and satisfaction data may be measured to determine whether structured mentorship programs are beneficial.
UNILATERAL CHEMOSIS, BULLOUS SEROUS RETINAL DETACHMENT, AND PRESUMED BACILLARY LAYER DETACHMENT IN SEVERE PREECLAMPSIA
Authors: Zatreanu Luca , Iyer Neel S.
Published: March 2021

Background/Purpose:

To report a case of unilateral chemosis, serous retinal detachment (SRD), and presumed bacillary layer detachment in pregnancy.

Methods:

Clinical examination and multimodal imaging findings were reviewed and analyzed.

Results:

A 17-year-old female patient with severe preeclampsia was found to have unilateral chemosis and bullous SRD. Postpartum optical coherence tomography revealed thickened choroid and presumed bacillary layer detachment. Two weeks later, chemosis and SRD resolved, leaving behind mottled hyperpigmentation, drusen, and subretinal drusenoid deposits.

Conclusion:

The combination of chemosis and SRD in preeclampsia is exceedingly, rare and it has never previously been reported to occur unilaterally. With delivery, visual acuity, chemosis, choroidal thickness, and SRD all normalize.
In Vivo Modeling of Zebrafish Zinc Finger, MIZ-Type Containing 1 Expression and Its Effect on Pigmentation
Authors: Sun Yong-Hu , Liu Ting-Ting , Mi Zi-Hao , Wang Chuan , Sun Lu-Lu , Ge Kang-Kang , Sheng Dong-Lai , Liu Hong , Zhang Fu-Ren
Published: March 2021

Objective:

The zinc finger, MIZ-type containing 1 (ZMIZ1) gene has been identified as a possible susceptibility gene associated with vitiligo, therefore we conducted this study to investigate the role of ZMIZ1 in pigmentation.

Methods:

We generate a zebrafish loss-of-function model using morpholino oligonucleotides (MOs), and two orthologs of human ZMIZ1 have been annotated (ZMIZ1a and ZMIZ1b). The expression profiles of ZMIZ1a and ZMIZ1b and their effects on the pigmentation in zebrafish were evaluated by using whole-mount in situ hybridization and melanin quantification. Statistical analysis was performed using the unpaired Student t-test or one-way analysis.

Results:

Investigation of the temporal and spatial expressions of these two transcripts suggested that the expressions of ZMIZ1a and ZMIZ1b in the brain start to emerge in a ubiquitous fashion from 2 days post-fertilization onwards. After the successful design and validation of MOs, we observed that ZMIZ1a and ZMIZ1b MOs caused embryonic developmental delays and malformations in zebrafish. Further analysis of the melanin content in the morphants revealed that ZMIZ1a significantly (49.1% for 0.667 mmol/L in ZMIZI1a group, P = 0.03) reduced the melanin content in a dose-dependent manner, but only the highest concentration of injected ZMIZ1b MOs significantly (50% for 0.667 mmol/L in ZMIZ1b group, P = 0.02) reduced the melanin content. A tyrosinase inhibition assay indicated no significant difference between the morphants and wild-type zebrafish.

Conclusion:

This study successfully modeled a susceptibility gene identified by genome-wide association studies in a zebrafish loss-of-function model and provides insights into the biological mechanism of pigmentation.
Blood pressure from the optical Aktiia Bracelet: a 1-month validation study using an extended ISO81060-2 protocol adapted for a cuffless wrist device
Authors: Vybornova Anna , Polychronopoulou Erietta , Wurzner-Ghajarzadeh Arlène , Fallet Sibylle , Sola Josep , Wuerzner Gregoire
Published: March 2021

Objective

The objective of this study (NCT04027777) was to assess the accuracy and precision of the Aktiia Bracelet, a CE-marked noninvasive optical blood pressure (BP) monitor worn at the wrist, over a period of 1 month.

Methods

In this study, participants aged between 21 and 65 years were recruited. The clinical investigation extended the ISO81060-2:2013 standard to the specificities of cuffless devices. Each BP assessment consisted of the simultaneous recording of optical signals with Aktiia Bracelet and double-blinded auscultation by two trained observers in the standard sitting position. The algorithms of Aktiia Bracelet further processed the recorded optical signals to perform a signal quality check and to calculate uncalibrated estimates of systolic BP (SBP) and diastolic BP (DBP). These estimates were transformed into mmHg using a subject-dependent calibration parameter, which was calculated using the first two available reference measurements per subject.

Results

Eighty-six participants were included in the analysis. The mean and SD of the differences between Aktiia Bracelet estimates and the reference (ISO81060-2 criterion 1) were 0.46 ± 7.75 mmHg for SBP and 0.39 ± 6.86 mmHg for DBP. The SD of the averaged paired difference per subject (ISO81060-2 criterion 2) were 3.9 mmHg for SBP and 3.6 mmHg for DBP.

Conclusion

After initialization and during 1 month, the overall accuracy of Aktiia Bracelet satisfied validation criteria 1 and 2 of ISO81060-2 in the sitting position. The Aktiia Bracelet can be recommended for BP measurement in the adult population.
Racial/Ethnic Disparities in Longitudinal Emotional–Behavioral Functioning Among Youth Born to Women Living With HIV
Authors: Bather Jemar R. , Williams Paige L. , Broadwell Carly , Smith Renee , Patel Kunjal , Garvie Patricia A. , Karalius Brad , Kacanek Deborah , Mellins Claude A. , Malee Kathleen ,   for the Pediatric HIV/AIDS Cohort Study (PHACS)
Published: March 2021

Background:

Youth with perinatal HIV exposure have demonstrated high rates of emotional–behavioral problems. Few studies have longitudinally examined racial/ethnic disparities in such functioning across adolescence, a critical time for targeting prevention/intervention efforts.

Setting:

The Pediatric HIV/AIDS Cohort Study Adolescent Master Protocol is one of the largest US-based cohort studies of youth with perinatal HIV (YPHIV) infection or HIV exposed but uninfected (YPHEU).

Methods:

Youth and caregivers individually completed the Behavior Assessment System for Children, second edition, every 2 years between ages 7 and 19 years. We used adjusted mixed-effects models to evaluate whether mean youth-reported emotional concerns and caregiver-reported behavioral concerns differed by race/ethnicity. We used group-based trajectory models to identify groups having similar emotional–behavioral trajectories, followed by multinomial models to determine which factors predicted group membership.

Results:

Three hundred ninety-one YPHIV and 209 YPHEU (7% White non-Hispanic, 21% White Hispanic, 66% Black non-Hispanic, and 6% Black Hispanic) completed a median of 4 assessments over follow-up. Adjusted models showed more caregiver-reported behavioral concerns for Black non-Hispanic YPHEU than for Black non-Hispanic YPHIV, White Hispanic YPHIV, and White Hispanic YPHEU, particularly later in adolescence. Race/ethnicity did not predict membership in subgroups of youth-reported emotional or caregiver-reported behavioral functioning identified using group-based trajectory models. However, factors predicting membership in vulnerable youth-reported emotional and caregiver-reported behavioral groups included experiencing a stressful life event and living with a caregiver who was married or screened positive for a psychiatric condition.

Conclusions:

Our study revealed that Black non-Hispanic YPHEU are a vulnerable subgroup. Contributing factors that could inform interventions include the caregiver's health, household characteristics, and psychiatric status.
Relationships Between Viral Load, Neuroimaging, and NP in Persons Living With HIV
Authors: Cooley Sarah A. , Navid Jaimie , Wisch Julie K. , Boerwinkle Anna , Doyle John , Paul Robert H. , Ances Beau M.
Published: March 2021

Background:

This study examined whether recommended viral load (VL) classifications by the Department of Health and Human Services map onto changes in brain integrity observed in people living with HIV (PLWH).

Methods:

Three hundred forty-nine PLWH on combination antiretroviral therapy meeting criteria for virologic suppression (VS) (VL ≤ 20 copies/mL; n = 206), “low-level viremia” (20–200 copies/mL; n = 63), or virologic failure (VF) (>200 copies/mL; n = 80) and 195 demographically similar HIV-negative controls were compared for cognition and brain volumes from 10 regions of interest that are sensitive to HIV. Changes in cognition and brain volumes were examined in a subset of PLWH (n = 132) who completed a follow-up evaluation (mean interval = 28 months) and had no change in treatment regimen.

Results:

Significant differences in cognition and brain volumes were observed between the HIV-negative control and VS groups compared with those in the VF groups, with few differences observed between the 3 PLWH subgroups. Longitudinally, PLWH who continued to have VF exhibited a greater decline in cognition and brain volumes compared with PLWH who remained with VS. Observed longitudinal changes in cognition correlated with brain volume changes.

Conclusion:

PLWH with continued VF (consecutive VL measurements of >200 copies/mL) represent a cause for clinical concern and may benefit from change in treatment in addition to consideration of other potential etiologies of VF to reduce loss of brain integrity.
The Effect of Priority Given to Donor Card Holders on the Allocation of Livers for Transplant—Evidence From 7 Years of the Israeli Priority Program
Authors: Ashkenazi Tamar , Stoler Avraham , Mor Eytan
Published: March 2021

Background.

The Israeli Transplant Law grants priority in organ allocation to patients signing a donor card. Liver transplant candidates get additional 2 points on their Model for End Stage Liver Disease score for signing a donor card, 0.1 points for a relative holding a card, and 5 points if a relative donated an organ. We studied the effect of the priority program on waiting list mortality and allocation changes due to priority.

Methods.

Using Israeli Transplant data of 531 adult liver transplant candidates with chronic liver disease listed between 2012 and 2018 we compared waitlist mortality and transplant rate of candidates with and without priority. Then we analyzed liver allocations resulting from additional priority points and followed outcome of patients who were skipped in line.

Results.

Of the 519 candidates, 294 did not sign a donor card, 82 signed, 140 had a relative sign, and for 3, a relative donated an organ. The rates of waitlist mortality in these 4 groups were 22.4%, 0%, 21.4%, and 0%, respectively, and the transplant rates were 50%, 59.8%, 49.3%, and 100%, respectively. Of the 30 patients who were skipped because of priority, 24 subsequently underwent transplant, 2 are on the waiting list, and 4 died within 0.75, 1.75, 7, and 17 mo.

Conclusions.

The 2 points added to the Model for End Stage Liver Disease score were associated with lower waitlist mortality and higher transplant rate for candidates signing a donor card without significantly affecting access to transplant during allocation. Further research and consideration of optimal policy when granting priority for candidates signing a donor card should continue.
The Thalamic and Intracortical Inhibitory Function of Somatosensory System Is Unchanged in Mesial Temporal Lobe Epilepsy With Hippocampal Sclerosis
Authors: Akıncı Tuba , Gündüz Ayşegül , Özkara Çiğdem , Kızıltan Meral E.
Published: March 2021

Purpose:

In mesial temporal lobe epilepsy with hippocampal sclerosis, there is parietal atrophy and cognitive involvement in related domains. In this context, we hypothesized that inhibitory input into somatosensory cortex and thalamus may be increased in these patients, which could improve after epilepsy surgery. Thus, we analyzed the inhibitory function of somatosensory system by studying surround inhibition (SI) and recovery function of somatosensory evoked potentials in patients with mesial temporal lobe epilepsy with hippocampal sclerosis.

Methods:

Nine patients with unoperated mesial temporal lobe epilepsy with hippocampal sclerosis, 10 patients who underwent epilepsy surgery, and 12 healthy subjects were included. For SI of somatosensory evoked potentials, we recorded somatosensory evoked potentials after stimulating median or ulnar nerve at wrist separately and after median and ulnar nerves simultaneously and calculated SI% in all participants. For recovery function of somatosensory evoked potentials, paired stimulation of median nerve at 40- and 100-millisecond intervals was performed. We compared the findings among groups. As a secondary analysis, we determined the outliers in the patient group and analyzed the relation to the clinical findings.

Results:

The mean SI% or recovery function was similar among three groups. However, there were five patients with SI loss on normal side in the patient group, which was related to the antiseizure drugs.

Conclusions:

In contrast to our hypothesis, both intracortical (SI) and thalamic/striatal (recovery function) inhibitory modulation of the somatosensory cortex was not altered in mesial temporal lobe epilepsy with hippocampal sclerosis and did not differ in surgical and nonsurgical groups.
EZH2 Abundance Regulated by UHRF1/UBE2L6/UBR4 Ubiquitin System is the Potential Therapeutic Target to Trigger Pigmented Phenotype in Melanoma
Authors: Abali Gamze Kuser , Zhang Youfang , Szeto Pacman , Zhao Peinan , Moghaddam Samar Masoumi , Leece Isobel , Huang Cheng , Cheung Jen , Ameratunga Malaka , Noguchi Fumihito , Andrews Miles , Wong Nicholas C. , Schittenhelm Ralf , Shackleton Mark
Published: March 2021

Cellular heterogeneity in cancer is linked to disease progression and therapy response, although the mechanisms regulating distinct cellular states within tumours are not well understood. To address this, we identified melanin pigment content as a major source of phenotypic and functional heterogeneity in melanoma and compared RNAseq data from high (HPC) and low pigmented melanoma cells (LPC), revealing the polycomb repressor complex protein, EZH2, as a master regulator of these states. EZH2 protein, but not RNA expression, was found to be upregulated in LPCs and inversely correlated with melanin in pigmented patient melanomas. Surprisingly, conventional EZH2 methyltransferase inhibitors, GSK126 and EPZ6438, had no effect on LPC survival, clonogenicity and pigmentation, despite fully inhibiting methyltransferase activity. In contrast, EZH2 silencing by siRNA strategy or DZNep, MS1943 that reduces EZH2 protein levels, significantly inhibited cell growth in LPCs by hampering ribosome biogenesis. In addition, decline in EZH2 protein level induces pigmented cell phenotype by inducing melanin biosynthesis. Proteasomal inhibitor, MG132 treatment induced EZH2 protein levels in HPCs prompted us to look for differentially regulated ubiquitin system proteins in HPC vs LPCs. UBE2L6, E2 conjugating enzyme has been shown to be downregulated significantly in LPCs by UHRF1-mediated CpG methylation. Both biochemical assays and animal studies demonstrated that UBE2L6 expression decline, in turn, promotes EZH2 protein stability due to lack of ubiquitination on K381 residue in LPCs. UBR4 cooperates with UBE2L6 to facilitate this ubiquitination process. Targeting UHRF1/UBE2L6/UBR4 axis can be a better treatment option to trigger HPC state in melanoma in which conventional EZH2 inhibitors are ineffective.
Multiomics Analyses Reveal Dynamic Bioenergetic Pathways and Functional Remodeling of the Heart During Intermittent Fasting
Authors: Arumugam Thiruma V. , Alli-Shaik Asfa , Liehn Elisa A. , Selvaraji Sharmelee , Poh Luting , Rajeev Vismitha , Cho Yoonsuk , Cho Yongeun , Kim Jongho , Kim Joonki , Swa Hannah L. F. , Hao David Tan Zhi , Ratttanasopa Chutima , Fann David Yang-Wei , Mayan David Castano , Ng Gavin Yong-Quan , Baik Sang-Ha , Mallilankaraman Karthik , Gelderblom Mathias , Drummond Grant R. , Sobey Christopher G. , Kennedy Brian K. , Singaraja Roshni R. , Mattson Mark P. , Jo Dong-Gyu , Gunaratne Jayantha
Published: March 2021

Aims

Intermittent fasting (IF) reduces cardiovascular risk factors in animals and humans, and can protect the heart against ischemic injury in models of myocardial infarction, but the underlying molecular mechanisms are unknown. To delineate molecular and cellular adaptations of the heart to IF, we carried out system-wide comprehensive analyses of proteome and phosphoproteome, complemented with transcriptome profiling, followed by functional analysis.

Methods and results

In order to understand molecular and cellular remodeling of the heart during IF, we employed advanced mass spectrometry for system-wide profiling of the proteome and phosphoproteome of heart tissues obtained from mice maintained for 6 months on either daily 12- or 16-hour fasting, every-other-day fasting or ad libitum control feeding regimens. We also performed transcriptome analyses using RNA sequencing to evaluate whether the observed molecular responses to IF occur at the transcriptional or post-transcriptional levels. IF regimens significantly affected pathways that regulate cyclic GMP signaling, lipid and amino acid metabolism, cell adhesion, cell death, and inflammation. Comparison of differentially expressed proteome and transcriptome upon IF showed the higher correlation of pathway alternation in short IF regimen but the inverse correlation of metabolic processes such as fatty acid oxidation and immune processes in longer IF regimens. In addition, functional echocardiographic analyses demonstrated that IF enhances stress-induced cardiac performance.

Conclusion

Our systematic multi-omics study elucidates a molecular framework for understanding how IF impacts the heart’s function and its vulnerability to injury and disease.

Translational perspective

Intermittent fasting is emerging as a desirable lifestyle adaptation to impact cardiovascular health through the modulation of molecular and cellular mechanisms, and by acting on disease risk factors. Evidence from numerous studies indicates that the fasting cycles are highly and consistently effective in protecting against cardiovascular diseases and improving cardiac health in animals and human. Using multi-omics, here we dissect distinct molecular adaptations of the heart to different intermittent fasting regimens. Our results unveil novel cardioprotective mechanisms and open up new avenues for innovative pharmacological approaches to prevent and treat cardiovascular diseases.
Hypnotic visual hallucination induces greater lateralised brain activity than visual imagery
Authors: Lanfranco Renzo C. , Rivera-Rei Álvaro , Huepe David , Ibáñez Agustín , Canales-Johnson Andrés
Published: March 2021

Hypnotic suggestions can produce a broad range of perceptual experiences, including hallucinations. Visual hypnotic hallucinations differ in many ways from regular mental images. For example, they are usually experienced as automatic, vivid, and real images, typically compromising the sense of reality. While both hypnotic hallucination and mental imagery are believed to mainly rely on the activation of the visual cortex via top-down mechanisms, it is unknown how they differ in the neural processes they engage. Here we used an adaptation paradigm to test and compare top-down processing between hypnotic hallucination, mental imagery, and visual perception in very highly hypnotisable individuals whose ability to hallucinate was assessed. By measuring the N170/VPP event-related complex and using multivariate decoding analysis, we found that hypnotic hallucination of faces involves greater top-down activation of sensory processing through lateralised mechanisms in the right hemisphere compared to mental imagery. Our findings suggest that the neural signatures that distinguish hypnotically hallucinated faces from imagined faces lie in the right brain hemisphere.
An atypical class of non-coding small RNAs produced in rice leaves upon bacterial infection
Authors: Reshetnyak Ganna , Jacobs Jonathan M. , Auguy Florence , Sciallano Coline , Claude Lisa , Medina Clemence , Perez-Quintero Alvaro L. , Comte Aurore , Thomas Emilie , Bogdanove Adam , Koebnik Ralf , Szurek Boris , Dievart Anne , Brugidou Christophe , Lacombe Severine , Cunnac Sebastien
Published: March 2021

Non-coding small RNAs (sRNA) act as mediators of gene silencing and regulate plant growth, development and stress responses. Early insights into plant sRNAs established a role in antiviral defense and they are now extensively studied across plant-microbe interactions. Here, sRNA sequencing discovered a class of sRNA in rice (Oryza sativa) specifically associated with foliar diseases caused byXanthomonas oryzaebacteria.Xanthomonas-induced small RNAs (xisRNAs) loci were distinctively upregulated in response to diverse virulent strains at an early stage of infection producing a single duplex of 20-22nt sRNAs. xisRNAs production was dependent on the Type III secretion system, a major bacterial virulence factor for host colonization. xisRNA loci overlap with annotated transcripts sequences often encoding protein kinase domain proteins. A number of the corresponding ricecis-genes have documented functions in immune signaling and some xisRNA loci coincide with the coding sequence of a conserved kinase motif. xisRNAs exhibit features of small interfering RNAs and their biosynthesis depend on canonical componentsOsDCL1andOsHEN1.xisRNA induction possibly mediates post-transcriptional gene silencing but they do not broadly suppresscis-genes expression on the basis of mRNA-seq data. Overall, our results identify a group of unusual sRNAs with a potential role in plant-microbe interactions.
Previous SARS-CoV-2 infection increases B.1.1.7 cross-neutralization by vaccinated individuals
Authors: Trinité Benjamin , Pradenas Edwards , Marfil Silvia , Rovirosa Carla , Urrea Víctor , Tarrés-Freixas Ferran , Ortiz Raquel , Vergara-Alert Júlia , Segalés Joaquim , Guallar Victor , Lepore Rosalba , Izquierdo-Useros Nuria , Trujillo Glòria , Trapé Jaume , González-Fernández Carolina , Flor Antonia , Pérez-Vidal Rafel , Chamorro Anna , Paredes Roger , Blanco Ignacio , Grau Eulalia , Massanella Marta , Carrillo Jorge , Clotet Bonaventura , Blanco Julià
Published: March 2021

To assess the potential impact of predominant circulating SARS-CoV-2 variants on neutralizing activity of infected and/or vaccinated individuals, we analyzed neutralization of pseudoviruses expressing the spike of the original Wuhan strain, the D614G and B.1.1.7 variants. Our data show that parameters of natural infection (time from infection and infecting variant) determined cross-neutralization. Importantly, upon vaccination, previously infected individuals developed equivalent B.1.1.7 and Wuhan neutralizing responses. In contrast, uninfected vaccinees showed reduced neutralization against B.1.1.7.

Funding

This study was funded by Grifols, theDepartament de Salutof theGeneralitat de Catalunya, the Spanish Health Institute Carlos III, CERCA Programme/Generalitat de Catalunya, and the crowdfunding initiatives #joemcorono, BonPreu/Esclat and Correos.
Transparent exploration of machine learning for biomarker discovery from proteomics and omics data
Authors: Torun Furkan M. , Winter Sebastian Virreira , Doll Sophia , Riese Felix M. , Vorobyev Artem , Mueller-Reif Johannes B. , Geyer Philipp E. , Strauss Maximilian T.
Published: March 2021

Biomarkers are of central importance for assessing the health state and to guide medical interventions and their efficacy, but they are lacking for most diseases. Mass spectrometry (MS)-based proteomics is a powerful technology for biomarker discovery, but requires sophisticated bioinformatics to identify robust patterns. Machine learning (ML) has become indispensable for this purpose, however, it is sometimes applied in an opaque manner, generally requires expert knowledge and complex and expensive software. To enable easy access to ML for biomarker discovery without any programming or bioinformatic skills, we developed ‘OmicLearn’ (https://OmicLearn.com), an open-source web-based ML tool using the latest advances in the Python ML ecosystem. We host a web server for the exploration of the researcher’s results that can readily be cloned for internal use. Output tables from proteomics experiments are easily uploaded to the central or a local webserver. OmicLearn enables rapid exploration of the suitability of various ML algorithms for the experimental datasets. It fosters open science via transparent assessment of state-of-the-art algorithms in a standardized format for proteomics and other omics sciences.

Graphical Abstract

Highlights

OmicLearn is an open-source platform allows researchers to apply machine learning (ML) for biomarker discovery

The ready-to-use structure of OmicLearn enables accessing state-of-the-art ML algorithms without requiring any prior bioinformatics knowledge

OmicLearn’s web-based interface provides an easy-to-follow platform for classification and gaining insights into the dataset

Several algorithms and methods for preprocessing, feature selection, classification and cross-validation of omics datasets are integrated

All results, settings and method text can be exported in publication-ready formats
Novel personalized cancer vaccine platform based on Bacillus Calmette-Guèrin
Authors: Ylösmäki Erkko , Martins Beatriz , Fusciello Manlio , Feola Sara , Hamdan Firas , Chiaro Jacopo , Ylösmäki Leena , Vaughan Matthew J. , Viitala Tapani , Kulkarni Prasad S. , Cerullo Vincenzo
Published: March 2021

Intratumoural bacillus Calmette-Guérin (BCG) therapy, one of the earliest immunotherapies, can lead to infiltration of immune cells into a treated tumour. Here, we have developed a novel cancer vaccine platform based on BCG that can direct BCG-induced immune responses against tumour antigens. By physically attaching tumour-specific peptides onto the mycobacterial outer membrane, we were able to induce strong systemic and intratumoural T cell-specific immune responses towards the attached tumour antigens. These therapeutic peptides can be attached to the mycobacterial outer membrane using a cell-penetrating peptide sequence derived from human immunodeficiency virus Tat, N-terminally fused to the tumour-specific peptides. Alternatively, therapeutic peptides can be conjugated with a poly-lysine sequence N-terminally fused to the tumour-specific peptides. Using two mouse models of melanoma and a mouse model of colorectal cancer, we observed that the anti-tumour responses of BCG can be significantly improved by coating the BCG with tumour-specific peptides. In addition, by combining this novel cancer vaccine platform with anti-PD-1 immune checkpoint inhibitor therapy, the number of responders to anti-PD-1 immunotherapy can be significantly increased.