bluuebunny/crossref_metadata_2025_split huggingface dataset:
The psychiatric risk gene BRD1 modulates mitochondrial bioenergetics by transcriptional regulation
Authors: Paternoster Veerle , Cömert Cagla , Kirk Louise Sand , la Cour Sanne Hage , Fryland Tue , Fernandez-Guerra Paula , Stougaard Magnus , Nyengaard Jens Randel , Qvist Per , Bross Peter , Børglum Anders Dupont , Christensen Jane Hvarregaard 
Published: August 2022

AbstractBromodomain containing 1 (BRD1) encodes an epigenetic regulator that controls the expression of genetic networks linked to mental illness. BRD1 is essential for normal brain development and its role in psychopathology has been demonstrated in genetic and preclinical studies. However, the neurobiology that bridges its molecular and neuropathological effects remains poorly explored. Here, using publicly available datasets, we find that BRD1 targets nuclear genes encoding mitochondrial proteins in cell lines and that modulation of BRD1 expression, irrespective of whether it is downregulation or upregulation of one or the other existing BRD1 isoforms (BRD1-L and BRD1-S), leads to distinct shifts in the expression profile of these genes. We further show that the expression of nuclear genes encoding mitochondrial proteins is negatively correlated with the expression of BRD1 mRNA during human brain development. In accordance, we identify the key gate-keeper of mitochondrial metabolism, Peroxisome proliferator-activated receptor (PPAR) among BRD1’s co-transcription factors and provide evidence that BRD1 acts as a co-repressor of PPAR-mediated transcription. Lastly, when using quantitative PCR, mitochondria-targeted fluorescent probes, and the Seahorse XFe96 Analyzer, we demonstrate that modulation of BRD1 expression in cell lines alters mitochondrial physiology (mtDNA content and mitochondrial mass), metabolism (reducing power), and bioenergetics (among others, basal, maximal, and spare respiration) in an expression level- and isoform-dependent manner. Collectively, our data suggest that BRD1 is a transcriptional regulator of nuclear-encoded mitochondrial proteins and that disruption of BRD1’s genomic actions alters mitochondrial functions. This may be the mechanism underlying the cellular and atrophic changes of neurons previously associated with BRD1 deficiency and suggests that mitochondrial dysfunction may be a possible link between genetic variation in BRD1 and psychopathology in humans.
Oxytocin-based therapies for treatment of Prader-Willi and Schaaf-Yang syndromes: evidence, disappointments, and future research strategies
Authors: Althammer Ferdinand , Muscatelli Francoise , Grinevich Valery , Schaaf Christian P. 
Published: August 2022

AbstractThe prosocial neuropeptide oxytocin is being developed as a potential treatment for various neuropsychiatric disorders including autism spectrum disorder (ASD). Early studies using intranasal oxytocin in patients with ASD yielded encouraging results and for some time, scientists and affected families placed high hopes on the use of intranasal oxytocin for behavioral therapy in ASD. However, a recent Phase III trial obtained negative results using intranasal oxytocin for the treatment of behavioral symptoms in children with ASD. Given the frequently observed autism-like behavioral phenotypes in Prader-Willi and Schaaf-Yang syndromes, it is unclear whether oxytocin treatment represents a viable option to treat behavioral symptoms in these diseases. Here we review the latest findings on intranasal OT treatment, Prader-Willi and Schaaf-Yang syndromes, and propose novel research strategies for tailored oxytocin-based therapies for affected individuals. Finally, we propose the critical period theory, which could explain why oxytocin-based treatment seems to be most efficient in infants, but not adolescents.
Patient attrition in Molecular Tumour Boards: a systematic review
Authors: Frost Hannah , Graham Donna M. , Carter Louise , O’Regan Paul , Landers Dónal , Freitas André 
Published: August 2022

Abstract
Background
Molecular Tumour Boards (MTBs) were created with the purpose of supporting clinical decision-making within precision medicine. Though in use globally, reporting on these meetings often focuses on the small percentages of patients that receive treatment via this process and are less likely to report on, and assess, patients who do not receive treatment.

Methods
A literature review was performed to understand patient attrition within MTBs and barriers to patients receiving treatment. A total of 51 papers were reviewed spanning a 6-year period from 11 different countries.

Results
In total, 20% of patients received treatment through the MTB process. Of those that did not receive treatment, the main reasons were no mutations identified (27%), no actionable mutations (22%) and clinical deterioration (15%). However, data were often incomplete due to inconsistent reporting of MTBs with only 55% reporting on patients having no mutations, 55% reporting on the presence of actionable mutations with no treatment options and 59% reporting on clinical deterioration.

Discussion
As patient attrition in MTBs is an issue which is very rarely alluded to in reporting, more transparent reporting is needed to understand barriers to treatment and integration of new technologies is required to process increasing omic and treatment data.
Interaction of LATS1 with SMAC links the MST2/Hippo pathway with apoptosis in an IAP-dependent manner
Authors: García-Gutiérrez Lucía , Fallahi Emma , Aboud Nourhan , Quinn Niall , Matallanas David 
Published: August 2022

AbstractMetastatic malignant melanoma is the deadliest skin cancer, and it is characterised by its high resistance to apoptosis. The main melanoma driving mutations are part of ERK pathway, with BRAF mutations being the most frequent ones, followed by NRAS, NF1 and MEK mutations. Increasing evidence shows that the MST2/Hippo pathway is also deregulated in melanoma. While mutations are rare, MST2/Hippo pathway core proteins expression levels are often dysregulated in melanoma. The expression of the tumour suppressor RASSF1A, a bona fide activator of the MST2 pathway, is silenced by promoter methylation in over half of melanomas and correlates with poor prognosis. Here, using mass spectrometry-based interaction proteomics we identified the Second Mitochondria-derived Activator of Caspases (SMAC) as a novel LATS1 interactor. We show that RASSF1A-dependent activation of the MST2 pathway promotes LATS1-SMAC interaction and negatively regulates the antiapoptotic signal mediated by the members of the IAP family. Moreover, proteomic experiments identified a common cluster of apoptotic regulators that bind to SMAC and LATS1. Mechanistic analysis shows that the LATS1-SMAC complex promotes XIAP ubiquitination and its subsequent degradation which ultimately results in apoptosis. Importantly, we show that the oncogenic BRAFV600E mutant prevents the proapoptotic signal mediated by the LATS1-SMAC complex while treatment of melanoma cell lines with BRAF inhibitors promotes the formation of this complex, indicating that inhibition of the LATS1-SMAC might be necessary for BRAFV600E-driven melanoma. Finally, we show that LATS1-SMAC interaction is regulated by the SMAC mimetic Birinapant, which requires C-IAP1 inhibition and the degradation of XIAP, suggesting that the MST2 pathway is part of the mechanism of action of Birinapant. Overall, the current work shows that SMAC-dependent apoptosis is regulated by the LATS1 tumour suppressor and supports the idea that LATS1 is a signalling hub that regulates the crosstalk between the MST2 pathway, the apoptotic network and the ERK pathway.
Visual performance following implantation of presbyopia correcting intraocular lenses
Authors: Torky Magda A. , Nokrashy Amgad El , Metwally Heba , Abdelhameed Ameera G. 
Published: August 2022

Abstract

Objective
To compare the visual outcomes following bilateral implantation of 3 presbyopia correcting IOLs.

Methods
Results are reported for patients who underwent phacoemulsification with bilateral implantation of one of the following IOLs: Panoptix IOL, AT LISA tri IOL and Symphony IOL. Six months postoperative examination included monocular UIVA at 80 and 60 cm and monocular UNVA and DCNVA at 40 cm, monocular UDVA and CDVA, Spherical equivalent (SE) refraction, binocular defocus curve, contrast sensitivity, photopic phenomena, and spectacle independence.

Results
UIVA at 80 cm was significantly better in the AT LISA group and the Symfony groups than the Panoptix group, while UIVA at 60 cm was better in the Symfony group and the Panoptix group than the AT LISA group. A worse DCNVA was recorded in the Symfony group. At a defocus of −2.50 D, the near VA was similar in the PanOptix and AT LISA groups (0.05, 0.07 logMAR respectively), which were significantly better than the Symfony group (0.3 LogMAR). Binocular photopic and scotopic contrast sensitivity outcomes were similar among the three groups at all spatial frequencies. In Symphony group, the frequency and the degree of bother of photic phenomena was relatively higher than the other two groups. Higher percentage of patients in symphony group reported their need for reading glasses.

Conclusion
PanOptix IOL and AT LISA IOL would be a good choice for patients aiming for an optimum near vision, while Symfony IOL seems suitable for patients having the priority for good intermediate vision.
Anomalous Ferromagnetism of quasiparticle doped holes in cuprate heterostructures revealed using resonant soft X-ray magnetic scattering
Authors: Ong B. L. , Jayaraman K. , Diao C. , Whitcher T. J. , Jain A. , Hung H. , Breese M. B. H. , Tok E. S. , Rusydi A. 
Published: August 2022

AbstractWe report strong ferromagnetism of quasiparticle doped holes both within the ab-plane and along the c-axis of Cu-O planes in low-dimensional Au/d-La1.8Ba0.2CuO4/LaAlO3(001) heterostructures (d = 4, 8 and 12 unit-cells) using resonant soft X-ray and magnetic scattering together with X-ray magnetic circular dichroism. Interestingly, ferromagnetism is stronger at a hole doped peak and at an upper Hubbard band of O with spin-polarization degree as high as 40%, revealing strong ferromagnetism of Mottness. For in-ab-plane spin-polarizations, the spin of doped holes in O2p–Cu3d–O2p is a triplet state yielding strong ferromagnetism. For out-of-ab-plane spin-polarization, while the spins of doped holes in both O2p–O2p and Cu3d–Cu3d are triplet states, the spin of doped holes in Cu3d–O2p is a singlet state yielding ferrimagnetism. A ferromagnetic-(002) Bragg-peak of the doped holes is observed and enhanced as a function of d revealing strong ferromagnetism coupling between Cu-O layers along the c-axis.
Systematic evidence and gap map of research linking food security and nutrition to mental health
Authors: Sparling Thalia M. , Deeney Megan , Cheng Bryan , Han Xuerui , Lier Chiara , Lin Zhuozhi , Offner Claudia , Santoso Marianne V. , Pfeiffer Erin , Emerson Jillian A. , Amadi Florence Mariamu , Mitu Khadija , Corvalan Camila , Verdeli Helen , Araya Ricardo , Kadiyala Suneetha 
Published: August 2022

AbstractConnections between food security and nutrition (FSN) and mental health have been analytically investigated, but conclusions are difficult to draw given the breadth of literature. Furthermore, there is little guidance for continued research. We searched three databases for analytical studies linking FSN to mental health. Out of 30,896 records, we characterized and mapped 1945 studies onto an interactive Evidence and Gap Map (EGM). In these studies, anthropometry (especially BMI) and diets were most linked to mental health (predominantly depression). There were fewer studies on infant and young child feeding, birth outcomes, and nutrient biomarkers related to anxiety, stress, and mental well-being. Two-thirds of studies hypothesized FSN measures as the exposure influencing mental health outcomes. Most studies were observational, followed by systematic reviews as the next largest category of study. One-third of studies were carried out in low- and middle-income countries. This map visualizes the extent and nature of analytical studies relating FSN to mental health and may be useful in guiding future research.
Competition between hematopoietic stem and progenitor cells controls hematopoietic stem cell compartment size
Authors: Miao Runfeng , Chun Harim , Feng Xing , Gomes Ana Cordeiro , Choi Jungmin , Pereira João P. 
Published: August 2022

AbstractCellular competition for limiting hematopoietic factors is a physiologically regulated but poorly understood process. Here, we studied this phenomenon by hampering hematopoietic progenitor access to Leptin receptor+ mesenchymal stem/progenitor cells (MSPCs) and endothelial cells (ECs). We show that HSC numbers increase by 2-fold when multipotent and lineage-restricted progenitors fail to respond to CXCL12 produced by MSPCs and ECs. HSCs are qualitatively normal, and HSC expansion only occurs when early hematopoietic progenitors but not differentiated hematopoietic cells lack CXCR4. Furthermore, the MSPC and EC transcriptomic heterogeneity is stable, suggesting that it is impervious to major changes in hematopoietic progenitor interactions. Instead, HSC expansion correlates with increased availability of membrane-bound stem cell factor (mSCF) on MSPCs and ECs presumably due to reduced consumption by cKit-expressing hematopoietic progenitors. These studies suggest that an intricate homeostatic balance between HSCs and proximal hematopoietic progenitors is regulated by cell competition for limited amounts of mSCF.
ChAdOx1 nCoV-19 (AZD1222) or nCoV-19-Beta (AZD2816) protect Syrian hamsters against Beta Delta and Omicron variants
Authors: van Doremalen Neeltje , Schulz Jonathan E. , Adney Danielle R. , Saturday Taylor A. , Fischer Robert J. , Yinda Claude Kwe , Thakur Nazia , Newman Joseph , Ulaszewska Marta , Belij-Rammerstorfer Sandra , Saturday Greg , Spencer Alexandra J. , Bailey Dalan , Russell Colin A. , Gilbert Sarah C. , Lambe Teresa , Munster Vincent J. 
Published: August 2022

AbstractChAdOx1 nCoV-19 (AZD1222) is a replication-deficient simian adenovirus–vectored vaccine encoding the spike (S) protein of SARS-CoV-2, based on the first published full-length sequence (Wuhan-1). AZD1222 has been shown to have 74% vaccine efficacy against symptomatic disease in clinical trials. However, variants of concern (VoCs) have been detected, with substitutions that are associated with a reduction in virus neutralizing antibody titer. Updating vaccines to include S proteins of VoCs may be beneficial, even though current real-world data is suggesting good efficacy following boosting with vaccines encoding the ancestral S protein. Using the Syrian hamster model, we evaluate the effect of a single dose of AZD2816, encoding the S protein of the Beta VoC, and efficacy of AZD1222/AZD2816 as a heterologous primary series against challenge with the Beta or Delta variant. Minimal to no viral sgRNA could be detected in lungs of vaccinated animals obtained at 3- or 5- days post inoculation, in contrast to lungs of control animals. In Omicron-challenged hamsters, a single dose of AZD2816 or AZD1222 reduced virus shedding. Thus, these vaccination regimens are protective against the Beta, Delta, and Omicron VoCs in the hamster model.
Antibody affinity and cross-variant neutralization of SARS-CoV-2 Omicron BA.1, BA.2 and BA.3 following third mRNA vaccination
Authors: Bellusci Lorenza , Grubbs Gabrielle , Zahra Fatema Tuz , Forgacs David , Golding Hana , Ross Ted M. , Khurana Surender 
Published: August 2022

AbstractThere is limited knowledge on durability of neutralization capacity and antibody affinity maturation generated following two versus three doses of SARS-CoV-2 mRNA vaccines in naïve versus convalescent individuals (hybrid immunity) against the highly transmissible Omicron BA.1, BA.2 and BA.3 subvariants. Virus neutralization titers against the vaccine-homologous strain (WA1) and Omicron sublineages are measured in a pseudovirus neutralization assay (PsVNA). In addition, antibody binding and antibody affinity against spike proteins from WA1, BA.1, and BA.2 is determined using surface plasmon resonance (SPR). The convalescent individuals who after SARS-CoV-2 infection got vaccinated develop hybrid immunity that shows broader neutralization activity and cross-reactive antibody affinity maturation against the Omicron BA.1 and BA.2 after either second or third vaccination compared with naïve individuals. Neutralization activity correlates with antibody affinity against Omicron subvariants BA.1 and BA.2 spikes. Importantly, at four months post-third vaccination the neutralization activity and antibody affinity against the Omicron subvariants is maintained and trended higher for the individuals with hybrid immunity compared with naïve adults. These findings about hybrid immunity resulting in superior immune kinetics, breadth, and durable high affinity antibodies support the need for booster vaccinations to provide effective protection from emerging SARS-CoV-2 variants like the rapidly spreading Omicron subvariants.
Allosteric modulation of GPCR-induced β-arrestin trafficking and signaling by a synthetic intrabody
Authors: Baidya Mithu , Chaturvedi Madhu , Dwivedi-Agnihotri Hemlata , Ranjan Ashutosh , Devost Dominic , Namkung Yoon , Stepniewski Tomasz Maciej , Pandey Shubhi , Baruah Minakshi , Panigrahi Bhanupriya , Sarma Parishmita , Yadav Manish K. , Maharana Jagannath , Banerjee Ramanuj , Kawakami Kouki , Inoue Asuka , Selent Jana , Laporte Stéphane A. , Hébert Terence E. , Shukla Arun K. 
Published: August 2022

AbstractAgonist-induced phosphorylation of G protein-coupled receptors (GPCRs) is a primary determinant of β-arrestin (βarr) recruitment and trafficking. For several GPCRs such as the vasopressin receptor subtype 2 (V2R), agonist-stimulation first drives the translocation of βarrs to the plasma membrane, followed by endosomal trafficking, which is generally considered to be orchestrated by multiple phosphorylation sites. We have previously shown that mutation of a single phosphorylation site in the V2R (i.e., V2RT360A) results in near-complete loss of βarr translocation to endosomes despite robust recruitment to the plasma membrane, and compromised ERK1/2 activation. Here, we discover that a synthetic intrabody (Ib30), which selectively recognizes activated βarr1, efficiently rescues the endosomal trafficking of βarr1 and ERK1/2 activation for V2RT360A. Molecular dynamics simulations reveal that Ib30 enriches active-like βarr1 conformation with respect to the inter-domain rotation, and cellular assays demonstrate that it also enhances βarr1-β2-adaptin interaction. Our data provide an experimental framework to positively modulate the receptor-transducer-effector axis for GPCRs using intrabodies, which can be potentially integrated in the paradigm of GPCR-targeted drug discovery.
Measuring anion binding at biomembrane interfaces
Authors: Wu Xin , Wang Patrick , Lewis William , Jiang Yun-Bao , Gale Philip A. 
Published: August 2022

AbstractThe quantification of anion binding by molecular receptors within lipid bilayers remains challenging. Here we measure anion binding in lipid bilayers by creating a fluorescent macrocycle featuring a strong sulfate affinity. We find the determinants of anion binding in lipid bilayers to be different from those expected that govern anion binding in solution. Charge-dense anions H2PO4–and Cl–that prevail in dimethyl sulfoxide fail to bind to the macrocycle in lipids. In stark contrast, ClO4–and I–that hardly bind in dimethyl sulfoxide show surprisingly significant affinities for the macrocycle in lipids. We reveal a lipid bilayer anion binding principle that depends on anion polarisability and bilayer penetration depth of complexes leading to unexpected advantages of charge-diffuse anions. These insights enhance our understanding of how biological systems select anions and guide the design of functional molecular systems operating at biomembrane interfaces.
Trastuzumab deruxtecan in HER2-positive breast cancer with brain metastases: a single-arm, phase 2 trial
Authors: Bartsch Rupert , Berghoff Anna Sophie , Furtner Julia , Marhold Maximilian , Bergen Elisabeth Sophie , Roider-Schur Sophie , Starzer Angelika Martina , Forstner Heidrun , Rottenmanner Beate , Dieckmann Karin , Bago-Horvath Zsuzsanna , Haslacher Helmuth , Widhalm Georg , Ilhan-Mutlu Aysegül , Minichsdorfer Christoph , Fuereder Thorsten , Szekeres Thomas , Oehler Leopold , Gruenberger Birgit , Singer Christian F. , Weltermann Ansgar , Puhr Rainer , Preusser Matthias 
Published: August 2022

AbstractTrastuzumab deruxtecan is an antibody–drug conjugate with high extracranial activity in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. We conducted the prospective, open-label, single-arm, phase 2 TUXEDO-1 trial. We enrolled patients aged ≥18 years with HER2-positive breast cancer and newly diagnosed untreated brain metastases or brain metastases progressing after previous local therapy, previous exposure to trastuzumab and pertuzumab and no indication for immediate local therapy. Patients received trastuzumab deruxtecan intravenously at the standard dose of 5.4 mg per kg bodyweight once every 3 weeks. The primary endpoint was intracranial response rate measured according to the response assessment in neuro-oncology brain metastases criteria. A Simon two-stage design was used to compare a null hypothesis of <26% response rate against an alternative of 61%. Fifteen patients were enrolled in the intention-to-treat population of patients who received at least one dose of study drug. Two patients (13.3%) had a complete intracranial response, nine (60%) had a partial intracranial response and three (20%) had stable disease as the best intracranial response, with a best overall intracranial response rate of 73.3% (95% confidential interval 48.1–89.1%), thus meeting the predefined primary outcome. No new safety signals were observed and global quality-of-life and cognitive functioning were maintained over the treatment duration. In the TUXEDO-1 trial (NCT04752059, EudraCT 2020-000981-41), trastuzumab deruxtecan showed a high intracranial response rate in patients with active brain metastases from HER2-positive breast cancer and should be considered as a treatment option in this setting.