bluuebunny/crossref_metadata_2025 huggingface dataset:
A case report of two systemic lupus erythematosus pregnancies with early placental exposure to belimumab: Case report with review
Authors: Nakai Takehiro , Ikeda Yukihiko , Yamaguchi Kenichi , Asano Takahiro , Iwata Futoshi , Kidoguchi Genki , Fukui Sho , Ozawa Hiroki , Kawaai Satoshi , Kitada Ayako , Suda Masei , Nomura Atsushi , Tamaki Hiromichi , Okada Masato
Published: August 2022

Since its approval for the management of systemic lupus erythematosus (SLE), belimumab has been widely used. However, its pregnancy safety profile has been underinvestigated. We present the pregnancy outcomes of two cases of early placental exposure to belimumab and summarise the pregnancy outcomes in previous reports regarding placental exposure to belimumab. Case 1 describes a 27-year-old woman with an 18-year history of SLE and lupus nephritis class III. We introduced belimumab 19 months prior to conception to control her proteinuria and discontinued its use at 5 weeks and 5 days of gestation. Her lupus activity was stable throughout pregnancy, and at 37 weeks and 1 day of gestation, she delivered a healthy girl with no anomaly. At delivery, the girl was small for gestational age, but at the 1-year follow-up, there was no delay in her growth or any serious infection. Case 2 describes a 32-year-old woman with a 15-year history of SLE. We introduced belimumab 9 months prior to conception and discontinued its use at 7 weeks and 1 day of gestation. Although her lupus was well controlled without belimumab, a missed abortion occurred, which was possibly due to foetal factors. Although there is accumulating data on the safety of belimumab use during pregnancy, it seems necessary to cautiously use this medication in pregnant women, until further analyses are conducted.
Programmable RNA base editing with a single gRNA-free enzyme
Authors: Han Wenjian , Huang Wendi , Wei Tong , Ye Yanwen , Mao Miaowei , Wang Zefeng
Published: August 2022

Programmable RNA editing enables rewriting gene expression without changing genome sequences. Current tools for specific RNA editing dependent on the assembly of guide RNA into an RNA/protein complex, causing delivery barrier and low editing efficiency. We report a new gRNA-free system, RNA editing with individual RNA-binding enzyme (REWIRE), to perform precise base editing with a single engineered protein. This artificial enzyme contains a human-originated programmable PUF domain to specifically recognize RNAs and different deaminase domains to achieve efficient A-to-I or C-to-U editing, which achieved 60–80% editing rate in human cells, with a few non-specific editing sites in the targeted region and a low level off-target effect globally. The RNA-binding domain in REWIREs was further optimized to improve editing efficiency and minimize off-target effects. We applied the REWIREs to correct disease-associated mutations and achieve both types of base editing in mice. As a single-component system originated from human proteins, REWIRE presents a precise and efficient RNA editing platform with broad applicability.
De novo stem cell establishment in meristems requires repression of organ boundary cell fate
Authors: Nicolas Antoine , Maugarny-Calès Aude , Adroher Bernard , Chelysheva Liudmila , Li Yu , Burguet Jasmine , Bågman Anne-Maarit , Smit Margot E , Brady Siobhan M , Li Yunhai , Laufs Patrick
Published: August 2022

Stem cells play important roles in animal and plant biology, as they sustain morphogenesis and tissue replenishment following aging or injury. In plants, stem cells are embedded in multicellular structures called meristems. The formation of new meristems is essential for the plastic expansion of the highly branched shoot and root systems. In particular, axillary meristems (AMs) that produce lateral shoots arise from the division of boundary domain cells at the leaf base. The CUP-SHAPED COTYLEDON (CUC) genes are major determinants of the boundary domain and are required for AM initiation. However, how AMs get structured and how stem cells become established de novo remain elusive. Here, we show that two NGATHA-LIKE (NGAL) transcription factors, DEVELOPMENT-RELATED PcG TARGET IN THE APEX4 (DPA4)/NGAL3 and SUPPRESSOR OF DA1-1 7 (SOD7)/NGAL2, redundantly repress CUC expression in initiating AMs of Arabidopsis thaliana. Ectopic boundary fate leads to abnormal growth and organization of the AM and prevents de novo stem cell establishment. Floral meristems of the dpa4 sod7 double mutant show a similar delay in de novo stem cell establishment. Altogether, while boundary fate is required for the initiation of AMs, our work reveals how it is later repressed to allow proper meristem establishment and de novo stem cell niche formation.
Cellular and gene expression patterns associated with root bifurcation inSelaginella
Authors: Motte Hans , Fang Tao , Parizot Boris , Smet Wouter , Yang Xilan , Poelmans Ward , Walker Liam , Njo Maria , Bassel George W , Beeckman Tom
Published: August 2022

The roots of lycophytes branch through dichotomy or bifurcation, during which the root apex splits into two daughter roots. This is morphologically distinct from lateral root (LR) branching in the extant euphyllophytes, with LRs developing along the root axis at different distances from the apex. Although the process of root bifurcation is poorly understood, such knowledge can be important, because it may represent an evolutionarily ancient strategy that roots recruited to form new stem cells or meristems. In this study, we examined root bifurcation in the lycophyte Selaginella moellendorffii. We characterized an in vitro developmental time frame based on repetitive apex bifurcations, allowing us to sample different stages of dichotomous root branching and analyze the root meristem and root branching in S. moellendorffii at the microscopic and transcriptomic level. Our results showed that, in contrast to previous assumptions, initial cells (ICs) in the root meristem are mostly not tetrahedral but rather show an irregular shape. Tracking down the early stages of root branching argues for the occurrence of a symmetric division of the single IC, resulting in two apical stem cells that initiate root meristem bifurcation. Moreover, we generated a S. moellendorffii root branching transcriptome that resulted in the delineation of a subset of core meristem genes. The occurrence of multiple putative orthologs of meristem genes in this dataset suggests the presence of conserved pathways in the control of meristem and root stem cell establishment or maintenance.
Fluctuations in pedestrian dynamics routing choices
Authors: Gabbana Alessandro , Toschi Federico , Ross Philip , Haans Antal , Corbetta Alessandro
Published: August 2022

Routing choices of walking pedestrians in geometrically complex environments are regulated by the interplay of a multitude of factors such as local crowding, (estimated) time to destination, and (perceived) comfort. As individual choices combine, macroscopic traffic flow patterns emerge. Understanding the physical mechanisms yielding macroscopic traffic distributions in environments with complex geometries is an outstanding scientific challenge, with implications in the design and management of crowded pedestrian facilities. In this work, we analyze, by means of extensive real-life pedestrian tracking data, unidirectional flow dynamics in an asymmetric setting, as a prototype for many common complex geometries. Our environment is composed of a main walkway and a slightly longer detour. Our measurements have been collected during a dedicated high-accuracy pedestrian tracking campaign held in Eindhoven (The Netherlands). We show that the dynamics can be quantitatively modeled by introducing a collective discomfort function, and that fluctuations on the behavior of single individuals are crucial to correctly recover the global statistical behavior. Notably, the observed traffic split substantially departs from an optimal, transport-wise, partition, as the global pedestrian throughput is not maximized.
Nanoscale shape-dependent histone modifications
Authors: Zhang Wei , Li Jingji , Silveira Camila P , Cai Qi , Dawson Kenneth A , Cagney Gerard , Yan Yan
Published: August 2022

Recent observations suggest a role for complex nanoscale particulate shape in the regulation of specific immune-related cellular and in vivo processes. We suspect that cellular recognition of nanostructure architecture could involve nonmolecular inputs, including cellular transduction of nanoscale spatially resolved stresses induced by complex shape. Here, we report nanoscale shape-dependent control of the cellular epigenome. Interpretation of ChIP-Seq sequencing suggests that differential marking of H3K27me3 may be linked to sensory and synapse-recognition of nanoscale forces induced by complex shape. The observations raise significant questions on the role of particle-shape-induced immune regulation and memory, with potential consequences in both causes and treatment of immune-related disease.
Magnetic fields produced by subsea high-voltage direct current cables reduce swimming activity of haddock larvae (Melanogrammus aeglefinus)
Authors: Cresci Alessandro , Durif Caroline M F , Larsen Torkel , Bjelland Reidun , Skiftesvik Anne Berit , Browman Howard I
Published: August 2022

High-voltage direct current (HVDC) subsea cables are used to transport power between locations and from/to nearshore and offshore facilities. HVDC cables produce magnetic fields (B-fields) that could impact marine fish. Atlantic haddock (Melanogrammus aeglefinus) is a demersal fish that is at risk of exposure to anthropogenic B-fields. Their larvae drift over the continental shelf, and use the Earth's magnetic field for orientation during dispersal. Therefore, anthropogenic magnetic fields from HVDC cables could alter their behavior. We tested the behavior of 92 haddock larvae using a setup designed to simulate the scenario of larvae drifting past a B-field in the intensity range of that produced by a DC subsea cable. We exposed the larvae to a B-field intensity ranging from 50  to 150 µT in a raceway tank. Exposure to the B-field did not affect the spatial distribution of haddock larvae in the raceway. Larvae were categorized by differences in their exploratory behavior in the raceway. The majority (78%) of larvae were nonexploratory, and exposure to the artificial B-field reduced their median swimming speed by 60% and decreased their median acceleration by 38%. There was no effect on swimming of the smaller proportion (22%) of exploratory larvae. These observations support the conclusion that the swimming performance of nonexploratory haddock larvae would be reduced following exposure to B-field from HVDC cables. The selective impact on nonexploratory individuals, and the lack of impact on exploratory individuals, could have population-scale implications for haddock in the wild.
Study of F-wave bottom mesons in heavy quark effective theory
Authors: Garg Ritu , Upadhyay A
Published: August 2022

We study F-wave bottom mesons in heavy quark effective theory. The available experimental and theoretical data is used to calculate the masses of F-wave bottom mesons. The decay widths of bottom mesons are analyzed to find upper bounds for the associated couplings. We also construct Regge trajectories for our predicted data in the (J, M2) plane, and our results nicely fit on Regge lines. Our results may provide crucial information for future experimental studies.
A possible solution to the helium anomaly of EMPRESS VIII by cuscuton gravity theory
Authors: Kohri Kazunori , Maeda Kei-ichi
Published: August 2022

We discuss cosmology based on the cuscuton gravity theory to resolve the anomaly of the observational 4He abundance reported by the EMPRESS collaboration. We find that the gravitational constant Gcos in the Friedmann equation should be smaller than Newton’s constant GN such that ${\Delta G_{\rm N}}/{G_{\rm N}} \equiv (G_{\rm cos}-G_{\rm N})/{G_{\rm N}} = -0.085_{-0.028}^{+0.026} \ (68 \% \text{ C.L.})$ in terms of big-bang nucleosynthesis, which excludes ΔGN = 0 at more than 95% C.L. To fit the data, we obtain a negative mass squared of a non-dynamical scalar field with the Planck-mass scale as $\sim - {\mathcal {O}}(1) {M_{\rm PL}^2} ({\mu }/{0.5 M_{\rm PL}})^{4}$ with the cuscuton mass parameter μ. This fact could suggest the need for modified gravity theories such as the cuscuton gravity theory with a quadratic potential, which can be regarded as the low-energy Hořava–Lifshitz gravity, and might give a hint of quantum gravity.
Determination of Entrance Surface dose for Three Common Planar Diagnostic X-Ray Examinations
Authors: Jeyasugiththan Jeyasingam , Ehalagasthanna G P N T , Hishaam Urshella , Satharasinghe D M
Published: August 2022

Patient dose during diagnostic radiography procedures primarily depends on the entrance surface dose (ESD) and the exposure area. The purpose of this study was to determine ESD for five common diagnostic X-ray examinations using dose area product and X-ray tube output. The ESDs were estimated in a sample of 340 patients using normalised X-ray output from Philips–PrimaryDiagnost digital X-ray machine equipped with digital flat panel scintillator detector. The resultant mean ESDs for chest postero-anterior/lateral, lumbar spine antero-posterior (AP)/lateral and abdomen AP were 0.49, 2.00, 5.74, 12.79 and 4.62 mGy, respectively. The mean and third quartile ESD values of this study were significantly higher than the values found in the literature. This can be attributed to the lower tube potential (kVp) values and the higher tube current–time products (mAs). The methodology used here is a better option for low-resources countries for routine dose monitoring.
Heightened COVID-19 Mortality in People With Severe Mental Illness Persists After Vaccination: A Cohort Study of Greater Manchester Residents
Authors: Hassan Lamiece , Sawyer Chelsea , Peek Niels , Lovell Karina , Carvalho Andre F , Solmi Marco , Tilston George , Sperrin Matthew , Firth Joseph
Published: August 2022

Background and Hypothesis

Previous studies show that people with severe mental illness (SMI) are at higher risk of COVID-19 mortality, however limited evidence exists regarding risk postvaccination. We investigated COVID-19 mortality among people with schizophrenia and other SMIs before, during and after the UK vaccine roll-out.

Study Design

Using the Greater Manchester (GM) Care Record to access routinely collected health data linked with death records, we plotted COVID-19 mortality rates over time in GM residents with schizophrenia/psychosis, bipolar disorder (BD), and/or recurrent major depressive disorder (MDD) from February 2020 to September 2021. Multivariable logistic regression was used to compare mortality risk (risk ratios; RRs) between people with SMI (N = 193 435) and age–sex matched controls (N = 773 734), adjusted for sociodemographic factors, preexisting comorbidities, and vaccination status.

Study Results

Mortality risks were significantly higher among people with SMI compared with matched controls, particularly among people with schizophrenia/psychosis (RR 3.18, CI 2.94–3.44) and/or BD (RR 2.69, CI 2.16–3.34). In adjusted models, the relative risk of COVID-19 mortality decreased, though remained significantly higher than matched controls for people with schizophrenia (RR 1.61, CI 1.45–1.79) and BD (RR 1.92, CI 1.47–2.50), but not recurrent MDD (RR 1.08, CI 0.99–1.17). People with SMI continued to show higher mortality rate ratios relative to controls throughout 2021, during vaccination roll-out.

Conclusions

People with SMI, notably schizophrenia and BD, were at greater risk of COVID-19 mortality compared to matched controls. Despite population vaccination efforts that have prioritized people with SMI, disparities still remain in COVID-19 mortality for people with SMI.
The Geography of Gentrification and Residential Mobility
Authors: Lee Hyojung , Perkins Kristin L
Published: August 2022

Gentrification research often starts with the hypothesis that gentrification causes displacement of a neighborhood’s original residents, particularly low-income and vulnerable residents. Recent research based on large-scale quantitative data suggests that the displacement effects of gentrification for low-income residents evident from case studies and qualitative data are modest at the macroscale. We use geocoded microdata from the American Community Survey to investigate the association between gentrification and residential mobility in the 2010s, the time period following the Great Recession. Our large national sample allows us to consider heterogeneity in the association between gentrification and residential mobility, investigating differential association by distinct clusters of metropolitan areas. We find a modest positive significant association between moderate and intense gentrification and residential mobility in our full national sample. The national estimates, however, mask considerable heterogeneity in the association between gentrification and residential mobility in different types of metropolitan areas. College Town and Retirement Destination metros see the largest positive association between gentrification and residential mobility, while Large Coastal and Large Southern/Midwestern metros experience a more modest positive association. We find weak or no significant association in Inland Empire/Texas Border metros. We heed a call for more investigation of heterogeneity in neighborhood processes across different contexts.
Should we treat with continuous positive airway pressure severe non-sleepy obstructive sleep apnea individuals without underlying cardiovascular disease?
Authors: Pengo Martino F , Gozal David , Martinez-Garcia Miguel Angel
Published: August 2022

The majority of the current international obstructive sleep apnea (OSA) guidelines base the recommendation to treat OSA with continuous positive airway pressure (CPAP) on the presence of symptoms (principally, albeit not exclusively on daytime hypersomnolence). In nonsleepy patients, even with severe OSA, controversies remain, as clear evidence supporting CPAP treatment of this subgroup of OSA patients is lacking. However, given the nonnegligible proportion of non-sleepy OSA patients, clinicians often face a serious dilemma since CPAP treatment in these patients may prove to be not cost-effective. Here, we propose a simple three-step-based algorithm that attempts to better phenotype non-sleepy OSA patients prior to reaching a CPAP treatment decision while also considering a series of clinically relevant elements in the process that may improve with CPAP therapy. Such algorithm focuses on the presence of several OSA symptoms that are susceptible to benefit from treatment and also relies on OSA phenotypes that need to be considered in an effort to achieve optimal cardiovascular prevention. Here, we attempt to establish a framework for clinicians who are evaluating severe nonsleepy OSA patients in their practices. However, the algorithm proposal needs to be extensively validated before being systematically implemented in clinical settings.
Cyto—genotoxicity of crystalline and amorphous niobium (V) oxide nanoparticles in CHO-K1 cells
Authors: Schardosim Raíne Fogliati De Carli , Cardozo Tatiane Rocha , de Souza Ana Paula , Seeber Allan , Flores Wladimir Hernandez , Lehmann Maurício , Dihl Rafael Rodrigues
Published: August 2022

Niobium (V) oxide nanoparticles (NINPs) have been widely and increasingly applied in various health products and industrial processes. This merits further study of their toxicity. Here, we investigated the potential of NINPs to induce DNA damage, cytotoxicity, and chromosome instability in cultured CHO-K1 cells. NINPs were physico-chemically characterized. As assessed by comet assay, crystalline and amorphous NINPs were genotoxic at the highest concentrations evaluated. The cytokinesis-block micronucleus assay demonstrated that a 24-h treatment with NINPs, for the crystalline and the amorphous samples, significantly reduced the nuclear division cytotoxicity index. In addition, a 4-h treatment period of crystalline NINPs increased micronucleus (MNi) frequencies. MNi, nucleoplasmic bridges and nuclear buds were detected after exposure of the cells for 24 h to crystalline NINPs. In the amorphous sample, chromosome instability was restricted to the induction of MNi, in the 24-h treatment, detected at all tested concentrations. The fluorescence and dark field microscopy demonstrated the uptake of NINPs by CHO-K1 cells and an intracellular distribution outlining the nucleus. Our data advance understanding of the cytotoxic and genotoxic effects of NINPs and should be taken into consideration when setting up guidelines for their use in industrial or health products.
A bioactive component of Portulaca Oleracea L., HM-chromanone, improves palmitate-induced insulin resistance by inhibiting mTOR/S6K1 through activation of the AMPK pathway in L6 skeletal muscle cells
Authors: Park Jae Eun , Han Ji Sook
Published: August 2022

Increased free fatty acid levels in the blood are common in obesity and cause insulin resistance associated with type 2 diabetes in the muscles. Previous studies have confirmed the antidiabetic and anti-obesity potential of (E)-5-hydroxy-7-methoxy-3-(2-hydroxybenzyl)-4-chromanone (HM-chromanone). However, it is unknown how HM-chromanone alleviates obesity-related insulin resistance in L6 skeletal muscle cells. Palmitate induced insulin resistance and reduced glucose uptake, whereas HM-chromanone significantly increased glucose uptake. In palmitate-treated L6 skeletal muscle cells, HM-chromanone stimulated liver kinase B1 (LKB1) and 5′-adenosine monophosphate-activated protein kinase (AMPK) phosphorylation. The AMPK inhibitor compound C, and the LKB1 inhibitor radicicol blocked the effects of HM-chromanone. Furthermore, HM-chromanone significantly inhibited mammalian target of rapamycin (mTOR) and ribosomal protein S6 kinase 1 (S6K1) activation, but there was no change in protein kinase C θ (PKC θ) expression. When pAMPK was inhibited with compound C, the effect of HM-chromanone on the inhibition of mTOR and S6K1 was significantly diminished. This indicates that HM-chromanone inhibits mTOR and S6K1 activation through pAMPK activation. Inhibition of mTOR and S6K1 by HM-chromanone significantly reduced IRS-1Ser307 and IRS-1Ser632 phosphorylation, leading to insulin resistance. This resulted in an increase in PM-GLUT4 (glucose transporter 4) expression, thereby stimulating glucose uptake in insulin-resistant muscle cells. HM-chromanone can improve palmitate-induced insulin resistance by inhibiting mTOR and S6K1 through activation of the AMPK pathway in L6 skeletal muscle cells. These results show the therapeutic potential of HM-chromanone for improving insulin resistance in type 2 diabetes.
Cochlear implantation: an effective modality for hearing restoration following vestibular schwannoma resection
Authors: Doyle Edward J. , Samy Ravi N.
Published: August 2022

Purpose of review

Preservation of hearing is one of the tenets of vestibular schwannoma management. In recent years, cochlear implants have been employed with increasing use in patients who have suffered profound sensorineural hearing loss due to the natural history of vestibular schwannoma or due to injury to neurovascular anatomy at time of surgical resection.

Recent findings

Cochlear implantation has been found to be an effective modality for hearing restoration following vestibular schwannoma. Simultaneous cochlear implantation has been employed by an increased number of centers around the world and has been shown to provide restoration of open set speech perception and return of binaural hearing. Ongoing use of electrically evoked auditory brainstem response (ABR) has improved our detection of viable cochlear nerves and provided insight into those who would benefit from this procedure. Finally, minimally invasive approaches to the internal auditory canal and intralabyrinthine tumors have been described. These methods frequently employ simultaneous cochlear implantation and have emphasized that hearing preservation remains possible with surgical excision despite the location of the tumor.

Cochlear implantation is an effective modality for hearing restoration following vestibular schwannoma excision.
Single cell multiomic analyses reveal divergent effects ofDNMT3AandTET2mutant clonal hematopoiesis in inflammatory response
Authors: Ismail Wazim Mohammed , Fernandez Jenna A. , Binder Moritz , Lasho Terra L. , Kim Minsuk , Geyer Susan M. , Mazzone Amelia , Finke Christy M. , Mangaonkar Abhishek A. , Lee Jeong-Heon , Wang Liguo , Hyun Kim Kwan , Simon Vernadette A. , Rohakthar Fariborz Rakhshan , Munankarmy Amik , Byeon Seul Kee , Schwager Susan M. , Harrington Jonathan J. , Snyder Melissa R. , Robertson Keith D. , Pandey Akhilesh , Wieben Eric D. , Chia Nicholas , Gaspar-Maia Alexandre , Patnaik Mrinal M.
Published: August 2022

DNMT3AandTET2are epigenetic regulators commonly mutated in age related clonal hematopoiesis (CH). Despite having opposed epigenetic functions, these mutations are associated with increased all-cause mortality and a low risk for progression to hematological neoplasms. While individual impacts on the epigenome have been described using different model systems, the phenotypic complexity in humans remains to be elucidated. Here we make use of a natural inflammatory response occurring during coronavirus disease 2019 (COVID-19), to understand the association of these mutations with inflammatory morbidity and mortality. We demonstrate the age-independent, negative impact ofDNMT3Amutant CH on COVID-19-related cytokine release severity and mortality. Using single cell proteogenomics we show thatDNMT3Amutations involve cells of myeloid and lymphoid lineages. Using single cell multiomics sequencing, we identify cell-specific gene expression changes associated withDNMT3Amutations, along with significant epigenomic deregulation affecting enhancer accessibility, resulting in overexpression of IL32, a proinflammatory cytokine that can result in inflammasome activation in monocytes and macrophages. Finally, we show with single cell resolution that the loss of function of DNMT3A is directly associated with increased chromatin accessibility in mutant cells. Together, these data provide a mechanistic insight into the poor inflammatory outcomes seen inDNMT3Amutant CH patients infected with Sars-COV2.
Antimicrobial copper as an effective and practical deterrent to surface transmission of SARS-CoV-2
Authors: Vera-Otarola Jorge , Mendez Nicolas , Martínez-Valdebenito Constanza , Mannheim Rodolfo , Rhodes Steve , Lu Kenneth
Published: August 2022

The aerosols are critical for SARS-CoV-2 transmission, however in areas with high confluence of people the contaminated surfaces take an important role that we could attack using antimicrobial surfaces including copper. In this study, we wanted to challenge infectious SARS-CoV-2 with two samples of copper surfaces and one plastic surface as control at different direct times contact. To evaluate and quantify virucidal activity of copper against SARS-CoV-2, two methods of experimental infection were performed, TCID50 and plaque assays on VeroE6 cells, showing significant inactivation of high titer of SARS-CoV-2 within minutes reaching 99.9 % of inactivation of infectivity on both copper surfaces. Daily high demand surfaces contamination is an issue that we have to worry about not only during the actual pandemic time but also for future, where copper or its alloys will have a pivotal role.

Importance

Quantitative data obtained of TCID50 and plaque assay with infectious SARS-CoV-2 virus showed that after direct contact with copper or copper alloys, viruses were inactivated within minutes. Notably, the SARS-CoV-2 virus used in these assays was in high titer (106 PFU/mL) showing strong copper inactivation of the infectious SARS-CoV-2.
Using adversarial networks to extend brain computer interface decoding accuracy over time
Authors: Ma Xuan , Rizzoglio Fabio , Perreault Eric J. , Miller Lee E. , Kennedy Ann
Published: August 2022

Existing intracortical brain computer interfaces (iBCIs) transform neural activity into control signals capable of restoring movement to persons with paralysis. However, the accuracy of the “decoder” at the heart of the iBCI typically degrades over time due to turnover of recorded neurons. To compensate, decoders can be recalibrated, but this requires the user to spend extra time and effort to provide the necessary data, then learn the new dynamics. As the recorded neurons change, one can think of the underlying movement intent signal being expressed in changing coordinates. If a mapping can be computed between the different coordinate systems, it may be possible to stabilize the original decoder’s mapping from brain to behavior without recalibration. We previously proposed a method based on Generalized Adversarial Networks (GANs), called “Adversarial Domain Adaptation Network” (ADAN), which aligns the distributions of latent signals within underlying low-dimensional neural manifolds. However, ADAN was tested on only a very limited dataset. Here we propose a method based on Cycle-Consistent Adversarial Networks (Cycle-GAN), which aligns the distributions of the full-dimensional neural recordings. We tested both Cycle-GAN and ADAN on data from multiple monkeys and behaviors and compared them to a linear method based on Procrustes Alignment of axes provided by Factor Analysis (PAF). Both GAN-based methods outperformed PAF. Cycle-GAN and ADAN (like PAF) are unsupervised and require little data, making them practical in real life. Overall, Cycle-GAN had the best performance and was easier to train and more robust than ADAN, making it ideal for stabilizing iBCI systems over time.

Significance Statement

The inherent instabilities in the neural signals acquired by intracortical microelectrode arrays cause the performance of an intracortical brain computer interface (iBCI) decoder to drop over time, as the movement intent signal must essentially be recorded from neurons representing an ever-changing coordinate system. Here, we address this problem using Generative Adversarial Networks (GANs) to align these coordinates and compare their success to another, recently proposed linear method that uses Factor Analysis and Procrustes alignment. Our proposed methods are fully unsupervised, can be trained quickly, and require remarkably little new data. These methods should give iBCI users access to decoders with unchanging dynamics, and without the need for periodic supervised recalibration.
Timeline of changes in spike conformational dynamics in emergent SARS-CoV-2 variants reveal progressive stabilization of trimer stalk and enhanced NTD dynamics
Authors: Braet Sean M. , Buckley Theresa S. C. , Venkatakrishnan Varun , Dam Kim-Marie A. , Bjorkman Pamela J. , Anand Ganesh S.
Published: August 2022

SARS-CoV-2 emergent variants are characterized by increased transmissibility and each show multiple mutations predominantly localized to the spike (S) protein. Here, amide hydrogen/deuterium exchange mass spectrometry has been applied to track correlative changes in S dynamics from multiple SARS-CoV-2 variants. Our results highlight large differences across variants at two loci with impacts on S dynamics and stability. A significant enhancement in stabilization first occurred with the emergence of D614G S followed by smaller, progressive stabilization in Omicron BA.1 S traced through Alpha S and Delta S variants. Stabilization preceded progressive enhancement in dynamics in the N-terminal domain, wherein Omicron BA.1 S showed the largest magnitude increases relative to other preceding variants. Changes in stabilization and dynamics resulting from specific S mutations detail the evolutionary trajectory of S protein in emerging variants. These carry major implications for SARS-CoV-2 viral fitness and offer new insights into variant-specific therapeutic development.
Orchestration of Proteins in cyanobacterial Circadian Clock System 1
Authors: Sugiyama Masaaki , Morishima Ken , Yunoki Yasuhiro , Inoue Rintaro , Sato Nobuhiro , Yagi Hirokazu , Kato Koichi
Published: August 2022

Circadian rhythm by Cyanobacteria is one of the simplest biological clocks: the clock consists of only three proteins, KaiA, KaiB, and KaiC. Their oligomers, KaiA dimer (A2), KaiB tetramer (B4), and KaiC hexamer (C6) oscillate an association–disassociation cycle with 24-hr period. In a widely accepted model, the oscillation process is as follows. From the viewpoint of a base unit (C6), C6 homo-oligomer → A2C6 complex → B6C6 complex → AnB6C6 complex (n≤12) →C6 homo-oligomer. In this study, Small-Angle X-ray Scattering, Contrast Matching-Small-Angle Neutron Scattering, Analytical Ultracentrifuge, and phosphorylation-analysis PAGE measurements were performed to reveal the kinetics not only of KaiC hexamer but also of all components in a working Kai clock. The complementary analysis disclosed that the oscillation is not the single process as the widely accepted model but composed with synchronized multiple association-dissociation reactions between components. Namely, there are various reactions between components, which proceed simultaneously, in a working Kai-clock.
Robust phylogenetic regression
Authors: Adams Richard , Cain Zoe , Assis Raquel , DeGiorgio Michael
Published: August 2022

Abstract

Modern comparative biology owes much to phylogenetic regression. At its conception, this technique sparked a revolution that armed biologists with phylogenetic comparative methods (PCMs) for combatting evolutionary pseudoreplication, which arises inherently from trait data sampled across related species. Over the past few decades, the phylogenetic regression framework has become a paradigm of modern comparative biology that has been widely embraced as a remedy for evolutionary pseudoreplication. However, recent evidence has sown doubt over the efficacy of phylogenetic regression, and PCMs more generally, with the suggestion that many of these methods fail to provide an adequate defense against unreplicated evolution—the primary justification for using them in the first place. Importantly, some of the most compelling examples of biological innovation in nature result from abrupt, lineage-specific evolutionary shifts, which current regression models are largely ill-equipped to deal with. Here we explore a solution to this problem by applying robust linear regression to comparative trait data. We formally introduce robust phylogenetic regression to the PCM toolkit with linear estimators that are less sensitive to model violations while still retaining high power to detect true trait associations. Our analyses also highlight an ingenuity of the original algorithm for phylogenetic regression based on independent contrasts, whereby robust estimators are particularly effective. Collectively, we find that robust estimators hold promise for improving tests of trait associations and offer a path forward in scenarios where classical approaches may fail. Our study joins recent arguments for increased vigilance against pseudoreplication and a better understanding of evolutionary model performance in challenging–yet biologically important–settings.
Chronic cholesterol administration to the brain supports complete and long-lasting cognitive and motor amelioration in Huntington’s disease
Authors: Birolini Giulia , Valenza Marta , Ottonelli Ilaria , Talpo Francesca , Minoli Lucia , Cappelleri Andrea , Bombaci Mauro , Caccia Claudio , Canevari Caterina , Trucco Arianna , Leoni Valerio , Passoni Alice , Favagrossa Monica , Nucera Maria Rosaria , Colombo Laura , Paltrinieri Saverio , Bagnati Renzo , Duskey Jason Thomas , Caraffi Riccardo , Vandelli Maria Angela , Taroni Franco , Salmona Mario , Scanziani Eugenio , Biella Gerardo , Ruozi Barbara , Tosi Giovanni , Cattaneo Elena
Published: August 2022

Evidence that Huntington’s disease (HD) is characterized by impaired cholesterol biosynthesis in the brain has led to strategies to increase its level in the brain of the rapidly progressing R6/2 mouse model, with a positive therapeutic outcome. Here we tested the long-term efficacy of chronic administration of cholesterol to the brain of the slowly progressing zQ175DN knock-in HD mice in preventing (“early treatment”) or reversing (“late treatment”) HD symptoms. To do this we used the most advanced formulation of cholesterol loaded brain-permeable nanoparticles (NPs), termed hybrid-g7-NPs-chol, which were injected intraperitoneally.

We show that one cycle of treatment with hybrid-g7-NPs-chol, administered in the presymptomatic (“early treatment”) or symptomatic (“late treatment”) stages is sufficient to normalize cognitive defects up to 5 months, as well as to improve other behavioral and neuropathological parameters. A multiple cycle treatment combining both early and late treatments (“2 cycle treatment”) lasting 6 months generates therapeutic effects for more than 11 months, without severe adverse reactions.

Sustained cholesterol delivery to the brain of zQ175DN mice also reduces mutant Huntingtin aggregates in both the striatum and cortex and completely normalizes synaptic communication in the striatal medium spiny neurons compared to saline-treated HD mice. Furthermore, through a meta-analysis of published and current data, we demonstrated the power of hybrid-g7-NPs-chol and other strategies able to increase brain cholesterol biosynthesis, to reverse cognitive decline and counteract the formation of mutant Huntingtin aggregates.

These results demonstrate that cholesterol delivery via brain-permeable NPs is a therapeutic option to sustainably reverse HD-related behavioral decline and neuropathological signs over time, highlighting the therapeutic potential of cholesterol-based strategies in HD patients.
Target-enriched enzymatic methyl sequencing: flexible, scalable and inexpensive hybridization capture for quantifying DNA methylation
Authors: Rubenstein Dustin R. , Solomon Joseph
Published: August 2022

The increasing interest in studying DNA methylation to understand how traits or diseases develop requires new and flexible approaches for quantifying DNA methylation in a diversity of organisms. In particular, we need efficient yet cost-effective ways to measure CpG methylation states over large and complete regions of the genome. Here, we develop TEEM-Seq (target-enriched enzymatic methyl sequencing), a method that combines enzymatic methyl sequencing with a custom-designed hybridization capture bait set that can be scaled to reactions including large numbers of samples in any species for which a reference genome is available. Using DNA from a passerine bird, the superb starling (Lamprotornis superbus), we show that TEEM-Seq is able to quantify DNA methylation states similarly well to the more traditional approaches of whole-genome and reduced-representation sequencing. Moreover, we demonstrate its reliability and repeatability, as duplicate libraries from the same samples were highly correlated. Importantly, the downstream bioinformatic analysis for TEEM-Seq is the same as for any sequence-based approach to studying DNA methylation, making it simple to incorporate into a variety of workflows. We believe that TEEM-Seq could replace traditional approaches for studying DNA methylation in candidate genes and pathways, and be effectively paired with other whole-genome or reduced-representation sequencing approaches to increase project sample sizes. In addition, TEEM-Seq can be combined with mRNA sequencing to examine how DNA methylation in promoters or other regulatory regions is related to the expression of individual genes or gene networks. By maximizing the number of samples in the hybridization reaction, TEEM-Seq is an inexpensive and flexible sequence-based approach for quantifying DNA methylation in species where other capture-based methods are unavailable or too expensive, particularly for non-model organisms.
Computational Modeling of the Human Compound Action Potential
Authors: Alamri Yousef , Jennings Skyler G.
Published: August 2022

The auditory nerve (AN) compound action potential (CAP) is an important tool for assessing auditory disorders and monitoring the health of the auditory periphery during surgical procedures. The CAP has been mathematically conceptualized as the convolution of a unit response (UR) waveform with the firing rate of a population of AN fibers. Here, an approach for predicting experimentally-recorded CAPs in humans is proposed, which involves the use of human-based computational models to simulate AN activity. CAPs elicited by clicks, chirps, and amplitude-modulated carriers were simulated and compared with empirically recorded CAPs from human subjects. In addition, narrowband CAPs derived from noise-masked clicks and tone bursts were simulated. Many morphological, temporal, and spectral aspects of human CAPs were captured by the simulations for all stimuli tested. These findings support the use of model simulations of the human CAP to refine existing human-based models of the auditory periphery, aid in the design and analysis of auditory experiments, and predict the effects of hearing loss, synaptopathy, and other auditory disorders on the human CAP.
Mitochondrial Phosphatidylethanolamine Directly Regulates UCP1 to Promote Brown Adipose Thermogenesis
Authors: Johnson Jordan M. , Peterlin Alek D. , Balderas Enrique , Sustarsic Elahu G. , Maschek J. Alan , Lang Marisa J. , Jara-Ramos Alejandro , Panic Vanja , Morgan Jeffrey T. , Villanueva Claudio J. , Sanchez Alejandro , Rutter Jared , Lodhi Irfan J. , Cox James E. , Fisher-Wellman Kelsey H. , Chaudhuri Dipayan , Gerhart-Hines Zachary , Funai Katsuhiko
Published: August 2022

Thermogenesis by uncoupling protein 1 (UCP1) is one of the primary mechanisms by which brown adipose tissue (BAT) increases energy expenditure. UCP1 resides in the inner mitochondrial membrane (IMM), where it dissipates membrane potential independent of ATP synthase. Here we provide evidence that mitochondrial phosphatidylethanolamine (PE) directly regulates UCP1-dependent proton conductance across IMM to modulate thermogenesis. Mitochondrial lipidomic analyses revealed PE as a signature molecule whose abundance bidirectionally responds to changes in thermogenic burden. Reduction in mitochondrial PE by deletion of phosphatidylserine decarboxylase (PSD) made mice cold intolerant and insensitive to β3 adrenergic receptor agonist-induced increase in whole-body oxygen consumption. High-resolution respirometry and fluorometry of BAT mitochondria showed that loss of mitochondrial PE specifically lowers UCP1-dependent respiration without compromising electron transfer efficiency or ATP synthesis. These findings were confirmed by a reduction in UCP1 proton current in PSD-deficient mitoplasts. Thus, PE performs a previously unknown role as a temperature-responsive rheostat that regulates UCP1-dependent thermogenesis.
Pharmacogenetic allele variant frequencies: An analysis of the VA’s Million Veteran Program (MVP) as a representation of the diversity in US population
Authors: Markianos K , Dong F , Gorman B , Shi Y , Dochterman D , Saxena U , Devineni P , Moser J , Muralidhar S , Ramoni R , Tsao P ,   Million Veteran Program, Pyarajan S , Przygodzki R
Published: August 2022

We present allele frequencies of pharmacogenomics relevant variants across multiple ancestry in a sample representative of the US population. We analyzed 658,582 individuals with genotype data and extracted pharmacogenomics relevant single nucleotide variant (SNV) alleles, human leukocyte antigens (HLA) 4-digit alleles and an important copy number variant (CNV), the full deletion/duplication of CYP2D6. We compiled distinct allele frequency tables for European, African American, Hispanic, and Asian ancestry individuals. In addition, we compiled allele frequencies based on local ancestry reconstruction in the African-American (2-way deconvolution) and Hispanic (3-way deconvolution) cohorts.
Once upon a time in Mexico: Holocene phylogeography of the spotted bat (Euderma maculatum)
Authors: Sanchez Daniel E. , Walker Faith M. , Sobek Colin J. , Lausen Cori , Chambers Carol L.
Published: August 2022

Holocene-era range expansions are relevant to understanding how a species might respond to the warming and drying climates of today. The harsh conditions of North American deserts have phylogenetically structured desert bat communities but differences in flight capabilities are expected to affect their ability to compete, locate, and use habitat in the face of modern climate change. A highly vagile but data-deficient bat species, the spotted bat (Euderma maculatum) is thought to have expanded its range from central Mexico to western Canada during the Holocene. With specimens spanning this latitudinal extent, we coupled phylogeography (mtDNA) with ecological niche modeling (ENM) to investigate the Holocene biogeography from the rear to leading edges. The ENM and phylogeny supported a Holocene range expansion from Mexico with increased expansion throughout the intermountain west within the last 6 kya. Long-term isolation at the southern-most margin of the range suggests one or more populations were left behind as climate space contracted and are currently of unknown status. The species appears historically suited to track shifts in climate space but differences in flight behaviors between leading edge and core-range lineages suggest that range expansions could be influenced by differences in habitat quality or climate (e.g., drought). Although its vagility could facilitate the tracking of environmental change and thereby extinction avoidance, anthropogenic pressures at the core range could still threaten the ability for beneficial alleles to expand into the leading edge.
Genome-wide CRISPR/Cas9 Screens Reveal Shared and Bespoke Mechanisms of Resistance to SHP2 inhibition
Authors: Wei Wei , Geer Mitchell J. , Guo Xinyi , Dolgalev Igor , Sanjana Neville E. , Neel Benjamin G.
Published: August 2022

SHP2 (PTPN11) acts upstream of SOS1/2 to enable RAS activation. Allosteric inhibitors (SHP2is) stabilize SHP2 auto-inhibition, preventing activation by upstream stimuli. SHP2is block proliferation of RTK- or cycling RAS mutant-driven cancers and overcome adaptive resistance to other RAS-ERK pathway drugs. Several SHP2is are in clinical trials. To identify potential SHP2i resistance mechanisms, we performed genome-wide CRISPR/Cas9 knockout screens on two SHP2i-sensitive AML cell lines and recovered genes expected to cause resistance, including tumor suppressor (NF1, PTEN, CDKN1B) and “RASopathy” (LZTR1, RASA2) genes, and several novel targets (INPPL1, MAP4K5, epigenetic modifiers). We then screened 14 cancer lines with a focused CRISPR library targeting common “hits” from the genome-wide screens. LZTR1 deletion conferred resistance in 12/14 lines, followed by MAP4K5 (8/14), SPRED2 (6/14), STK40 (6/14), and INPPL1 (5/14). INPPL1, MAP4K5, or LZTR1 deletion reactivated ERK signaling. INPPL1-mediated sensitization to SHP2i required its NPXY motif but not its lipid phosphatase domain. MAP4K5 acted upstream of MEK via a kinase-dependent target(s), whereas LZTR1 showed cell-dependent effects on RIT and RAS stability. INPPLI, MAP4K5, or LZTR1 deletion also conferred SHP2i resistance in mice. Our results reveal multiple SHP2i resistance genes, emphasizing the need for detailed understanding of the resistance landscape to arrive at effective combinations.