bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intensity-dependent effects of tDCS on motor learning are related to dopamine
Authors: Leow Li-Ann , Jiang Jiaqin , Bowers Samantha , Zhang Yuhan , Dux Paul E , Filmer Hannah L 
Published: October 2023

AbstractNon-invasive brain stimulation techniques, such as transcranial direct current stimulation (tDCS), are popular methods for inducing neuroplastic changes to alter cognition and behaviour. One challenge for the field is to optimise stimulation protocols to maximise benefits. For this to happen, we need a better understanding ofhowstimulation modulates cortical functioning/behaviour. To date, there is increasing evidence for a dose-response relationship between tDCS and brain excitability, however how this relates to behaviour is not well understood. Even less is known about the neurochemical mechanisms which may drive the dose-response relationship between stimulation intensities and behaviour. Here, we examine the effect of three different tDCS stimulation intensities (1mA, 2mA, 4mA anodal motor cortex tDCS) administered during the explicit learning of motor sequences. Further, to assess the role of dopamine in the dose-response relationship between tDCS intensities and behaviour, we examined how pharmacologically increasing dopamine availability, via 100mg of levodopa, modulated the effect of stimulation on learning. In the absence of levodopa, we found that 4mA tDCS improved and 1mA tDCS impaired acquisition of motor sequences relative to sham stimulation. Conversely, levodopa reversed the beneficial effect of 4mA tDCS. This effect of levodopa was no longer evident at the 48-hour follow-up, consistent with previous work characterising the persistence of neuroplastic changes in the motor cortex resulting from combining levodopa with tDCS. These results provide the first direct evidence for a role of dopamine in the intensity-dependent effects of tDCS on behaviour.
Retinoic Acid Boosts HIV-1 Replication in MacrophagesviaCCR5/SAMHD1-Dependent and mTOR-Modulated Mechanisms
Authors: Dias Jonathan , Cattin Amélie , Goulet Jean-Philippe , Fert Augustine , Raymond Marchand Laurence , Wiche Salinas Tomas Raul , Ngassaki Yoka Christ-Dominique , Moreira Gabriel Etiene , Caballero Edwin Ramon , Routy Jean-Pierre , Ancuta Petronela 
Published: October 2023

ABSTRACTThe intestinal environment facilitates HIV-1 infectionviamechanisms involving the gut-homing elixir retinoic acid (RA), which transcriptionally reprograms CD4+T-cells for increased HIV-1 permissiveness. Consistently, colon-infiltrating CD4+T-cells carry replication-competent viral reservoirs in people living with HIV-1 (PLWH) receiving antiretroviral therapy (ART). Intriguingly, integrative infection in colon macrophages, a pool replenished by circulating monocytes, represents a rare event in ART-treated PLWH, thus questioning on HIV-1 permissiveness in gut-resident macrophages. Here, we demonstrate that RA significantly boosts R5 but not X4 HIV-1 replication in monocyte-derived macrophages (MDMs). RNA-Sequencing, Gene Set Variation Analysis, and HIV interactor NCBI database interrogation, revealed RA- mediated transcriptional reprogramming associated with metabolic/inflammatory processes and HIV-1 resistance/dependency factors. Functional validations pointed to mechanisms of RA action, including CCR5 upregulation and SAMHD1 phosphorylation under the control of mTOR. These results support a model in which intestinal MDM contribute to viral replication/dissemination before ART and upon treatment interruption in mTOR-sensitive manner.Figure 1:
Glial activity load on PET (GALP) reveals persistent ‘smoldering’ inflammation in MS despite disease modifying treatment: [F-18]PBR06 study
Authors: Singhal Tarun , Cicero Steven , Rissanen Eero , Ficke John Hunter , Kukreja Preksha , Vaquerano Steven , Glanz Bonnie , Dubey Shipra , Sticka William , Seaver Kyle , Kijewski Marie , Callen Alexis M. , Chu Renxin , Carter Kelsey , Silbersweig David , Chitnis Tanuja , Bakshi Rohit , Weiner Howard L 
Published: October 2023

IntroductionCortical grey (CoGM) and white matter (WM) microglial activation (MA) is involved in the pathogenesis of multiple sclerosis (MS). [F-18]PBR06 positron emission tomography (PET) targeting 18kilodalton-translocator protein (TSPO) can detect abnormal MA in MS.Aims and ObjectivesThe goal of this study is to determine the effect of disease modifying treatment (DMT) efficacy on modulating the extent and clinical and radiological correlates of MA in MS patients.MethodsThirty [F-18]PBR06 PET scans were performed in 22 MS patients (13 RR, 9 SP, mean age 46±14 years, 15 females, median EDSS 3.5, mean T25FW 7.2±4.6s) and 8 healthy controls (HC). Individualized z-score maps of brain parenchymal MA were generated by voxel-by-voxel comparison between each subject’s PET SUVR images and a HC dataset. Logarithmically transformed ‘Glial activity load on PET’ scores (calculated as the sum of voxel-by-voxel z-scores ≥4 in CoGM and WM regions), ‘lnGALP’, were compared between MS subjects on DMT with high efficacy (HT; including rituximab, ocrelizumab, natalizumab and fingolimod, n=13) versus those on no or lower efficacy treatment (LT; including glatiramer acetate and interferons), and correlated with clinical measures and cortical thickness (measured using Freesurfer). p<0.05 was considered statistically significant.ResultsCoGM and WM lnGALP scores were higher in MS vs. HCs (10.0±1.5 vs. 7.5±1.5 and 9.8±1.5 vs. 6.6±2.4, both p<0.01) and were inversely correlated with cortical thickness across groups (r=-0.44 and - 0.48, both p<0.05, n=30). In HT-MS group, CoGM and WM lnGALP was significantly lower as compared to LT-MS group (9.1±1.0 vs. 11.3±1.1 and 9.1±1.3 vs. 10.8±1.4, p=0.000075 and 0.006) but remained abnormally higher than in HC group (p=0.006 and 0.02, respectively). Within HT-MS patients, CoGM lnGALP scores were higher in SP vs. RR subgroups (p=0.008), correlated positively with EDSS, T25FW, fatigue scores and serum GFAP levels (r=0.65,0.79, 0.75 and 0.67, all p<0.05), and inversely with cortical thickness (r=-0.66, p=0.01).ConclusionsHigh-efficacy DMTs decrease, but do not normalize, CoGM and WM MA in MS patients. Such “residual” MA in CoGM is associated with clinical disability, symptom severity and cortical degeneration. Individualized mapping of TSPO-PET using [F-18]PBR06 can potentially serve as an imaging biomarker for evaluating emerging therapies targeting MA in MS patients who are worsening despite high-efficacy DMTs.
Characteristics, treatment and outcomes of myelodysplastic syndrome in two Finnish hospital districts
Authors: Tuominen Samuli , Miettinen Tatu , Dünweber Christina 
Published: October 2023

AbstractIntroductionMyelodysplastic syndromes (MDS) are hematologic malignancies characterized by changes in haematopoiesis and a high risk for progressing into acute myeloid leukemia (AML). In this retrospective registry based real-world study, from two Finnish hospital data lakes we characterized specialised health care treated MDS patients, their treatment landscape, outcomes, and healthcare resource utilization.MethodsThis study consisted of adult patients with MDS diagnosed in either of two hospital districts in Finland: hospital district of Southwest Finland (HDSF) and Pirkanmaa hospital district (PHD). Two different time windows were used depending on data availability: 1.1.2010-31.12.2019 (HDSF) and 1.1.2012-31.12.2019 (PHD). Electronic health record data, including demographics, diagnoses, and medications was accessed via the respective hospital data lakes and dates and causes of death data was collected from Statistics Finland.ResultsWe identified 565 adult MDS patients, of whom 424 received active life-prolonging treatment at specialized healthcare and 141 were treated with watchful observation or supportive care at primary care. 72 patients were treated with azacitidine and 26 patients received allogeneic hematologic stem cell transplant. Median overall survival for the specialty healthcare treated patients was 27,5 months (95 confidence interval [CI] 24,1-35,2) and costs per patient year were 17 563€.ConclusionThis hospital data lake-based analysis identified patient groups with differing disease severity and need for treatment. High-risk, azacitidine treated patients have suboptimal outcomes and high costs, highlighting the need for new therapeutic approaches to prevent disease progression and reduce disease burden.
Network alterations in temporal lobe epilepsy during non-rapid eye movement sleep and wakefulness
Authors: Rigoni I , Vorderwülbecke BJ , Carboni M , Roehri N , Spinelli L , Tononi G , Seeck M , Perogamvros L , Vulliémoz S 
Published: October 2023

AbstractObjectiveInvestigate sleep and temporal lobe epilepsy (TLE) effects on EEG-derived brain networks.MethodsHigh-density EEG was recorded during non-REM sleep (N2) and wakefulness in 23 patients and healthy controls (HC). Epochs without epileptic discharges were source-reconstructed in 72 brain regions and connectivity was estimated. Network integration (Efficiency, E) and segregation (Clustering Coefficient, CC) at global and hemispheric level (GE, avgCC, HE, HCC) were calculated. These were compared between groups across frequency bands and correlated with the individual proportion of wakefulness-or sleep-related seizures.ResultsPatients had higher delta GE, delta avgCC and theta avgCC than controls, irrespective of the vigilance state (TLE > HC, p<.01). During wakefulness, theta GE of patients was higher than controls (p<.001) and, for patients, theta GE during wakefulness was higher than during N2 (p<.05). Wake-to-sleep differences in TLE were notable only in the ipsilateral hemisphere (HE and HCC, p<.05). Only measures from wakefulness recordings correlated with the proportion of wakefulness-or sleep-related seizures.ConclusionsTLE network alterations are more prominent during wakefulness and at lower frequencies. Increased integrationandsegregation suggest a pathological ‘small world’ configuration with a possible inhibitory role.SignificanceNetwork alterations in TLE occur and are easier to detect during wakefulness.
Polygenic effects on the risk of Alzheimer’s disease in the Japanese population
Authors: Kikuchi Masataka , Miyashita Akinori , Hara Norikazu , Kasuga Kensaku , Saito Yuko , Murayama Shigeo , Kakita Akiyoshi , Akatsu Hiroyasu , Ozaki Kouichi , Niida Shumpei , Kuwano Ryozo , Iwatsubo Takeshi , Nakaya Akihiro , Ikeuchi Takeshi ,   Alzheimer’s Disease Neuroimaging Initiative,   the Japanese Alzheimer’s Disease Neuroimaging Initiative
Published: October 2023

AbstractBackgroundPolygenic effects have been proposed to account for some disease phenotypes; these effects are calculated as a polygenic risk score (PRS). This score is correlated with Alzheimer’s disease (AD)-related phenotypes, such as biomarker abnormalities and brain atrophy, and is associated with conversion from mild cognitive impairment (MCI) to AD. However, the AD PRS has been examined mainly in Europeans, and owing to differences in genetic structure and lifestyle, it is unclear whether the same relationships between the PRS and AD-related phenotypes exist in non-European populations. In this study, we calculated and evaluated the AD PRS in Japanese individuals using GWAS statistics from Europeans.MethodsIn this study, we calculated the AD PRS in 504 Japanese participants (145 cognitively unimpaired (CU) participants, 220 participants with late mild cognitive impairment (MCI), and 139 patients with mild AD dementia) enrolled in the Japanese Alzheimer’s Disease Neuroimaging Initiative (J-ADNI) project. In order to evaluate the clinical value of this score, we (1) determined the polygenic effects on AD in the J-ADNI and validated it using two independent cohorts (a Japanese neuropathology (NP) cohort (n=565) and the North American ADNI (NA-ADNI) cohort (n=617)), (2) examined the AD-related phenotypes associated with the PRS, and (3) tested whether the PRS helps predict the conversion of MCI to AD.ResultsThe PRS using 131 SNPs had an effect independent ofAPOE. The PRS differentiated between CU participants and AD patients with an area under the curve (AUC) of 0.755 when combined with theAPOEvariants. Similar AUC was obtained when PRS calculated by the NP and NA-ADNI cohorts was applied. In MCI patients, the PRS was associated with cerebrospinal fluid phosphorylated-tau levels (β estimate = 0.235, p value = 0.026). MCI with a high PRS showed a significantly increased conversion to AD inAPOEε4 noncarriers with a hazard rate of 2.22.ConclusionsWe showed that the AD PRS is useful in the Japanese population, whose genetic structure is different from that of the European population. These findings suggest that the polygenicity of AD is partially common across ethnic differences.
Integrative analysis reveals a conserved role for the amyloid precursor protein in proteostasis during aging
Authors: Nithianandam Vanitha , Bukhari Hassan , Leventhal Matthew J. , Battaglia Rachel A. , Dong Xianjun , Fraenkel Ernest , Feany Mel B. 
Published: October 2023

AbstractAβ peptides derived from the amyloid precursor protein (APP) have been strongly implicated in the pathogenesis of Alzheimer’s disease. However, the normal function of APP and the importance of that role in neurodegenerative disease is less clear. We recovered theDrosophilaortholog of APP, Appl, in an unbiased forward genetic screen for neurodegeneration mutants. We performed comprehensive single cell transcriptional and proteomic studies of Appl mutant flies to investigate Appl function in the aging brain. We found an unexpected role for Appl in control of multiple cellular pathways, including translation, mitochondrial function, nucleic acid and lipid metabolism, cellular signaling and proteostasis. We mechanistically defined a role for Appl in regulating autophagy through TGFβ signaling and documented the broader relevance of our findings using mouse genetic, human iPSC and in vivo tauopathy models. Our results demonstrate a conserved role for APP in controlling age-dependent proteostasis with plausible relevance to Alzheimer’s disease.
Pharmacological cAMP stimulation via prostaglandin receptors rescues ciliary defects in CEP290-deficient human and mouse models
Authors: de Malglaive France , Barny Iris , Machroub Shahd , Fares-Taie Lucas , Cano Ema , Goudin Nicolas , Attie-Bittach Tania , Kaplan Josseline , Perrault Isabelle , Briseno-Roa Luis , Rozet Jean-Michel , Annereau Jean-Philippe 
Published: October 2023

ABSTRACTThe retina’s sensitivity to light depends on the primary cilium of photoreceptors, known as the outer segment (OS). OS defects are a primary cause of inherited retinal dystrophies (IRDs) and can also indicate wider ciliary dysfunctions. One such IRD is Leber congenital amaurosis type 10 (LCA10), which occurs as a monosymptomatic retinal disease or the presenting symptom of syndromic ciliopathies within the Senior-Loken-Joubert-Meckel spectrum. LCA10 patients are born blind but retain dormant photoreceptors for decades, offering the potential for reactivation. AAV-based gene therapies for IRDs cannot accommodate the largeCEP290gene, prompting the search for innovative treatments.LCA10 is caused by mutations inCEP290, which plays a vital role in ciliation, similar to cAMP signaling. Utilizing fibroblasts displaying variableCEP290mutations and associated ciliary defects, we show that exposure to Taprenepag, a specific PGE2 receptor agonist, substantially stimulated cAMP synthesis and consistently improved cilia formation and elongation. We also found that intraperitoneal injection of Taprenepag in mice reached the retina and slowed retinal degeneration, promoting OS formation, and improving light sensitivity in aCep290mutant mouse. These findings demonstrate the potential of Taprenepag to treat the CEP290-related visual dysfunction and suggest evaluation for other CEP290-related organ issues and ciliopathies.
Anti-Windup Protection Circuits for Biomolecular Integral Controllers
Authors: Filo Maurice , Gupta Ankit , Khammash Mustafa 
Published: October 2023

AbstractRobust Perfect Adaptation (RPA) is a desired property of biological systems wherein a system’s output perfectly adapts to a steady state, irrespective of a broad class of perturbations. Achieving RPA typically requires the deployment of integral controllers, which continually adjust the system’s output based on the cumulative error over time. However, the action of these integral controllers can lead to a phenomenon known as “windup”. Windup occurs when an actuator in the system is unable to respond to the controller’s commands, often due to physical constraints, causing the integral error to accumulate significantly. In biomolecular control systems, this phenomenon is especially pronounced due to the positivity of molecular concentrations, inevitable promoter saturation and resource limitations. To protect against such performance deterioration or even instability, we present three biomolecular anti-windup topologies. The underlying architectures of these topologies are then linked to classical control-theoretic anti-windup strategies. This link is made possible due the development of a general model reduction result for chemical reaction networks with fast sequestration reactions that is valid in both the deterministic and stochastic settings. The topologies are realized as chemical reaction networks for which genetic designs, harnessing the flexibility of inteins, are proposed. To validate the efficacy of our designs in mitigating windup effects, we perform simulations across a range of biological systems, including a complex model of Type I diabetic patients and advanced biomolecular proportional-integral-derivative (PID) controllers. This work lays a foundation for developing robust and reliable biomolecular control systems, providing necessary safety and protection against windup-induced instability.
Collaborative Augmented Reconstruction for Scaled Production of 3D Neuron Morphology in Mouse and Human Brains
Authors: Zhang Lingli , Huang Lei , Yuan Zexin , Hang Yuning , Zeng Ying , Li Kaixiang , Wang Lijun , Zeng Haoyu , Chen Xin , Zhang Hairuo , Xi Jiaqi , Chen Danni , Gao Ziqin , Le Longxin , Chen Jie , Ye Wen , Liu Lijuan , Wang Yimin , Peng Hanchuan 
Published: October 2023

AbstractDigital reconstruction of the intricate 3D morphology of individual neurons from microscopic images is widely recognized as a crucial challenge in both individual research laboratories and large-scale scientific projects focusing on cell types and brain anatomy. This task often fails both conventional manual reconstruction and state-of-the-art automatic reconstruction algorithms, even many of which are based on artificial intelligence (AI). It is also critical but challenging to organize multiple neuroanatomists to produce and cross-validate biologically relevant and agreeable reconstructions in scaled data production. Here we propose an approach based on collaborative human intelligence augmented by AI. Specifically, we have developed a Collaborative Augmented Reconstruction (CAR) platform for neuron reconstruction at scale. This platform allows for immersive interaction and efficient collaborative-editing of neuron anatomy using a variety of client devices, such as desktop workstations, virtual reality headsets, and mobile phones, enabling users to contribute anytime and anywhere and take advantage of several AI-based automation tools. We have tested CAR’s applicability for challenging mouse and human neurons towards a scaled and faithful data production. Our data indicate that the CAR platform is suitable for generating tens of thousands of neuronal reconstructions used in our companion studies.
Physically stressed bees expect less reward in an active choice judgement bias test
Authors: Procenko Olga , Read Jenny , Nityananda Vivek 
Published: October 2023

AbstractEmotion-like states in animals are commonly assessed using judgment bias tests, which measure responses to ambiguous information. A few studies have recently used these tests to argue for the presence of emotion-like states in insects. However, the results from most of these studies could have other explanations, including changes in motivation and attention. To control for these explanations, we therefore developed a novel judgment bias test, requiring bumblebees to make an active choice indicating their interpretation of ambiguous stimuli. Bumblebees were trained to associate high or low rewards, delivered in two different reward chambers, with distinct colors. Two groups of bees were then physically stressed by shaking or trapping, while the third group served as a control. We subsequently presented the bees with ambiguous colors between the two learnt colors and noted which reward chamber they chose. When presented with ambiguous colors, stressed bees were less likely than control bees to enter the reward chamber previously associated with high reward. We modelled bee behavior using signal detection and drift diffusion models and showed that control bees and stressed bees were, respectively, more likely to respond optimistically and pessimistically to ambiguous cues. The signal detection model further showed that the behavior of stressed bees was explained by a reduction in their prior expectation of high rewards. Our findings thus provide strong evidence for emotion-like states in bees and suggest that their stress-induced pessimistic behavior is explained by a reduced expectation of higher rewards.
A dynamic link between respiration and arousal
Authors: Kluger Daniel S. , Gross Joachim , Keitel Christian 
Published: October 2023

AbstractViewing brain function through the lense of other physiological processes has critically added to our understanding of human cognition. Further advances though may need a closer look at the interactions between these physiological processes themselves. Here we characterise the interplay of the highly periodic, and metabolically vital respiratory process and fluctuations in arousal neuromodulation, a process classically seen as non-periodic. In data of three experiments (N = 56 / 27 / 25 women and men) we tested for covariations in respiratory and pupil size (arousal) dynamics. After substantiating a robust coupling in the largest dataset, we further show that coupling strength decreases during task performance compared with rest, and that it mirrors a decreased respiratory rate when participants take deeper breaths. Taken together, these findings suggest a stronger link between respiratory and arousal processes than previously thought. Moreover, these links imply a stronger coupling during periods of rest, and the effect of respiratory rate on the coupling suggests a driving role. As a consequence, studying the role of neuromodulatory arousal on cortical function may also need to consider respiratory influences.Significance statementWe characterise the interplay of the respiratory rhythm and pupil diameter dynamics as a well-known proxy for arousal. Although we consistently find respiratory modulation of pupillary changes, they were most pronounced during periods of rest (compared to during task performance) and dependent on respiratory rate (deep vs. normal breathing).