bluuebunny/crossref_metadata_2025_split huggingface dataset:
Automated clustering reveals CD4+ T cell subset imbalances in rheumatoid arthritis
Authors: Mulhearn Ben , Marshall Lysette , Sutcliffe Megan , Hannes Susan K. , Fonseka Chamith , Hussell Tracy , Raychaudhuri Soumya , Barton Anne , Viatte Sebastien 
Published: May 2023

BackgroundDespite the report of an imbalance between CD4+ T helper (Th) cell subsets in rheumatoid arthritis (RA), patient stratification for precision medicine has been hindered by the discovery of ever more Th cell subsets, as well as contradictory association results.ObjectivesTo capture previously reported Th imbalance in RA with deep immunophenotyping techniques; to compare hypothesis-free unsupervised automated clustering with hypothesis-driven conventional biaxial gating and explore if Th cell heterogeneity accounts for conflicting association results.MethodsUnstimulated and stimulated peripheral blood mononuclear cells from 10 patients with RA and 10 controls were immunophenotyped with a 37-marker panel by mass cytometry (chemokine receptors, intra-cellular cytokines, intra-nuclear transcription factors). First, conventional biaxial gating and standard definitions of Th cell subsets were applied to compare subset frequencies between cases and controls. Second, unsupervised clustering was performed with FlowSOM and analysed using mixed-effects modelling of Associations of Single Cells (MASC).ResultsConventional analytical techniques fail to identify classical Th subset imbalance, while unsupervised automated clustering, by allowing for unusual marker combinations, identified an imbalance between pro- and anti-inflammatory subsets. For example, a pro-inflammatory Th1-like (IL-2+ T-bet+) subset and an unconventional but pro-inflammatory IL-17+ T-bet+ subset were significantly enriched in RA (odds ratio=5.7, p=2.2 x 10-3; odds ratio=9.7, p=1.5x10-3, respectively). In contrast, a FoxP3+ IL-2+ HLA-DR+ Treg-like subset was reduced in RA (odds ratio=0.1, p=7.7x10-7).ConclusionTaking an unbiased approach to large dataset analysis using automated clustering algorithms captures non-canonical CD4+ T cell subset imbalances in RA blood.
Mechanisms of action of monoclonal antibodies in oncology integrated in IMGT/mAb-DB
Authors: Manso Taciana , Kushwaha Anjana , Abdollahi Nika , Duroux Patrice , Giudicelli Véronique , Kossida Sofia 
Published: May 2023

BackgroundCancer cells activate different immune checkpoint (IC) pathways in order to evade immunosurveillance. Immunotherapies involving ICs either block or stimulate these pathways and enhance the efficiency of the immune system to recognize and attack cancer cells. In this way, the development of monoclonal antibodies (mAbs) targeting ICs has significant success in cancer treatment. Recently, a systematic description of the mechanisms of action (MOA) of the mAbs has been introduced in IMGT/mAb-DB, the IMGT® database dedicated to mAbs for therapeutic applications. The characterization of these antibodies provides a comprehensive understanding of how mAbs work in cancer.MethodsIn depth biocuration taking advantage of the abundant literature data as well as amino acid sequence analyses from mAbs managed in IMGT/2Dstructure-DB, the IMGT® protein database, allowed to define a standardized and consistent description of the MOA of mAbs targeting immune checkpoints in cancer therapy.ResultsA fine description and a standardized graphical representation of the MOA of selected mAbs are integrated within IMGT/mAb-DB highlighting two main mechanisms in cancer immunotherapy, either Blocking or Agonist. In both cases, the mAbs enhance cytotoxic T lymphocyte (CTL)-mediated anti-tumor immune response (Immunostimulant effect) against tumor cells. On the one hand, mAbs targeting co-inhibitory receptors may have a functional Fc region to increase anti-tumor activity by effector properties that deplete Treg cells (Fc-effector function effect) or may have limited FcγR binding to prevent Teff cells depletion and reduce adverse events. On the other hand, agonist mAbs targeting co-stimulatory receptors may bind to FcγRs, resulting in antibody crosslinking (FcγR crosslinking effect) and substantial agonism.ConclusionIn IMGT/mAb-DB, mAbs for cancer therapy are characterized by their chains, domains and sequence and by several therapeutic metadata, including their MOA. MOAs were recently included as a search criterion to query the database. IMGT® is continuing standardized work to describe the MOA of mAbs targeting additional immune checkpoints and novel molecules in cancer therapy, as well as expanding this study to other clinical domains.
Chromosomal microarray analysis supplements exome sequencing to diagnose children with suspected inborn errors of immunity
Authors: Beers Breanna J. , Similuk Morgan N. , Ghosh Rajarshi , Seifert Bryce A. , Jamal Leila , Kamen Michael , Setzer Michael R. , Jodarski Colleen , Duncan Rylee , Hunt Devin , Mixer Madison , Cao Wenjia , Bi Weimin , Veltri Daniel , Karlins Eric , Zhang Lingwen , Li Zhiwen , Oler Andrew J. , Jevtich Kathleen , Yu Yunting , Hullfish Haley , Bielekova Bibiana , Frischmeyer-Guerrerio Pamela , Dang Do An , Huryn Laryssa A. , Olivier Kenneth N. , Su Helen C. , Lyons Jonathan J. , Zerbe Christa S. , Rao V. Koneti , Keller Michael D. , Freeman Alexandra F. , Holland Steven M. , Franco Luis M. , Walkiewicz Magdalena A. , Yan Jia 
Published: May 2023

PurposeThough copy number variants (CNVs) have been suggested to play a significant role in inborn errors of immunity (IEI), the precise nature of this role remains largely unexplored. We sought to determine the diagnostic contribution of CNVs using genome-wide chromosomal microarray analysis (CMA) in children with IEI.MethodsWe performed exome sequencing (ES) and CMA for 332 unrelated pediatric probands referred for evaluation of IEI. The analysis included primary, secondary, and incidental findings.ResultsOf the 332 probands, 134 (40.4%) received molecular diagnoses. Of these, 116/134 (86.6%) were diagnosed by ES alone. An additional 15/134 (11.2%) were diagnosed by CMA alone, including two likely de novo changes. Three (2.2%) participants had diagnostic molecular findings from both ES and CMA, including two compound heterozygotes and one participant with two distinct diagnoses. Half of the participants with CMA contribution to diagnosis had CNVs in at least one non-immune gene, highlighting the clinical complexity of these cases. Overall, CMA contributed to 18/134 diagnoses (13.4%), increasing the overall diagnostic yield by 15.5% beyond ES alone.ConclusionPairing ES and CMA can provide a comprehensive evaluation to clarify the complex factors that contribute to both immune and non-immune phenotypes. Such a combined approach to genetic testing helps untangle complex phenotypes, not only by clarifying the differential diagnosis, but in some cases by identifying multiple diagnoses contributing to the overall clinical presentation.
Preserved blood-brain barrier and neurovascular coupling in female 5xFAD model of Alzheimer’s disease
Authors: Zhukov Oleg , He Chen , Soylu-Kucharz Rana , Cai Changsi , Lauritzen Andreas D. , Aldana Blanca Irene , Björkqvist Maria , Lauritzen Martin , Kucharz Krzysztof 
Published: May 2023

IntroductionDysfunction of the cerebral vasculature is considered one of the key components of Alzheimer’s disease (AD), but the mechanisms affecting individual brain vessels are poorly understood.MethodsHere, using in vivo two-photon microscopy in superficial cortical layers and ex vivo imaging across brain regions, we characterized blood–brain barrier (BBB) function and neurovascular coupling (NVC) at the level of individual brain vessels in adult female 5xFAD mice, an aggressive amyloid-β (Aβ) model of AD.ResultsWe report a lack of abnormal increase in adsorptive-mediated transcytosis of albumin and preserved paracellular barrier for fibrinogen and small molecules despite an extensive load of Aβ. Likewise, the NVC responses to somatosensory stimulation were preserved at all regulatory segments of the microvasculature: penetrating arterioles, precapillary sphincters, and capillaries. Lastly, the Aβ plaques did not affect the density of capillary pericytes.ConclusionOur findings provide direct evidence of preserved microvascular function in the 5xFAD mice and highlight the critical dependence of the experimental outcomes on the choice of preclinical models of AD. We propose that the presence of parenchymal Aβ does not warrant BBB and NVC dysfunction and that the generalized view that microvascular impairment is inherent to Aβ aggregation may need to be revised.
CSF oligoclonal IgG bands are not associated with ALS progression and prognosis
Authors: Klose Veronika , Jesse Sarah , Lewerenz Jan , Kassubek Jan , Dorst Johannes , Tumani Hayrettin , Ludolph Albert C. , Roselli Francesco 
Published: May 2023

IntroductionAmyotrophic Lateral Sclerosis (ALS) is characterized by progressive motoneuron degeneration through cell autonomous and non-cell autonomous mechanisms; and the involvement of the innate and adaptive immune system has been hypothesized based on human and murine model data. We have explored if B-cell activation and IgG responses, as detected by IgG Oligoclonal bands (OCB) in serum and cerebrospinal fluid, were associated with ALS or with a subgroup of patients with distinct clinical features.MethodsIgG OCB were determined in patients affected by ALS (n=457), Alzheimer Disease (n=516), Mild Cognitive Impairment (n=91), Tension-type Headache (n=152) and idiopathic Facial Palsy (n=94). For ALS patients, clinico-demographic and survival data were prospectively collected in the Register Schabia.ResultsThe prevalence of IgG OCB is comparable in ALS and the four neurological cohorts. When the OCB pattern was considered (highlighting either intrathecal or systemic B-cells activation), no effect of OCB pattern on clinic-demographic parameters and overall. ALS patients with intrathecal IgG synthesis (type 2 and 3) were more likely to display infectious, inflammatory or systemic autoimmune conditions.DiscussionThese data suggest that OCB are not related to ALS pathophysiology but rather are a finding possibly indicative a coincidental infectious or inflammatory comorbidity that merits further investigation.
Differences in spontaneous speech fluency between Parkinson's disease and spinocerebellar ataxia type 3
Authors: dos Santos Vanessa Brzoskowski , Ayres Annelise , Kieling Maiara Laís Mallmann , Miglorini Elaine Cristina , Jardim Laura Bannach , Schumacher-Schuh Artur Francisco , Rieder Carlos Roberto de Mello , Castilhos Raphael Machado de , Spencer Kristie , Rothe-Neves Rui , Olchik Maira Rozenfeld 
Published: May 2023

BackgroundThe basal ganglia and cerebellum both have a role in speech production although the effect of isolated involvement of these structures on speech fluency remains unclear.ObjectiveThe study aimed to assess the differences in the articulatory pattern in patients with cerebellar vs. basal ganglia disorders.MethodsA total of 20 individuals with Parkinson's disease (PD), 20 with spinocerebellar ataxia type 3 (SCA3), and 40 controls (control group, CG) were included. Diadochokinesis (DDK) and monolog tasks were collected.ResultsThe only variable that distinguished SCA3 carriers from the CG was the number of syllables in the monolog, with SCA3 patients of a significantly lower number. For patients with PD, the number of syllables, phonation time, DDK, and monolog were significantly lower than for CG. Patients with PD were significantly worse compared to patients with SCA3 in the number of syllables and phonation time in DDK, and phonation time in monolog. Additionally, there was a significant correlation between the number of syllables in the monolog and the MDS-UPDRS III for participants with PD, and the Friedreich Ataxia Rating Scale for participants with SCA3 suggesting a relationship between speech and general motor functioning.ConclusionThe monolog task is better at discriminating individuals with cerebellar vs. Parkinson's diseases as well as differentiating healthy control and was related to the severity of the disease.
Orientation selective stimulation with tetrahedral electrodes of the rat infralimbic cortex to indirectly target the amygdala
Authors: Gureviciene Irina , Laakso Hanne , Narvaez Omar , Paasonen Ekaterina , Lehto Lauri , Gurevicius Kestutis , Mangia Silvia , Michaeli Shalom , Gröhn Olli , Sierra Alejandra , Tanila Heikki 
Published: May 2023

IntroductionDeep brain stimulation (DBS) is a rapidly developing therapeutic intervention with constantly expanding neurological and psychiatric indications. A major challenge for the approach is the precise targeting and limitation of the effect on the desired neural pathways. We have introduced a new approach, orientation selective stimulation (OSS) that allows free rotation of the induced electric field on a plane when using a probe with three parallel electrodes forming an equilateral triangle at the tip. Here, we expand the technique by introducing a tetrahedral stimulation probe that enables adjustment of the primary electric field direction freely at any angle in a 3D space around the stimulating probe. OSS in 3D will enable better targeting of the electric field according to the local brain anatomy. We tested its utility in a rat model of DBS for treatment-resistant depression. The stimulation directed to the subgenual anterior cingulate cortex (sgACC) has yielded dramatic improvement in individual patients suffering from therapy resistant depression, but no consistent benefit in larger series. This failure has been ascribed to the challenging anatomy of sgACC with several crossing neural tracts and individual differences in the local anatomy.MethodsWe stimulated infralimbic cortex (IL), the rat analog of sgACC, and recorded local electrical responses in amygdala (AMG) that is monosynaptically connected to IL and plays a central role in emotional states. We further traced AMG–IL connections using a viral vector and tractography using diffusion magnetic resonance imaging (MRI). Finally, we mimicked the clinical situation by delivering sustained 130 Hz stimulation at IL at the most effective field orientation and followed changes in resting-state functional connectivity with IL using functional MRI. To help interpretation of responses in functional connectivity, we stimulated only the left IL, which we did not expect to evoke measurable changes in the rat behavior.ResultsThe AMG evoked responses depended systematically on the IL stimulation field orientation and yielded the maximum response in near vertical field orientation in accordance with tractography. Sustained 130 Hz stimulation at a field orientation yielding the strongest AMG evoked responses increased functional connectivity between IL and AMG on the stimulation side.ConclusionThese findings suggest that OSS in 3D provides a new approach to optimize the DBS for every individual patient with a single stimulation probe implantation.
Developmental ethanol exposure has minimal impact on cerebellar microglial dynamics, morphology, and interactions with Purkinje cells during adolescence
Authors: Cealie MaKenna Y. , Douglas James C. , Le Linh H. D. , Vonkaenel Erik D. , McCall Matthew N. , Drew Paul D. , Majewska Ania K. 
Published: May 2023

IntroductionFetal alcohol spectrum disorders (FASD) are the most common cause of non-heritable, preventable mental disability, occurring in almost 5% of births in the United States. FASD lead to physical, behavioral, and cognitive impairments, including deficits related to the cerebellum. There is no known cure for FASD and their mechanisms remain poorly understood. To better understand these mechanisms, we examined the cerebellum on a cellular level by studying microglia, the principal immune cells of the central nervous system, and Purkinje cells, the sole output of the cerebellum. Both cell types have been shown to be affected in models of FASD, with increased cell death, immune activation of microglia, and altered firing in Purkinje cells. While ethanol administered in adulthood can acutely depress the dynamics of the microglial process arbor, it is unknown how developmental ethanol exposure impacts microglia dynamics and their interactions with Purkinje cells in the long term.MethodsTo address this question, we used a mouse model of human 3rd trimester exposure, whereby L7cre/Ai9+/−/Cx3cr1G/+ mice (with fluorescently labeled microglia and Purkinje cells) of both sexes were subcutaneously treated with a binge-level dose of ethanol (5.0 g/kg/day) or saline from postnatal days 4–9. Cranial windows were implanted in adolescent mice above the cerebellum to examine the long-term effects of developmental ethanol exposure on cerebellar microglia and Purkinje cell interactions using in vivo two-photon imaging.ResultsWe found that cerebellar microglia dynamics and morphology were not affected after developmental ethanol exposure. Microglia dynamics were also largely unaltered with respect to how they interact with Purkinje cells, although subtle changes in these interactions were observed in females in the molecular layer of the cerebellum.DiscussionThis work suggests that there are limited in vivo long-term effects of ethanol exposure on microglia morphology, dynamics, and neuronal interactions, so other avenues of research may be important in elucidating the mechanisms of FASD.
Impact of zinc and iron agronomic biofortification on grain mineral concentration of finger millet varieties as affected by location and slope
Authors: Teklu Demeke , Gashu Dawd , Joy Edward J. M. , Lark R. Murray , Bailey Elizabeth H. , Wilson Lolita , Amede Tilahun , Broadley Martin R. 
Published: May 2023

BackgroundFood crop micronutrient concentrations can be enhanced through agronomic biofortification, with the potential to reduce micronutrient deficiencies among rural population if they have access to fertilizers. Here we reported the impact of agronomic biofortification on finger millet grain zinc (Zn) and iron (Fe) concentration.MethodsA field experiment was conducted in farmers’ fields in Ethiopia in two locations; over two seasons in one district (2019 and 2020), and over a single season (2019) in a second district. The experimental design had 15 treatment combinations comprising 3 finger millet varieties and 5 soil-applied fertilizer treatments: (T1) 20 kg ha−1 FeSO4 + 25 kg ha−1 ZnSO4 + NPKS; (T2) 25 kg ha−1 ZnSO4 + NPKS; (T3) NPKS; (T4) 30% NPKS; (T5) 20 kg ha−1 FeSO4 + NPKS. The treatments were studied at two slope positions (foot and hill), replicated four times in a randomized complete block design.ResultsGrain Zn concentration increased by 20% in response to Fe and Zn and by 18.9% due to Zn addition. Similarly, grain Fe concentration increased by 21.4% in T1 and 17.8% in T5 (Fe). Zinc fertilizer application (p &lt; 0.001), finger millet variety (p &lt; 0.001), and an interaction of Fe and Zn had significant effect on grain Zn concentration. Iron fertilizer (p &lt; 0.001) and interactive effect of Fe fertilizer and finger millet variety (p &lt; 0.01) had significant effects on grain Fe concentration. Location but not slope position was a source of variation for both grain Zn and Fe concentrations.ConclusionSoil application of Zn and Fe could be a viable strategy to enhance grain Zn and Fe concentration to finger millet grain. If increased grain Zn and Fe is bioavailable, it could help to combat micronutrient deficiencies.
The influence of conventional and novel blanching methods on potato granules, phytochemicals, and thermal properties of colored varieties
Authors: Saini Rajni , Kaur Sukhpreet , Aggarwal Poonam , Dhiman Atul 
Published: May 2023

IntroductionColored potatoes comprise many bioactive compounds that potentially support human health. Polyphenols present in them have associated therapeutic benefits like antimutagenic and anticarcinogenic properties.MethodThe current study aimed to explore the effects of different blanching methods (steam blanching, hot water blanching, and microwave-assisted blanching) on the phytochemical and structural aspects of PP-1901 and Lady Rosetta (LR) potato varieties. Changes in the antioxidant activity, color, total ascorbic acid, phenolic, and flavonoid content were based on the variations in parameters including temperature (blanching using hot water and steam) and capacity 100– 900 W (blanching using microwave).ResultsFor both PP-1901 and LR varieties, all the blanching methods led to a significant reduction in residual peroxidase activity, as well as affecting their color. The preservation of bioactive substances exhibited a microwave steam&gt;hot water blanching trend. Blanching significantly increased the antioxidant activity of all the samples. Additionally, Fourier-transform infrared spectroscopy revealed that phytocompounds were retained to their maximum in microwave-blanched samples, especially at 300 W. The type of blanching method significantly affected the thermal properties of potatoes by disrupting the ordered structure of the matrix.DiscussionMicrowaves at 300 W can be used as a novel and suitable alternative technique for blanching potatoes, which successfully retained the original quality of it in comparison to steam and hot water blanching.
Risk factors for early-onset colorectal cancer: systematic review and meta-analysis
Authors: Hua Hongmei , Jiang Qiuping , Sun Pan , Xu Xing 
Published: May 2023

BackgroundThe incidence of early-onset colorectal cancer (EOCRC), which means colorectal cancer diagnosed in patients under 50 years, has been increasing around the world. However, the etiology remains unclear. This study aims to identify risk factors for EOCRC.MethodsThis systematic review was conducted in PubMed, Embase, Scopus, and Cochrane Library databases from inception to November 25, 2022. We examined risk factors for EOCRC, including demographic factors, chronic conditions, and lifestyle behaviors or environmental factors. Random-effects/fixed-effects meta-analysis was adopted to combine effect estimates from published data. Study quality was evaluated with the Newcastle-Ottawa Scale (NOS). Statistical analysis was performed Revman5.3. Studies not suitable for the meta-analysis were analyzed by a systematic review.ResultsA total of 36 studies were identified for this review, and 30 studies were included in the meta-analysis. Significant risk factors for EOCRC included male (OR=1.20; 95% CI, 1.08-1.33), Caucasian (OR=1.44; 95% CI, 1.15-1.80), a family history of CRC (OR=5.90; 95% CI, 3.67-9.48), inflammatory bowel disease (OR=4.43; 95% CI, 4.05-4.84), obesity (OR=1.52; 95%CI, 1.20-1.91), overweight (OR=1.18; 95% CI, 1.12-1.25), triglycerides (OR=1.12; 95% CI, 1, 08-1.18), hypertension (OR=1.16; 95% CI, 1.12-1.21), metabolic syndrome (OR=1.29; 95% CI, 1.15-1.45), smoking (OR=1.44; 95% CI, 1.10-1.88), alcohol consumption (OR=1.41; 95% CI, 1.22-1.62), a sedentary lifestyle (OR=1.24; 95% CI, 1.05-1.46), red meat (OR=1.10; 95% CI, 1.04-1.16), processed meat (OR=1.53; 95% CI, 1.13-2.06), Western dietary patterns (OR=1.43; 95% CI, 1.18-1.73) and sugar-sweetened beverages (OR=1.55; 95% CI, 1.23-1.95). However, no statistical differences were found for hyperlipidemia and hyperglycemia. Vitamin D may be a protective factor (OR=0.72; 95% CI, 0.56-0.92). There was considerable heterogeneity among studies (I2&gt;60%).ConclusionsThe study provides an overview of the etiology and risk factors of EOCRC. Current evidence can provide baseline data for risk prediction models specific to EOCRC and risk-tailored screening strategies.