Deep phenotyping of unaffected carriers of pathogenic BMPR2 variants screened for pulmonary arterial hypertension.

INTRODUCTION: Pathogenic variants in the gene encoding for BMPR2 are a major genetic risk factor for heritable pulmonary arterial hypertension. Owing to incomplete penetrance, deep phenotyping of unaffected carriers of a pathogenic BMPR2 variant through multimodality screening may aid in early diagnosis and identify susceptibility traits for future development of pulmonary arterial hypertension. METHODS: 28 unaffected carriers (44±16 years, 57% female) and 21 healthy controls (44±18 years, 48% female) underwent annual screening, including cardiac magnetic resonance imaging, transthoracic echocardiography, cardiopulmonary exercise testing and right heart catheterisation. Right ventricular pressure-volume loops were constructed to assess load-independent contractility and compared with a healthy control group. A transgenic Bmpr2Δ71Ex1/+ rat model was employed to validate findings from humans. RESULTS: Unaffected carriers had lower indexed right ventricular end-diastolic (79.5±17.6 mL·m-2 versus 62.7±15.3 mL·m-2; p=0.001), end-systolic (34.2±10.5 mL·m-2 versus 27.1±8.3 mL·m-2; p=0.014) and left ventricular end-diastolic (68.9±14.1 mL·m-2 versus 58.5±10.7 mL·m-2; p=0.007) volumes than control subjects. Bmpr2Δ71Ex1/+ rats were also observed to have smaller cardiac volumes than wild-type rats. Pressure-volume loop analysis showed that unaffected carriers had significantly higher afterload (arterial elastance 0.15±0.06 versus 0.27±0.08 mmHg·mL-1; p<0.001) and end-systolic elastance (0.28±0.07 versus 0.35±0.10 mmHg·mL-1; p=0.047) in addition to lower right ventricular pulmonary artery coupling (end-systolic elastance/arterial elastance 2.24±1.03 versus 1.36±0.37; p=0.006). During the 4-year follow-up period, two unaffected carriers developed pulmonary arterial hypertension, with normal N-terminal pro-brain natriuretic peptide and transthoracic echocardiography indices at diagnosis. CONCLUSION: Unaffected BMPR2 mutation carriers have an altered cardiac phenotype mimicked in Bmpr2Δ71Ex1/+ transgenic rats. Future efforts to establish an effective screening protocol for individuals at risk for developing pulmonary arterial hypertension warrant longer follow-up periods.

Case report: Complex evaluation of coagulation, fibrinolysis and inflammatory cytokines in a SARS-CoV-2 infected pregnant woman with fetal loss.

Background: SARS-CoV-2 infection during pregnancy increases the risk of severe obstetrical complications. Detailed evaluation of COVID-19-associated coagulopathy in a pregnancy with stillbirth hasn't been described so far. Besides knowledge gaps in the pathomechanism leading to stillbirth in COVID-19 pregnancies, currently, no prognostic biomarker is available to identify pregnant patients who are at imminent risk of COVID-19-associated maternal and fetal complications, requiring immediate medical attention. Case: Here we report the case of a 28-year-old SARS-CoV-2 infected pregnant patient, admitted to our hospital at 28 weeks of gestation with intrauterine fetal loss. The presence of SARS-CoV-2 placentitis was confirmed by immunohistological evaluation of the placenta. She had only mild upper respiratory symptoms and her vital signs were within reference throughout labor and postpartum. The stillborn infant was delivered per vias naturales. Fibrinogen concentrate was administered before and after labor due to markedly decreased fibrinogen levels (1.49 g/l) at admission and excessive bleeding during and after delivery. Although coagulation screening tests were not alarming at admission, the balance of hemostasis was strikingly distorted in the patient. As compared to healthy age- and gestational age-matched pregnant controls, increased D-dimer, low FVIII activity, low FXIII level, marked hypocoagulability as demonstrated by the thrombin generation assay, together with shortened clot lysis and decreased levels of fibrinolytic proteins were observed. These alterations most likely have contributed to the increased bleeding observed during labor and in the early postpartum period. Interestingly, at the same time, only moderately altered inflammatory cytokine levels were found at admission. Serum ACE2 activity did not differ in the patient from that of age- and gestational age-matched healthy controls, suggesting that despite previous speculations in the literature, ACE2 may not be used as a potential biomarker for the prediction of COVID-19 placentitis and threatening fetal loss in SARS-CoV-2-infected pregnancies. Conclusions: Although based on this case report no prognostic biomarker could be identified for use in pregnant patients with imminent risk of fetal loss associated with COVID-19 placentitis, the above-described hemostasis alterations warrant awareness of postpartum hemorrhagic complications and could be helpful to identify patients requiring intensified medical attention.

Decreased Expression of Placental Proteins in Recurrent Pregnancy Loss: Functional Relevance and Diagnostic Value.

Miscarriages affect 50-70% of all conceptions and 15-20% of clinically recognized pregnancies. Recurrent pregnancy loss (RPL, ≥2 miscarriages) affects 1-5% of recognized pregnancies. Nevertheless, our knowledge about the etiologies and pathophysiology of RPL is incomplete, and thus, reliable diagnostic/preventive tools are not yet available. Here, we aimed to define the diagnostic value of three placental proteins for RPL: human chorionic gonadotropin free beta-subunit (free-ß-hCG), pregnancy-associated plasma protein-A (PAPP-A), and placental growth factor (PlGF). Blood samples were collected from women with RPL (n = 14) and controls undergoing elective termination of pregnancy (n = 30) at the time of surgery. Maternal serum protein concentrations were measured by BRAHMS KRYPTOR Analyzer. Daily multiple of median (dMoM) values were calculated for gestational age-specific normalization. To obtain classifiers, logistic regression analysis was performed, and ROC curves were calculated. There were differences in changes of maternal serum protein concentrations with advancing healthy gestation. Between 6 and 13 weeks, women with RPL had lower concentrations and dMoMs of free ß-hCG, PAPP-A, and PlGF than controls. PAPP-A dMoM had the best discriminative properties (AUC = 0.880). Between 9 and 13 weeks, discriminative properties of all protein dMoMs were excellent (free ß-hCG: AUC = 0.975; PAPP-A: AUC = 0.998; PlGF: AUC = 0.924). In conclusion, free-ß-hCG and PAPP-A are valuable biomarkers for RPL, especially between 9 and 13 weeks. Their decreased concentrations indicate the deterioration of placental functions, while lower PlGF levels indicate problems with placental angiogenesis after 9 weeks.

Primary Localized Cutaneous Amyloidosis in Central Europe: A Retrospective Monocentric Study on Epidemiology and Therapy.

Amyloid deposits can be the cause of many chronic diseases. Primary localized cutaneous amyloidosis (PLCA) is a chronic dermatologic condition with amyloid deposits in the papillary dermis. The most common types of the keratinocyte-derived form of PLCA include macular (MA), lichen (LA), and biphasic (BA) amyloidosis. The estimated prevalence of PLCA in the Asian population is 0.98/10,000, which is higher than in the European population; thus, epidemiologic data on PLCA in the Caucasian population are limited. We performed a retrospective single-center study analyzing epidemiologic characteristics of a Central European PLCA population. Epidemiologic data regarding age, sex, skin phototype (Fitzpatrick scale I-VI), disease duration, comorbidities, history of atopy, and family history of PLCA were collected. Clinical characteristics, localization of PLCA lesions, applied therapies and treatment outcomes were also analyzed. Dermoscopic characteristics were also evaluated. A total of 41 patients diagnosed with PLCA were included, with 22 presenting with macular, 18 with lichen, and 1 with biphasic amyloidosis. The male/female ratio was 16/25, and mean age at diagnosis was 54.6 ± 15.2 years (range 27-87 years). The mean age at the onset of PLCA was 53 ± 16.1 years (range 19-79 years) in MA, 46.7 ± 18.2 years (range 14-73 years) in LA, and 26 years in BA. The interscapular region in MA and the extensor surface of the lower extremities in LA proved to be localization-related areas. In our center, a wide range of therapeutic options was applied, with the most prescribed being topical corticosteroids in all types of PLCA. We presented a retrospective, monocentric study on the epidemiology of PLCA in the Central European region. By examining the medical data of a significant number of PLCA patients, we compared our epidemiologic data with that of the Asian PLCA population. Due to the rarity of the condition, further randomized controlled trials and guidelines are needed to improve therapeutic outcomes.

A cleavage rule for selection of increased-fidelity SpCas9 variants with high efficiency and no detectable off-targets.

Streptococcus pyogenes Cas9 (SpCas9) has been employed as a genome engineering tool with a promising potential within therapeutics. However, its off-target effects present major safety concerns for applications requiring high specificity. Approaches developed to date to mitigate this effect, including any of the increased-fidelity (i.e., high-fidelity) SpCas9 variants, only provide efficient editing on a relatively small fraction of targets without detectable off-targets. Upon addressing this problem, we reveal a rather unexpected cleavability ranking of target sequences, and a cleavage rule that governs the on-target and off-target cleavage of increased-fidelity SpCas9 variants but not that of SpCas9-NG or xCas9. According to this rule, for each target, an optimal variant with matching fidelity must be identified for efficient cleavage without detectable off-target effects. Based on this insight, we develop here an extended set of variants, the CRISPRecise set, with increased fidelity spanning across a wide range, with differences in fidelity small enough to comprise an optimal variant for each target, regardless of its cleavability ranking. We demonstrate efficient editing with maximum specificity even on those targets that have not been possible in previous studies.

Position-dependent sequence motif preferences of SpCas9 are largely determined by scaffold-complementary spacer motifs.

Streptococcus pyogenes Cas9 (SpCas9) nuclease exhibits considerable position-dependent sequence preferences. The reason behind these preferences is not well understood and is difficult to rationalise, since the protein establishes interactions with the target-spacer duplex in a sequence-independent manner. We revealed here that intramolecular interactions within the single guide RNA (sgRNA), between the spacer and the scaffold, cause most of these preferences. By using in cellulo and in vitro SpCas9 activity assays with systematically designed spacer and scaffold sequences and by analysing activity data from a large SpCas9 sequence library, we show that some long (>8 nucleotides) spacer motifs, that are complementary to the RAR unit of the scaffold, interfere with sgRNA loading, and that some motifs of more than 4 nucleotides, that are complementary to the SL1 unit, inhibit DNA binding and cleavage. Furthermore, we show that intramolecular interactions are present in the majority of the inactive sgRNA sequences of the library, suggesting that they are the most important intrinsic determinants of the activity of the SpCas9 ribonucleoprotein complex. We also found that in pegRNAs, sequences at the 3' extension of the sgRNA that are complementary to the SL2 unit are also inhibitory to prime editing, but not to the nuclease activity of SpCas9.

Evaluation of transorbital sonography measures of optic nerve diameter in the context of global and regional brain volume in multiple sclerosis.

Transorbital sonography (TOS) could be a swift and convenient method to detect the atrophy of the optic nerve, possibly providing a marker that might reflect other quantitative structural markers of multiple sclerosis (MS). Here we evaluate the utility of TOS as a complementary tool for assessing optic nerve atrophy, and investigate how TOS-derived measures correspond to volumetric brain markers in MS. We recruited 25 healthy controls (HC) and 45 patients with relapsing-remitting MS and performed B-mode ultrasonographic examination of the optic nerve. Patients additionally underwent MRI scans to obtain T1-weighted, FLAIR and STIR images. Optic nerve diameters (OND) were compared between HC, MS patients with and without history of optic neuritis (non-ON) using a mixed-effects ANOVA model. The relationship between within-subject-average OND and global and regional brain volumetric measures was investigated using FSL SIENAX, voxel-based morphometry and FSL FIRST. OND was significantly different between HC-MS (HC = 3.2 ± 0.4 mm, MS = 3 ± 0.4 mm; p < 0.019) and we found significant correlation between average OND and normalised whole brain (ß = 0.42, p < 0.005), grey matter (ß = 0.33, p < 0.035), white matter (ß = 0.38, p < 0.012) and ventricular cerebrospinal fluid volume (ß = - 0.36, p < 0.021) in the MS group. History of ON had no impact on the association between OND and volumetric data. In conclusion, OND is a promising surrogate marker in MS, that can be simply and reliably measured using TOS, and its derived measures correspond to brain volumetric measures. It should be further explored in larger and longitudinal studies.

Dean-Flow Affected Lateral Focusing and Separation of Particles and Cells in Periodically Inhomogeneous Microfluidic Channels.

The purpose of the recent work is to give a better explanation of how Dean vortices affect lateral focusing, and to understand how cell morphology can alter the focusing position compared to spherical particles. The position and extent of the focused region were investigated using polystyrene fluorescent beads with different bead diameters (Ø = 0.5, 1.1, 1.97, 2.9, 4.8, 5.4, 6.08, 10.2, 15.8, 16.5 µm) at different flow rates (0.5, 1, 2 µL/s). Size-dependent focusing generated a precise map of the equilibrium positions of the spherical beads at the end of the periodically altering channels, which gave a good benchmark for focusing multi-dimensional particles and cells. The biological samples used for experiments were rod-shaped Escherichia coli (E. coli), discoid biconcave-shaped red blood cells (RBC), round or ovoid-shaped yeast, Saccharomyces cerevisiae, and soft-irregular-shaped HeLa cancer-cell-line cells to understand how the shape of the cells affects the focusing position at the end of the channel.

Deep-SAGA: a deep-learning-based system for automatic gaze annotation from eye-tracking data.

With continued advancements in portable eye-tracker technology liberating experimenters from the restraints of artificial laboratory designs, research can now collect gaze data from real-world, natural navigation. However, the field lacks a robust method for achieving this, as past approaches relied upon the time-consuming manual annotation of eye-tracking data, while previous attempts at automation lack the necessary versatility for in-the-wild navigation trials consisting of complex and dynamic scenes. Here, we propose a system capable of informing researchers of where and what a user's gaze is focused upon at any one time. The system achieves this by first running footage recorded on a head-mounted camera through a deep-learning-based object detection algorithm called Masked Region-based Convolutional Neural Network (Mask R-CNN). The algorithm's output is combined with frame-by-frame gaze coordinates measured by an eye-tracking device synchronized with the head-mounted camera to detect and annotate, without any manual intervention, what a user looked at for each frame of the provided footage. The effectiveness of the presented methodology was legitimized by a comparison between the system output and that of manual coders. High levels of agreement between the two validated the system as a preferable data collection technique as it was capable of processing data at a significantly faster rate than its human counterpart. Support for the system's practicality was then further demonstrated via a case study exploring the mediatory effects of gaze behaviors on an environment-driven attentional bias.

Non-tuberculous mycobacterial infections in patients with end-stage renal disease: Prevalence, risk factors, and mortality.

Non-tuberculous mycobacterial (NTM) disease has increased in prevalence in the USA, however, little is known on NTM in the population with end-stage renal disease (ESRD). Thus, we investigated patients with ESRD to determine risk factors for NTM disease and mortality. We queried the United States Renal Data System from 2005 to 2015 using International Classification of Diseases (ICD)-9/ICD-10 codes to identify NTM and risk factors. Logistic regression was used to examine the association of risk factors with NTM and Cox proportional hazards modeling was used to assess the association of NTM with mortality. Of 1,068,634 included subjects, 3232 (0.3%) individuals were identified with any NTM diagnosis. Hemodialysis versus peritoneal dialysis (OR=0.10, 95% CI=0.08 to 0.13) was protective for NTM, whereas black (OR=1.27, 95% CI=1.18 to 1.37) or other race compared with white race (OR=1.39, 95% CI=1.21 to 1.59) increased the risk of NTM. HIV (OR=15.71, 95% CI=14.24 to 17.33), history of any transplant (OR=4.25, 95% CI=3.93 to 4.60), kidney transplant (OR=3.00, 95% CI=2.75 to 3.27), diabetes (OR=1.32, 95% CI=1.23 to 1.43), rheumatologic disease (OR=1.92, 95% CI=1.77 to 2.08), and liver disease (OR=2.09, 95% CI=1.91 to 2.30) were associated with increased risk for NTM diagnosis. In multivariable analysis, there was a significant increase in mortality with any NTM diagnosis (HR=1.83, 95% CI=1.76 to 1.91, p≤0.0001). Controlling for relevant demographic and clinical risk factors, there was an increased risk of mortality associated with any diagnosis of NTM. Early diagnosis and treatment of NTM infection may improve survival in patients with ESRD.

Distorted TCR repertoires define multisystem inflammatory syndrome in children.

While the majority of children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) display mild or no symptoms, rare individuals develop severe disease presenting with multisystem inflammatory syndrome (MIS-C). The reason for variable clinical manifestations is not understood. Here, we carried out TCR sequencing and conducted comparative analyses of TCR repertoires between children with MIS-C (n = 12) and mild (n = 8) COVID-19. We compared these repertoires with unexposed individuals (samples collected pre-COVID-19 pandemic: n = 8) and with the Adaptive Biotechnologies MIRA dataset, which includes over 135,000 high-confidence SARS-CoV-2-specific TCRs. We show that the repertoires of children with MIS-C are characterised by the expansion of TRBV11-2 chains with high junctional and CDR3 diversity. Moreover, the CDR3 sequences of TRBV11-2 clones shift away from SARS-CoV-2 specific T cell clones, resulting in distorted TCR repertoires. In conclusion, our study reports that CDR3-independent expansion of TRBV11-2+ cells, lacking SARS-CoV-2 specificity, defines MIS-C in children.

Modulation of cortical resting state functional connectivity during a visuospatial attention task in Parkinson's disease.

Visual dysfunction is a recognized early symptom of Parkinson's disease (PD) that partly scales motor symptoms, yet its background is heterogeneous. With additional deficits in visuospatial attention, the two systems are hard to disentangle and it is not known whether impaired functional connectivity in the visual cortex is translative in nature or disrupted attentional modulation also contributes. In this study, we investigate functional connectivity modulation during a visuospatial attention task in patients with PD. In total, 15 PD and 16 age-matched healthy controls performed a visuospatial attention task while undergoing fMRI, in addition to a resting-state fMRI scan. Tensorial independent component analysis was used to investigate task-related network activity patterns. Independently, an atlas-based connectivity modulation analysis was performed using the task potency method. Spearman's rank correlation was calculated between task-related network expression, connectivity modulation, and clinical characteristics. Task-related networks including mostly visual, parietal, and prefrontal cortices were expressed to a significantly lesser degree in patients with PD (p < 0.027). Resting-state functional connectivity did not differ between the healthy and diseased cohorts. Connectivity between the precuneus and ventromedial prefrontal cortex was modulated to a higher degree in patients with PD (p < 0.004), while connections between the posterior parietal cortex and primary visual cortex, and also the superior frontal gyrus and opercular cortex were modulated to a lesser degree (p < 0.001 and p < 0.011). Task-related network expression and superior frontal gyrus-opercular cortex connectivity modulation were significantly associated with UPDRSIII motor scores and the Hoehn-Yahr stages (R = -0.72, p < 0.006 and R = -0.90, p < 0.001; R = -0.68, p < 0.01 and R = -0.71, p < 0.007). Task-related networks function differently in patients with PD in association with motor symptoms, whereas impaired modulation of visual and default-mode network connectivity was not correlated with motor function.

Proteomic Changes of Osteoclast Differentiation in Rheumatoid and Psoriatic Arthritis Reveal Functional Differences.

Background: Osteoclasts play a crucial role in the maintenance, repair, and remodeling of bones of the adult vertebral skeleton due to their bone resorption capability. Rheumatoid arthritis (RA) and psoriatic arthritis (PsA) are associated with increased activity of osteoclasts. Objectives: Our study aimed to investigate the dynamic proteomic changes during osteoclast differentiation in healthy donors, in RA, and PsA. Methods: Blood samples of healthy donors, RA, and PsA patients were collected, and monocytes were isolated and differentiated into osteoclasts in vitro using macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor κB ligand (RANK-L). Mass spectrometry-based proteomics was used to analyze proteins from cell lysates. The expression changes were analyzed with Gene Set Enrichment Analysis (GSEA). Results: The analysis of the proteomic changes revealed that during the differentiation of the human osteoclasts, expression of the proteins involved in metabolic activity, secretory function, and cell polarity is increased; by contrast, signaling pathways involved in the immune functions are downregulated. Interestingly, the differences between cells of healthy donors and RA/PsA patients are most pronounced after the final steps of differentiation to osteoclasts. In addition, both in RA and PsA the differentiation is characterized by decreased metabolic activity, associated with various immune pathway activities; furthermore by accelerated cytokine production in RA. Conclusions: Our results shed light on the characteristic proteomic changes during human osteoclast differentiation and expression differences in RA and PsA, which reveal important pathophysiological insights in both diseases.

Geometry-Dependent Efficiency of Dean-Flow Affected Lateral Particle Focusing and Separation in Periodically Inhomogeneous Microfluidic Channels.

In this study, inertial focusing phenomenon was investigated, which can be used as a passive method for sample preparation and target manipulation in case of particulate suspensions. Asymmetric channel geometry was designed to apply additional inertial forces besides lift forces to promote laterally ordered particles to achieve sheathless focusing or size-dependent sorting. The evolving hydrodynamic forces were tailored with altered channel parameters (width and height), and different flow rates, to get a better understanding of smaller beads' lateral migration. Fluorescent beads (with the diameter of 4.8 µm and 15.8 µm) were used to distinguish the focusing position in continuous flow, and experimental results were compared to in silico models for particle movement prediction, made in COMSOL Multiphysics. The focusing behaviour of the applied microfluidic system was mainly characterised for particle size in the range close to blood cells and bacteria.

Reproducibility of Lesion Count in Various Subregions on MRI Scans in Multiple Sclerosis.

Purpose: Lesion number and burden can predict the long-term outcome of multiple sclerosis, while the localization of the lesions is also a good predictive marker of disease progression. These biomarkers are used in studies and in clinical practice, but the reproducibility of lesion count is not well-known. Methods: In total, five raters evaluated T2 hyperintense lesions in 140 patients with multiple sclerosis in six localizations: periventricular, juxtacortical, deep white matter, infratentorial, spinal cord, and optic nerve. Black holes on T1-weighted images and brain atrophy were subjectively measured on a binary scale. Reproducibility was measured using the intraclass correlation coefficient (ICC). ICCs were also calculated for the four most accurate raters to see how one outlier can influence the results. Results: Overall, moderate reproducibility (ICC 0.5-0.75) was shown, which did not improve considerably when the most divergent rater was excluded. The areas that produced the worst results were the optic nerve region (ICC: 0.118) and atrophy judgment (ICC: 0.364). Comparing high- and low-lesion burdens in each region revealed that the ICC is higher when the lesion count is in the mid-range. In the periventricular and deep white matter area, where lesions are common, higher ICC was found in patients who had a lower lesion count. On the other hand, juxtacortical lesions and black holes that are less common showed higher ICC when the subjects had more lesions. This difference was significant in the juxtacortical region when the most accurate raters compared patients with low (ICC: 0.406 CI: 0.273-0.546) and high (0.702 CI: 0.603-0.785) lesion loads. Conclusion: Lesion classification showed high variability by location and overall moderate reproducibility. The excellent range was not achieved, owing to the fact that some areas showed poor performance. Hence, putting effort toward the development of artificial intelligence for the evaluation of lesion burden should be considered.

Connection between microstructural alterations detected by diffusion MRI and cognitive dysfunction in MS: A model-free analysis approach.

BACKGROUND: Cognitive decline is a prominent symptom of MS. Clear connection between cognitive status and white matter microstructural changes has not been unequivocally observed to date. OBJECTIVE: To characterise the relationship between white matter microstructure and cognitive performance a partial least squares (PLS) approach was used. METHODS: 53 RR MS patients' T1 and DTI images and BICAMS subtests were used in our analysis. Standard FSL pipeline was used to obtain diffusion parameters. A PLS approach was applied to reveal the diffusion parameter patterns responsible for the cognitive dysfunction. RESULTS: The first latent variable (LV) was mainly associated with demyelination, while the second and third explained axonal damage. While the first two LV represented mainly Brief Visuospatial Memory Test (BVMT) and Single Digit Modality Test (SDMT), the third LV depicted diffusion alterations mainly the verbal subtest. The first LVs spatial map showed demyelination in the corpus callosum. The second LVs spatial map showed the diffusion alterations in the thalamus. The third LV depicted diffusion alterations in the putative left superior longitudinal fascicle. CONCLUSION: Visual memory demanding tasks versus language functions depend on distinct patterns of diffusion parameters and the spatial organisation. Axial diffusivity alterations, a putative marker of irreversible axonal loss explained around 20% of variability in the cognitive functions.

The effect of lesion location on visuospatial attentional bias in patients with multiple sclerosis.

OBJECTIVE: Lateralization of visuospatial attention in healthy people, known as pseudoneglect, results in leftward bias during the Landmark or line bisection tasks. Cognitive dysfunctions in patients with multiple sclerosis (MS) might affect the visuospatial attentional abilities as well. In this study, we aimed to examine the association between atrophy and lesion location and the extent of lateralization of visuospatial attentional bias in patients with MS. METHOD: Visuospatial attentional bias was measured in 35 relapsing-remitting MS patients using the Landmark task. To evaluate the relation between spatial attentional bias and gray matter atrophy, voxel-based morphometry was performed on T1-weighted magnetic resonance (MR) images. In order to examine the effect of lesion location on visuospatial attentional bias, lesion-symptom mapping was conducted on the manually segmented lesions. RESULTS: The variability of visuospatial attentional bias was higher in MS patients compared to healthy controls (p < .04). Lesion probability mapping showed that lesions located along the left superior longitudinal fascicle are associated with the extent of visuospatial bias (p < .05). No correlation was found between gray matter atrophy and the attentional bias of the patients. CONCLUSIONS: Our results indicate that lesions affecting the integrity of white matter pathways in the fronto-parietal attentional network might be accountable for the higher variability of spatial attentional bias in patients with MS. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Placental galectins regulate innate and adaptive immune responses in pregnancy.

Introduction: Galectins are master regulators of maternal immune responses and placentation in pregnancy. Galectin-13 (gal-13) and galectin-14 (gal-14) are expressed solely by the placenta and contribute to maternal-fetal immune tolerance by inducing the apoptosis of activated T lymphocytes and the polarization of neutrophils toward an immune-regulatory phenotype.Furthermore, their decreased placental expression is associated with pregnancy complications, such as preeclampsia and miscarriage. Yet, our knowledge of the immunoregulatory role of placental galectins is incomplete. Methods: This study aimed to investigate the effects of recombinant gal-13 and gal-14 on cell viability, apoptosis, and cytokine production of peripheral blood mononuclear cells (PBMCs) and the signaling pathways involved. Results: Herein, we show that gal-13 and gal-14 bind to the surface of non-activated PBMCs (monocytes, natural killer cells, B cells, and T cells) and increase their viability while decreasing the rate of their apoptosis without promoting cell proliferation. We also demonstrate that gal-13 and gal-14 induce the production of interleukin (IL)-8, IL-10, and interferon-gamma cytokines in a concentration-dependent manner in PBMCs. The parallel activation of Erk1/2, p38, and NF-ĸB signaling evidenced by kinase phosphorylation in PBMCs suggests the involvement of these pathways in the regulation of the galectin-affected immune cell functions. Discussion: These findings provide further evidence on how placenta-specific galectins assist in the establishment and maintenance of a proper immune environment during a healthy pregnancy.

Functional Connectivity Lateralisation Shift of Resting State Networks is Linked to Visuospatial Memory and White Matter Microstructure in Relapsing-Remitting Multiple Sclerosis.

Laterality patterns of resting state networks (RSN) change in various neuropsychiatric conditions. Multiple sclerosis (MS) causes neuro-cognitive symptoms involving dysfunctional large-scale brain networks. Yet, whether healthy laterality patterns of RSNs are maintained in MS and whether altered laterality patterns explain disease symptoms has not been explicitly investigated. We analysed functional MRI and diffusion tensor imaging data from 24 relapsing-remitting MS patients and 25 healthy participants. We performed group-level independent component analysis and used dual regression to estimate individual versions of well-established RSNs. Voxelwise laterality indices were calculated for each RSN. Group differences were assessed via a general linear model-based approach. The relationship between functional laterality and white matter microstructural asymmetry was assessed using Tract-Based Spatial Statistics. Spearman's correlation was calculated between laterality indices and Brief International Cognitive Assessment for Multiple Sclerosis scores. Functional laterality of the dorsal attention network showed a significant leftward shift in the MS group in the posterior intraparietal sulcus (p < 0.033). Default-mode network laterality showed a significant leftward shift in the MS group in the angular gyrus (p < 0.005). Diminished dorsal attention network laterality was associated with increased fractional anisotropy asymmetry in the superior longitudinal fasciculus (p < 0.02). In the default-mode network, leftward laterality of the angular gyrus was associated with higher BVMT-R scores (R = - 0.52, p < 0.023). Our results confirm previous descriptions of RSN dysfunction in relapsing-remitting MS and show that altered functional connectivity lateralisation patterns of RSNs might contibute to cognitive performance and structural remodellation even in patients with mild clinical symptoms.