Task-specific contribution of the right posterior cerebellum to language processing in healthy individuals

Clinical and neuroscientific studies in healthy volunteers have established that the cerebellum contributes to language comprehension and production. Yet most evidence is correlational and the exact role of the cerebellum remains unclear. The aim of this study was to investigate the role of the right cerebellum in unimpaired language comprehension and production using non-invasive brain stimulation. In this double-blind, sham-controlled experiment, thirty-six healthy participants received anodal or sham transcranial direct current (tDCS) stimulation to the right cerebellum while performing a lexical decision, sentence comprehension, verbal fluency and language-unrelated control task. Results showed that anodal relative to sham tDCS caused faster manual responses in the lexical decision task. Additional exploratory analyses suggest load-specific performance modulation in the sentence comprehension and lexical decision task, with tDCS improving performance in low-load trials of the sentence comprehension task and high-load trials in the lexical decision task. Overall, our findings provide evidence for the involvement of the right posterior cerebellum in comprehension-based language tasks requiring a manual response. Further research is needed to dissociate the influence of task difficulty and timing of the underlying cognitive processes.

Association of the IRF6 rs2235371 and rs861019 Polymorphisms with Non-Syndromic Cleft Lip with or without Cleft Palate in the Yakut Population

Background: Non-syndromic cleft lip with or without cleft palate (NSCL/P) is one of the most common birth defects. NSCL/P can be broadly divided into cleft lip only (CLO), cleft palate only (CPO), and cleft lip with cleft palate (CLP) based on clinical presentation. The aim of this study was to investigate the relationship between the IRF6 gene polymorphisms and non-syndromic cleft lip with or without cleft palate (NSCL/P) in the Yakut population. Methods and Results: In 23 OFC patients and 58 unrelated control subjects from the Yakut population, we tested two SNPs (rs2235371 and rs861019) with a minor allele frequency of more than 5% in the candidate gene IRF6. We found that the SNP marker rs861019 showed significant differences in allele frequencies (OR=2.07, 95%CI: 1.01–4.23, P=0.04) between the NSCL/P patients and the comparison group. Analysis of allele frequencies for rs861019 SNP in subgroups showed that there was a difference in the frequency between CLP and control (OR=5, 95% CI: 1.61-15.53, P=0.11); however, this result was not significant. Genotype analysis showed significant differences in patients from the CLP subgroup in comparison with controls for homozygous (AA compared with GG) (OR=9.00, 95% CI: 1.03–78.58, P=0.03), heterozygous (GA compared with GG) (OR=5.50, 95% CI: 1.05-28.75, P=0.04,), recessive (GG compared with GA + AA) (OR=6.67, 95% CI: 1.61-27.58; RR=4.78, 95% CI: 1.42–16.10, P=0.008,) and co-dominant (GG compared with GA, compared with AA) (P=0.02) inheritance models. Diplotype analysis showed that the NSCL/P group was more likely to have the [CC]-[GG] diplotype than the comparison group. This diplotype carries the risk GG genotype (rs861019) (30.4%) and does not carry the risk T allele(rs2235371). In the CLP subgroup, two diplotypes ([CT]-[GG] and [CC]-[GG]) were found more often than in the comparison group. Both diplotypes carry the risk GG genotype(rs861019; 33.3%). In the CPO subgroup, the [CT]-[GG] diplotype was more common. In the CLO subgroup, only two diplotypes ([CC]-[GA] and [CC]-[GG]) were found, both of which were more common than in the comparison group (75% and 25%).. It is likely that these results for the CLO and CPO subgroups were influenced by the small size of both samples. Unlike the NSCL/P and CLP groups, in these samples, diplotypes with the homozygous genotype GG (rs861019) without the homozygous genotype TT (rs2235371) were more common. Diplotypes with a homozygous genotype of the TT risk allele were not found in the studied groups except for the comparison group, where the [TT]-[AA] diplotype was represented by a low frequency (0.17%). Conclusion: The present study provides strong statistical support (for the first time to our knowledge) that genetic variants of the IRF6 rs861019 SNP are associated with NSCL/P in Yakuts.

Blood Groups of Recipients of COVID-19 Convalescent plasma

Introduction/Objective COVID -19 Convalescent plasma therapy (CCP) is under an FDA Emergency Use Authorization to treat hospitalized patients with COVID-19. However, being ill enough to require hospitalization for COVID-19 is a negative outcome. There is also contradictory literature on whether ABO blood group is associated with worse outcomes with COVID-19 disease. Therefore, we share a regional Veterans Administration Medical Center (VAMC) experience comparing the blood groups of patients intended to receive CCP to a control group of patients positive for SARS-CoV-2. Methods/Case Report A retrospective review of all patients who had CCP ordered in the year 2020 was performed to identify the blood group of these patients, which was compared to a control population of positive patients early in the pandemic (March 17th, 2020 to May 20th, 2020). Results (if a Case Study enter NA) A total of 15 patients had CCP ordered as part of their care with an age range of 56-85 (average 69.7) years of age, entirely male composition, and a racial breakdown of 13 African Americans (86.7%), 1 Caucasian American (6.7%), and 1 Asian American (6.7%). The blood group distribution amongst these 15 patients for CCP was 1 AB+ (6.7%), 5 A+ (33.3%), 4 B+ (26.7%), and 5 O+ (33.3%). The unrelated control population consisted of 81 SARS-CoV-2 positive patients whose blood groups were distributed as 3 group AB (3.7%), 21 group A (25.9%), 15 group B (18.5%), and 42 group O (51.8%). A Chi squared test did not show a statistically significant difference between the two groups in ABO composition. Conclusion The ABO proportions of patients for whom CCP was ordered compared to the control group was not statistically significant. This provides support to the literature arguing that ABO may not be related to worse outcomes such as hospitalization or need for CCP transfusion.

Investigating the link between linguistic and non-linguistic cognitive control in bilinguals using Laplacian-transformed event related potentials

Bilinguals’ need to suppress the activation of their other language while speaking has been proposed to result in enhanced cognitive control abilities outside of language. Several studies therefore suggest shared cognitive control processes across linguistic and non-linguistic tasks. Here we investigate this potential overlap using scalp electroencephalographic recordings and the Laplacian transformation, providing an estimation of the current source density and allowing to separate EEG components in space. Fourteen Spanish-English bilinguals performed a pictureword matching task contrasting incongruent trials using cross-linguistic false cognates (e.g., a picture- foot, overlaid with distractor text: English word- PIE, i.e. the false cognate for the Spanish “pie” meaning “foot”) with congruent trials (matching English picture names and words, i.e., picture-foot, overlaid text: English word FOOT), and an unrelated control condition. In addition, participants performed an arrow-version of the Eriksen flanker task. Worse behavioral performance was observed in incongruent compared to congruent trials in both tasks. In the non-linguistic task, we replicated the previously observed congruency effect on a medialfrontal ERP peaking around 50 ms before EMG onset. A similar ERP was present in the linguistic task, was sensitive to congruency, and peaked earlier, around 150ms before EMG onset. In addition, another component was found in the linguistic task at a left lateralized anterior frontal site peaking around 200 ms before EMG onset, but was absent in the non-linguistic task. Our results suggest a partial overlap between linguistic and non-linguistic cognitive control processes and that linguistic conflict resolution may engage additional left anterior frontal control processes.

A Missense Variant in SLC39A4 in a Litter of Turkish Van Cats with Acrodermatitis Enteropathica

In a litter of Turkish Van cats, three out of six kittens developed severe signs of skin disease, diarrhea, and systemic signs of stunted growth at 6 weeks of age. Massive secondary infections of the skin lesions evolved. Histopathological examinations showed a mild to moderate hyperplastic epidermis, covered by a thick layer of laminar to compact, mostly parakeratotic keratin. The dermis was infiltrated with moderate amounts of lymphocytes and plasma cells. Due to the severity of the clinical signs, one affected kitten died and the other two had to be euthanized. We sequenced the genome of one affected kitten and compared the data to 54 control genomes. A search for private variants in the two candidate genes for the observed phenotype, MKLN1 and SLC39A4, revealed a single protein-changing variant, SLC39A4:c.1057G>C or p.Gly353Arg. The solute carrier family 39 member 4 gene (SLC39A4) encodes an intestinal zinc transporter required for the uptake of dietary zinc. The variant is predicted to change a highly conserved glycine residue within the first transmembrane domain, which most likely leads to a loss of function. The genotypes of the index family showed the expected co-segregation with the phenotype and the mutant allele was absent from 173 unrelated control cats. Together with the knowledge on the effects of SLC39A4 variants in other species, these data suggest SLC39A4:c.1057G>C as candidate causative genetic variant for the phenotype in the investigated kittens. In line with the human phenotype, we propose to designate this disease acrodermatitis enteropathica (AE).

Altered neuronal physiology, development, and function associated with a common chromosome 15 duplication involving CHRNA7

Background Copy number variants (CNVs) linked to genes involved in nervous system development or function are often associated with neuropsychiatric disease. While CNVs involving deletions generally cause severe and highly penetrant patient phenotypes, CNVs leading to duplications tend instead to exhibit widely variable and less penetrant phenotypic expressivity among affected individuals. CNVs located on chromosome 15q13.3 affecting the alpha-7 nicotinic acetylcholine receptor subunit (CHRNA7) gene contribute to multiple neuropsychiatric disorders with highly variable penetrance. However, the basis of such differential penetrance remains uncharacterized. Here, we generated induced pluripotent stem cell (iPSC) models from first-degree relatives with a 15q13.3 duplication and analyzed their cellular phenotypes to uncover a basis for the dissimilar phenotypic expressivity. Results The first-degree relatives studied included a boy with autism and emotional dysregulation (the affected proband-AP) and his clinically unaffected mother (UM), with comparison to unrelated control models lacking this duplication. Potential contributors to neuropsychiatric impairment were modeled in iPSC-derived cortical excitatory and inhibitory neurons. The AP-derived model uniquely exhibited disruptions of cellular physiology and neurodevelopment not observed in either the UM or unrelated controls. These included enhanced neural progenitor proliferation but impaired neuronal differentiation, maturation, and migration, and increased endoplasmic reticulum (ER) stress. Both the neuronal migration deficit and elevated ER stress could be selectively rescued by different pharmacologic agents. Neuronal gene expression was also dysregulated in the AP, including reduced expression of genes related to behavior, psychological disorders, neuritogenesis, neuronal migration, and Wnt, axonal guidance, and GABA receptor signaling. The UM model instead exhibited upregulated expression of genes in many of these same pathways, suggesting that molecular compensation could have contributed to the lack of neurodevelopmental phenotypes in this model. However, both AP- and UM-derived neurons exhibited shared alterations of neuronal function, including increased action potential firing and elevated cholinergic activity, consistent with increased homomeric CHRNA7 channel activity. Conclusions These data define both diagnosis-associated cellular phenotypes and shared functional anomalies related to CHRNA7 duplication that may contribute to variable phenotypic penetrance in individuals with 15q13.3 duplication. The capacity for pharmacological agents to rescue some neurodevelopmental anomalies associated with diagnosis suggests avenues for intervention for carriers of this duplication and other CNVs that cause related disorders.

Moral reframing of messages about mask-wearing during the COVID-19 pandemic

Despite evidence in support of the benefits of wearing masks, attitudes about mask-wearing during the COVID-19 pandemic became politicized, and therefore tied with political values and group identities. When communicating about political issues, messages targeted to resonate with the core values of the receiver may be effective, an approach known as moral reframing. We first tested the relationships between moral values and mask-wearing in a sample (N=540) of self-identified liberals, conservatives, and moderates in the United States. Anti-mask attitudes were stronger in conservatives, and were associated with increased concerns for in-group loyalty, national identity, and personal liberty. We then crafted messages about the benefits of mask-wearing framed to resonate with these moral concerns, and in a pre-registered study of N=597 self-identified U.S. conservatives, tested the effect of moral reframing on anti-mask attitudes and behaviors. We found that messages framed in terms of loyalty, with appeals to the protection of the community and America, were effective in reducing anti-mask beliefs, compared with unrelated control messages and messages delivering purely scientific information, and that these changes in belief persisted for at least one week. Exploratory analyses showed that participants who saw loyalty-framed messages reported wearing masks in public more frequently in the subsequent week. These data provide evidence that moral reframing of messages about politicized issues can be effective, and specifically that framing messages about health behaviors in terms of group loyalty may be the most productive way of communicating with conservative audiences.

Synthetic Fibrin-Derived Bβ15-42 Peptide Delays Thrombus Resolution in a Mouse Model

Objective: Thrombus resolution is driven by leukocyte recruitment and thrombus angiogenesis. An effective inhibition of leukocyte transmigration in vitro is mediated by naturally occurring peptide Bβ 15-42 , which is a competitive inhibitor of the interaction between the N-terminus of the fibrin beta chain and vascular endothelial cadherin. We investigated the effect of Bβ 15-42 on thrombus resolution in a murine stagnant flow venous thrombosis model and studied Bβ 15-42 levels in venous thrombus of human patients. Approach and Results: We investigated 2 mouse models of subtotal inferior vena cava ligation. In the first model, we ligated the inferior vena cava. In the second model, we additionally ligated all visible inferior vena cava side and back branches. Study groups of 8 to 12 weeks old BALB/c mice were then injected intraperitoneal twice daily with 2.4 mg/kg of Bβ 15-42 , unrelated control peptide or saline. Bβ 15-42 attenuated thrombus resolution after inferior vena cava ligation. We observed decreased numbers of thrombus macrophages and microvessels and less urokinase-type plasminogen activator expression in mice that were injected with Bβ 15-42 . Mechanistic experiments demonstrated that Bβ 15-42 blocks monocyte transmigration through an endothelial cell monolayer. Measurements of Bβ 15-42 in red clot and plasma of chronic thromboembolic pulmonary hypertension cases indicated high concentrations compared with controls. Conclusions: Our data suggest that excess of the fibrin fragment Bβ 15-42 misguides thrombus resolution, presumably by inhibiting vascular endothelial cadherin-mediated leukocyte migration during early thrombus organization.

An ERP Study on the Role of Phonological Processing in Reading Two-Character Compound Chinese Words of High and Low Frequency

Unlike in English, the role of phonology in word recognition in Chinese is unclear. In this event-related potential experiment, we investigated the role of phonology in reading both high- and low-frequency two-character compound Chinese words. Participants executed semantic and homophone judgment tasks of the same precede-target pairs. Each pair of either high- or low-frequency words were either unrelated (control condition) or related semantically or phonologically (homophones). The induced P200 component was greater for low- than for high-frequency word-pairs both in semantic and phonological tasks. Homophones in the semantic judgment task and semantically-related words in the phonology task both elicited a smaller N400 than the control condition, word frequency-independently. However, for low-frequency words in the phonological judgment task, it was found that the semantically related pairs released a significantly larger P200 than the control condition. Thus, the semantic activation of both high- and low-frequency words may be no later than phonological activation.

Polymorphisms in mitochondrial ribosomal protein S5 (MRPS5) are associated with leprosy risk in Chinese

Leprosy is an infectious disease caused by Mycobacterium leprae (M. leprae), with about 210,000 new cases per year worldwide. Although numerous risk loci have been uncovered by genome-wide association studies, the effects of common genetic variants are relatively modest. To identify possible new genetic locus involved in susceptibility to leprosy, whole exome sequencing was performed for 28 subjects including 14 patients and 12 unaffected members from 8 leprosy-affected families as well as another case and an unrelated control, and then the follow-up SNP genotyping of the candidate variants was studied in case-control sample sets. A rare missense variant in mitochondrial ribosomal protein S5 (MRPS5), rs200730619 (c. 95108402T>C [p. Tyr137Cys]) was identified and validated in 369 cases and 270 controls of Chinese descent (Padjusted = 0.006, odds ratio [OR] = 2.74) as a contributing factor to leprosy risk. Moreover, the mRNA level of MRPS5 was downregulated in M. leprae sonicate-stimulated peripheral blood mononuclear cells. Our results indicated that MRPS5 may be involved in leprosy pathogenesis. Further studies are needed to determine if defective MRPS5 could lead to impairment of energy metabolism of host immune cells, which could further cause defect in clearing M. leprae and increase susceptibility to infection.