Psychiatric symptoms and TDP-43 pathology in amyotrophic lateral sclerosis.

BACKGROUND: ALS is not a pure motor neuron disease but co-occurs with cognitive impairment and psychiatric symptoms. The neuropathological origin of the psychiatric symptoms is unclear. This study examined the association between the psychiatric symptoms and neuropathology of ALS. METHODS: We investigated the clinicopathological characteristics of 15 autopsy cases of ALS, including neuronal loss, gliosis, and the burden of TDP-43 pathology. We divided TDP-43-positive structures by morphology into four categories (neuronal cytoplasmic inclusion, dystrophic neurite, dot, and glial cytoplasmic inclusion) and gave each a semiquantitative score in nine brain regions. Braak neurofibrillary tangle stage, Thal amyloid phase, Lewy-related pathology, and argyrophilic grains were also assessed. RESULTS: Of the 15 ALS patients, seven had presented with psychiatric symptoms and eight had not. Significantly higher TDP-43 pathology scores were found in the group with psychiatric symptoms in the temporal tip, transentorhinal cortex, entorhinal cortex, subiculum, and the hippocampal CA1 region and dentate gyrus. Cognitive impairment was not significantly associated with the degree of TDP-43 pathology. There were no significant differences in the degree of neuronal loss/gliosis or in other concurrent pathologies between patients with and without psychiatric symptoms. Morphological evaluation showed that neuronal cytoplasmic inclusions, dystrophic neurites, and dots tended to be more common in the group with psychiatric symptoms. CONCLUSION: Psychiatric symptoms in ALS may be related to TDP-43 pathology in the perforant pathway. (224 words).

Temporal dynamics of N-hydroxypipecolic acid and salicylic acid pathways in the disease response to powdery mildew in wheat.

Wheat (Triticum aestivum) is a major staple crop worldwide, and its yields are significantly threatened by wheat powdery mildew (Blumeria graminis f. sp. tritici). Enhancing disease resistance in wheat is crucial for meeting global food demand. This study investigated the disease response in wheat, focusing on the bioactive small molecules salicylic acid (SA), pipecolic acid (Pip), and N-hydroxypipecolic acid (NHP), to provide new insights for molecular breeding. We found that endogenous levels of SA, Pip, and NHP significantly increased in infected plants, with Pip and NHP levels rising earlier than those of SA. Notably, the rate of increase of NHP was substantially higher than that of SA. The gene expression levels of SARD1 and CBP60g, which are transcription factors for SA, Pip, and NHP biosynthesis, increased significantly during the early stages of infection. We also found that during the later stages of infection, the expression of ALD1, SARD4, and FMO1, which encode enzymes for Pip and NHP biosynthesis, dramatically increased. Additionally, ICS1, which encodes a key enzyme involved in SA biosynthesis, also showed increased expression during the later stages of infection. The temporal changes in ICS1 transcription closely mirrored the behavior of endogenous SA levels, suggesting that the ICS pathway is the primary route for SA biosynthesis in wheat. In conclusion, our results suggest that the early accumulation of Pip and NHP cooperates with SA in the disease response against wheat powdery mildew infection.

Uncoupling endocardial bundles coupled by an epicardial bundle in the left atrium and pulmonary veins.

Uncoupling of the endocardial bundles in the left atrium was suggested during modified posterior wall isolation. Although this fact may not be observed because of the possible bridging conduction by epicardial bundles in humans, partially failed transmural ablation in the atrial roof may have iatrogenically unveiled this fact.

Zinc-finger (ZiF) fold secreted effectors form a functionally diverse family across lineages of the blast fungus Magnaporthe oryzae.

Filamentous plant pathogens deliver effector proteins into host cells to suppress host defence responses and manipulate metabolic processes to support colonization. Understanding the evolution and molecular function of these effectors provides knowledge about pathogenesis and can suggest novel strategies to reduce damage caused by pathogens. However, effector proteins are highly variable, share weak sequence similarity and, although they can be grouped according to their structure, only a few structurally conserved effector families have been functionally characterized to date. Here, we demonstrate that Zinc-finger fold (ZiF) secreted proteins form a functionally diverse effector family in the blast fungus Magnaporthe oryzae. This family relies on the Zinc-finger motif for protein stability and is ubiquitously present in blast fungus lineages infecting 13 different host species, forming different effector tribes. Homologs of the canonical ZiF effector, AVR-Pii, from rice infecting isolates are present in multiple M. oryzae lineages. Wheat infecting strains of the fungus also possess an AVR-Pii like allele that binds host Exo70 proteins and activates the immune receptor Pii. Furthermore, ZiF tribes may vary in the proteins they bind to, indicating functional diversification and an intricate effector/host interactome. Altogether, we uncovered a new effector family with a common protein fold that has functionally diversified in lineages of M. oryzae. This work expands our understanding of the diversity of M. oryzae effectors, the molecular basis of plant pathogenesis and may ultimately facilitate the development of new sources for pathogen resistance.

Identification of the causal mutation in early heading mutant of bread wheat (Triticum aestivum L.) using MutMap approach.

In bread wheat (Triticum aestivum L.), fine-tuning the heading time is essential to maximize grain yield. Photoperiod-1 (Ppd-1) and VERNALIZATION 1 (Vrn-1) are major genes affecting photoperiod sensitivity and vernalization requirements, respectively. These genes have predominantly governed heading timing. However, Ppd-1 and Vrn-1 significantly impact heading dates, necessitating another gene that can slightly modify heading dates for fine-tuning. In this study, we developed an early heading mutant from the ethyl methanesulfonate-mutagenized population of the Japanese winter wheat cultivar "Kitahonami." MutMap analysis identified a nonsense mutation in the clock component gene Wheat PHYTOCLOCK 1/LUX ARRHYTHMO (WPCL-D1) as the probable SNP responsible for the early heading mutant on chromosome 3D. Segregation analysis using F2 and F3 populations confirmed that plants carrying the wpcl-D1 allele headed significantly earlier than those with the functional WPCL-D1. The early heading mutant exhibited increased expression levels of Ppd-1 and circadian clock genes, such as WPCL1 and LATE ELONGATED HYPOCOTYL (LHY). Notably, the transcript accumulation levels of Ppd-A1 and Ppd-D1 were influenced by the copy number of the functional WPCL1 gene. These results suggest that a loss-of-function mutation in WPCL-D1 is the causal mutation for the early heading phenotype. Adjusting the functional copy number of WPCL1 will be beneficial in fine-tuning of heading dates. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-024-01478-5.

Vein of Marshall chemical ablation decreases atrial fibrillation drivers detected by CARTOFINDER.

INTRODUCTION: This study sought to elucidate the impact of vein of Marshall (VOM) chemical ablation on atrial fibrillation (AF) drivers by investigating the changes in CARTOFINDER mappings before and after VOM chemical ablation in patients with persistent AF. METHODS: This study included 23 consecutive patients undergoing catheter ablation for long-persistent AF (>18 months). VOM chemical ablation was performed following pulmonary vein isolation. CARTOFINDER and AF cycle length (AFCL) maps were created in the left atrium (LA) before and after VOM chemical ablation. The LA was divided into 8 segments, and the number of focal activation points with 6 or more repetitions was counted in each segment. RESULTS: The number of focal activation points was largest in the LA appendage (LAA). After VOM chemical ablation, the number of focal activation points in the LA decreased significantly (37 [interquartile range, IQR: 19-55] vs. 15 [IQR: 7-21], p < .001), and median AFCL was significantly prolonged (159 [147-168] vs. 164 [150-173] ms, p < .001). In the assessment of each segment, significant decreases in focal activation points were observed in the inferior, lateral, and anterior segments and LAA. Among the focal activation points disappearing after chemical ablation, the number in the non-ethanol-affected area was significantly larger than that in the affected area (13 [8-25] vs. 4 [1-10], p < .001). CONCLUSIONS: VOM chemical ablation decreases AF drivers detected by CARTOFINDER. Mechanisms other than direct myocardial damage are considered to contribute the attenuation of AF drivers.

An NLR paralog Pit2 generated from tandem duplication of Pit1 fine-tunes Pit1 localization and function.

NLR family proteins act as intracellular receptors. Gene duplication amplifies the number of NLR genes, and subsequent mutations occasionally provide modifications to the second gene that benefits immunity. However, evolutionary processes after gene duplication and functional relationships between duplicated NLRs remain largely unclear. Here, we report that the rice NLR protein Pit1 is associated with its paralogue Pit2. The two are required for the resistance to rice blast fungus but have different functions: Pit1 induces cell death, while Pit2 competitively suppresses Pit1-mediated cell death. During evolution, the suppression of Pit1 by Pit2 was probably generated through positive selection on two fate-determining residues in the NB-ARC domain of Pit2, which account for functional differences between Pit1 and Pit2. Consequently, Pit2 lost its plasma membrane localization but acquired a new function to interfere with Pit1 in the cytosol. These findings illuminate the evolutionary trajectory of tandemly duplicated NLR genes after gene duplication.

Immediate pharmacotherapy intensification after cardiac resynchronization therapy: incidence, characteristics, and impact.

AIMS: Cardiac resynchronization therapy (CRT) is an established treatment for drug-refractory heart failure (HF) in patients with left bundle branch block (LBBB). Acute haemodynamic improvement after CRT implantation may enable the intensification of HF medication soon thereafter. Immediate pharmacotherapy intensification (IPI) after CRT implantation achieves a synergetic effect, possibly leading to a better prognosis. This study aimed to explore the incidence, characteristics, and impact of IPI on real-world outcomes among CRT recipients with a history of hospitalization for acute HF. METHODS AND RESULTS: This multicentre retrospective study enrolled CRT recipients with LBBB morphology, a QRS width ≥120 ms, a left ventricular ejection fraction ≤35%, and New York Heart Association II-IV HF symptoms. All patients had previous HF hospitalizations within the previous year and received guideline-directed medical therapy before CRT implantation. Patient baseline characteristics, including HF medication, were collected. IPI was defined as the intensification of beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor antagonists within 30 days of CRT implantation. The primary endpoint was all-cause death or first hospitalization for HF; the secondary endpoint was all-cause death. We enrolled 194 patients (75% male; mean age, 65 ± 13 years; 78% with non-ischaemic cardiomyopathy). One hundred five (54%) patients received IPI. Patients who received IPI exhibited a significantly shorter QRS duration (159 ± 26 vs. 171 ± 32 ms; P = 0.004), higher estimated glomerular filtration rate (55.2 ± 20.0 vs. 47.8 ± 24.7 mL/min/1.73 m2; P = 0.022), and more dilated cardiomyopathy. During a median follow-up period of 29 months, 70 (36%) patients reached the primary endpoint and 42 (22%) patients died. Patients with IPI showed significantly better outcomes for the primary and secondary endpoints than patients without IPI. The volumetric responder ratio at 6 months after implantation was not significantly different between patients with and without IPI; however, patients who received IPI had reduced mortality even at 6 months after implantation. In the multivariate analysis, IPI was an independent predictor of the primary endpoint (hazard ratio, 0.51; 95% confidence interval, 0.27-0.97; P = 0.043). CONCLUSIONS: Immediate intensification of HF medication was achieved in 54% of CRT recipients and was significantly higher in patients without excessive QRS prolongation, preserved renal function, and dilated cardiomyopathy than others. In patients with LBBB morphology and QRS ≥ 120 ms, IPI was associated with a significantly better prognosis and fewer HF hospitalizations after CRT implantation than others.

Discrepancy of flowering time between genetically close sublineages of Aegilops umbellulata Zhuk.

Aegilops umbellulata Zhuk., a wild diploid wheat-related species, has been used as a genetic resource for several important agronomic traits. However, its genetic variations have not been comprehensively studied. We sequenced RNA from 114 accessions of Ae. umbellulata to evaluate DNA polymorphisms and phenotypic variations. Bayesian clustering and phylogenetic analysis based on SNPs detected by RNA sequencing revealed two divergent lineages, UmbL1 and UmbL2. The main differences between them were in the sizes of spikes and spikelets, and culm diameter. UmbL1 is divided into two sublineages, UmbL1e and UmbL1w. These genetic differences corresponded to geographic distributions. UmbL1e, UmbL1w, and UmbL2 are found in Turkey, Iran/Iraq, and Greece, respectively. Although UmbL1e and UmbL1w were genetically similar, flowering time and other morphological traits were more distinct between these sublineages than those between the lineages. This discrepancy can be explained by the latitudinal and longitudinal differences in habitats. Specifically, latitudinal clines of flowering time were clearly observed in Ae. umbellulata, strongly correlated with solar radiation in the winter season. This observation implies that latitudinal differences are a factor in differences in the flowering times of Ae. umbellulata. Differences in flowering time could influence other morphological differences and promote genetic divergence between sublineages.

Corticobasal degeneration with visual hallucination as an initial symptom: A case report.

Although the initial symptoms of corticobasal degeneration (CBD) are varied, psychiatric symptoms are uncommon. Here, we report the autopsy findings of a patient with early CBD who presented with hallucinations. A 68-year-old man developed memory loss and visions of bears and insects. Because of slow vertical eye movement, postural instability, and levodopa-unresponsive parkinsonism, the patient initially was clinically diagnosed with progressive supranuclear palsy. He died of a urinary tract infection 11 months after the onset of the disease. Histopathological examination revealed neuronal loss and gliosis, which were severe in the substantia nigra and moderate in the globus pallidus and subthalamic nucleus. Astrocytic plaques were scattered throughout the amygdala and premotor cortex. The superficial cortical layers lacked ballooned neurons and spongiosis, and tau deposition was greater in glia than in neurons. The amygdala contained a moderate number of argyrophilic grains and pretangles. Western blot analysis showed a 37-kDa band among the low-molecular-weight tau fragments. Because the CBD pathology was mild, we attributed the patient's visual hallucinations to the marked argyrophilic grain pathology. CBD can occur with psychiatric symptoms, including visual hallucinations, and argyrophilic grain pathology may be associated with psychiatric symptoms.

Atypical TDP-43 proteinopathy clinically presenting with progressive nonfluent aphasia: A case report.

Progressive nonfluent aphasia (PNFA) is a form of frontotemporal lobar degeneration (FTLD) caused by tau and transactive response DNA-binding protein of 43 kDa (TDP-43) accumulation. Here we report the autopsy findings of a 64-year-old right-handed man with an atypical TDP-43 proteinopathy who presented with difficulties with speech, verbal paraphasia, and dysphagia that progressed over the 36 months prior to his death. He did not show pyramidal tract signs until his death. At autopsy, macroscopic brain examination revealed atrophy of the left dominant precentral, superior, and middle frontal gyri and discoloration of the putamen. Spongiform change and neuronal loss were severe on the cortical surfaces of the precentral, superior frontal, and middle frontal gyri and the temporal tip. Immunostaining with anti-phosphorylated TDP-43 revealed neuronal cytoplasmic inclusions and long and short dystrophic neurites in the frontal cortex, predominantly in layers II, V, and VI of the temporal tip, amygdala, and transentorhinal cortex. Immunoblot analysis of the sarkosyl-insoluble fractions showed hyperphosphorylated TDP-43 bands at 45 kDa and phosphorylated C-terminal fragments at approximately 25 kDa. The pathological distribution and immunoblot band pattern differ from the major TDP-43 subtype and therefore may represent a new FTLD-TDP phenotype.

Unidirectional conduction characterizing epicardial connections in patients with atrial tachyarrhythmias.

INTRODUCTION: Electrophysiological characteristics of epicardial connections (ECs) in atria and pulmonary veins (PVs) are unclear despite their important contributions to atrial fibrillation (AF). Unidirectional conduction associated with source-sink mismatch can occur in ECs due to their fine fibers with abrupt changes in orientation. We detailed the prevalence and electrophysiological characteristics of unidirectional conduction in the atria and investigated its association with the clinical manifestation of AF. METHODS: This study retrospectively reviewed electrophysiological studies and radiofrequency catheter ablation in 261 consecutive patients with AF. RESULTS: Unidirectional conduction was observed during ablation encircling the PVs in eight (3.1%) patients, and all occurred in the suspected (N = 4) or definitively (N = 4) recognized ECs. These ECs included three intercaval bundles, four septopulmonary bundles, and one Marshall bundle, and were first manifested in a second procedure in 6 (75%) patients. The unidirectional property was from PV to atrium (exit conduction) in all intercaval bundles and three septopulmonary bundles, and from atrium to PV (entrance conduction) in the remaining two bundles. Intercaval bundles acted as a limb of bi-atrial macro-reentrant tachycardia (50%, three of the six including previous cases). Ablation of the exit outside the PVs, including the right atrium, eliminated ECs in three (38%) patients. All patients remain free from arrhythmia recurrence after a mean 13-month follow-up. CONCLUSION: A unidirectional conduction property was closely associated with the EC, as estimated by histological findings. Recognition of this fact by electrophysiologists may help to clarify mechanisms for AF and atrial tachycardia and guide the creation of efficient and safe ablation lesion sets.