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peutic implications for both diseases.

In this cross-sectional study, we identified patients with arhinia who meet the full genetic and epigenetic criteria for FSHD2 and display the molecular hallmark of FSHD-DUX4 de-repression and expression in vitro-but who do not manifest with the typical clinicopathologic phenotype of FSHD2. The distinct dichotomy between FSHD2 and arhinia phenotypes despite an otherwise poised DUX4 locus implies the presence of novel disease-modifying factors that seem to operate as a switch, resulting in one phenotype and not the other. Identification and further understanding of these disease-modifying factors will provide valuable insight with therapeutic implications for both diseases.Deep cerebral venous thrombosis is an uncommon condition, which usually produces headache, altered consciousness, and ocular movement abnormality. Parkinsonism occasionally occurs when there is basal ganglia involvement. We report a case of a 78-year-old man who presented with a rapidly progressive parkinsonism with poor response to dopaminergic therapy. The patient had bilateral and symmetrical hypokinesia, rigidity, and marked gait impairment with festination. Brain MRI showed bilateral thalamic hyperintensity on T2-weighted and FLAIR sequences, with right thalamic and intraventricular hemorrhage due to straight sinus thrombosis. Angiography revealed an arteriovenous malformation in the quadrigeminal cistern with afferent supply from the posterior cerebral arteries, as well as partial thrombosis of the vein of Galen and half of the straight sinus. No predisposing factor for thrombosis was found. Given the location and size of the malformation, and the substantial amount of thalamic and intraventricular hemorrhage, conservative management was decided, with slow but progressive gait improvement. The presence of deep cerebral venous thrombosis should be suspected in cases of rapidly progressive parkinsonism with cognitive decline. As in this case, thrombosis may be secondary to a deep arteriovenous malformation, a very rare occurrence that may require specific therapy.

Limbic-predominant age-related Tar DNA binding protein 43 (TDP-43) encephalopathy neuropathologic change (LATE-NC) is present in ≈25% of older persons' brains and is strongly associated with cognitive impairment. Hippocampal sclerosis (HS) pathology is often comorbid with LATE-NC, but the clinical and pathologic correlates of HS in LATE-NC are not well understood.

This retrospective autopsy cohort study used data derived from the National Alzheimer's Coordinating Center Neuropathology Data Set, which included neurologic status, medical histories, and neuropathologic results. All autopsies were performed in 2014 or later. Among participants with LATE-NC, those who also had HS pathology were compared with those without HS with regard to candidate risk factors or common underlying diseases. Statistical significance was set at nominal

< 0.05 in this exploratory study.

A total of 408 participants were included (n = 221 were LATE-NC+/HS-, n = 145 were LATE-NC+/HS+, and n = 42 were LATE-NC-/HS+). https://www.selleckchem.com/products/brd7389.html Most ofTE-NC stage 1) and more likely to have neocortical TDP-43 proteinopathy (LATE-NC stage 3) (

< 0.001). LATE-NC+ brains with HS also tended to have more severe circle of Willis atherosclerosis and arteriolosclerosis pathologies.

In this cohort skewed toward participants with severe dementia, LATE-NC+ HS pathology was not associated with seizures or with Alzheimer-type pathologies. Rather, the presence of comorbid HS pathology was associated with more widespread TDP-43 proteinopathy and with more severe non-β-amyloid vessel wall pathologies.

In this cohort skewed toward participants with severe dementia, LATE-NC+ HS pathology was not associated with seizures or with Alzheimer-type pathologies. Rather, the presence of comorbid HS pathology was associated with more widespread TDP-43 proteinopathy and with more severe non-β-amyloid vessel wall pathologies.There is an increasing body of evidence describing an association between anti-Kelch-like protein 11 (KLHL11) encephalitis and various tumors such as seminoma. However, when the diagnosis of neoplasia is uncertain and the clinical syndrome resembles those caused by other etiologies, the possibility of anti-KLHL11 encephalitis may not be obvious during early clinical evaluations. We present the case of a 68-year-old man with clinical features of anti-KLHL11 encephalitis, in whom no clear signs of an active neoplasia could be found. However, a burnt-out germ cell tumor was suspected. This case highlights the importance of having a high clinical suspicion for anti-KLHL11 encephalitis in patients who exhibit symptoms and signs, even in the absence of an active tumor.

Little is known about the effect of education or other indicators of cognitive reserve on the rate of reversion from mild cognitive impairment (MCI) to normal cognition (NC) or the relative rate (RR) of reversion from MCI to NC vs progression from MCI to dementia. Our objectives were to (1) estimate transition rates from MCI to NC and dementia and (2) determine the effect of age,

, and indicators of cognitive reserve on the RR of reversion vs progression using multistate Markov modeling.

We estimated instantaneous transition rates between NC, MCI, and dementia after accounting for transition to death across up to 12 assessments in the Nun Study, a cohort study of religious sisters aged 75+ years. We estimated RRs of reversion vs progression for age,

, and potential cognitive reserve indicators education, academic performance (high school grades), and written language skills (idea density, grammatical complexity).

Of the 619 participants, 472 were assessed with MCI during the study period. Of these 4 into statistical modeling. These results may inform the design and interpretation of MCI clinical trials, given that a substantial proportion of participants may experience improvement without intervention.

Knowledge of frequent reversion from MCI to NC may alleviate concerns of inevitable cognitive decline in those with MCI. Identification of characteristics predicting the rate of reversion from MCI to NC vs progression from MCI to dementia may guide population-level interventions targeting these characteristics to prevent or postpone MCI and dementia. Research on cognitive trajectories would benefit from incorporating predictors of reverse transitions and competing events, such as death, into statistical modeling. These results may inform the design and interpretation of MCI clinical trials, given that a substantial proportion of participants may experience improvement without intervention.We apply the theory of learning to physically renormalizable systems in an attempt to outline a theory of biological evolution, including the origin of life, as multilevel learning. We formulate seven fundamental principles of evolution that appear to be necessary and sufficient to render a universe observable and show that they entail the major features of biological evolution, including replication and natural selection. It is shown that these cornerstone phenomena of biology emerge from the fundamental features of learning dynamics such as the existence of a loss function, which is minimized during learning. We then sketch the theory of evolution using the mathematical framework of neural networks, which provides for detailed analysis of evolutionary phenomena. To demonstrate the potential of the proposed theoretical framework, we derive a generalized version of the Central Dogma of molecular biology by analyzing the flow of information during learning (back propagation) and predicting (forward propagation) the environment by evolving organisms. The more complex evolutionary phenomena, such as major transitions in evolution (in particular, the origin of life), have to be analyzed in the thermodynamic limit, which is described in detail in the paper by Vanchurin et al. [V. Vanchurin, Y. I. Wolf, E. V. Koonin, M. I. Katsnelson, Proc. Natl. Acad. Sci. U.S.A. 119, 10.1073/pnas.2120042119 (2022)].Spatial tuning of neocortical pyramidal cells has been observed in diverse cortical regions and is thought to rely primarily on input from the hippocampal formation. Despite the well-studied hippocampal place code, many properties of the neocortical spatial tuning system are still insufficiently understood. In particular, it has remained unclear how the topography of direct anatomical connections from hippocampus to neocortex affects spatial tuning depth, and whether the dynamics of spatial coding in the hippocampal output region CA1, such as remapping in novel environments, is transmitted to the neocortex. Using mice navigating through virtual environments, we addressed these questions in the mouse medial prefrontal cortex, which receives direct input from the hippocampus. We found a rapidly emerging prefrontal representation of space in the absence of task rules, which discriminates familiar from novel environments and is reinstated upon reexposure to the same familiar environment. Topographical analysis revealed a dorsoventral gradient in the representation of the own position, which runs opposite to the innervation density of hippocampal inputs. Jointly, these results reveal a dynamically emerging and topographically organized prefrontal place code during spontaneous locomotion.The core plant microprocessor consists of DICER-LIKE 1 (DCL1), SERRATE (SE), and HYPONASTIC LEAVES 1 (HYL1) and plays a pivotal role in microRNA (miRNA) biogenesis. However, the proteolytic regulation of each component remains elusive. Here, we show that HYL1-CLEAVAGE SUBTILASE 1 (HCS1) is a cytoplasmic protease for HYL1-destabilization. HCS1-excessiveness reduces HYL1 that disrupts miRNA biogenesis, while HCS1-deficiency accumulates HYL1. Consistently, we identified the HYL1K154A mutant that is insensitive to the proteolytic activity of HCS1, confirming the importance of HCS1 in HYL1 proteostasis. Moreover, HCS1-activity is regulated by light/dark transition. Under light, cytoplasmic CONSTITUTIVE PHOTOMORPHOGENIC 1 (COP1) E3 ligase suppresses HCS1-activity. COP1 sterically inhibits HCS1 by obstructing HYL1 access into the catalytic sites of HCS1. In contrast, darkness unshackles HCS1-activity for HYL1-destabilization due to nuclear COP1 relocation. Overall, the COP1-HYL1-HCS1 network may integrate two essential cellular pathways the miRNA-biogenetic pathway and light signaling pathway.Predicting and disrupting transmission of human parasites from wildlife hosts or vectors remains challenging because ecological interactions can influence their epidemiological traits. Human schistosomes, parasitic flatworms that cycle between freshwater snails and humans, typify this challenge. Human exposure risk, given water contact, is driven by the production of free-living cercariae by snail populations. Conventional epidemiological models and management focus on the density of infected snails under the assumption that all snails are equally infectious. However, individual-level experiments contradict this assumption, showing increased production of schistosome cercariae with greater access to food resources. We built bioenergetics theory to predict how resource competition among snails drives the temporal dynamics of transmission potential to humans and tested these predictions with experimental epidemics and demonstrated consistency with field observations. This resource-explicit approach predicted an intense pulse of transmission potential when snail populations grow from low densities, i.