Clinical Utility of LC-MS/MS for Blood Myo-Inositol in Patients with Acute Kidney Injury and Chronic Kidney Disease.

BACKGROUND: Diagnosing acute kidney injury (AKI) and chronic kidney disease (CKD) relies on creatinine, which lacks optimal diagnostic sensitivity. The kidney-specific proximal tubular enzyme myo-inositol oxygenase (MIOX) catalyzes the conversion of myo-inositol (MI) to D-glucuronic acid. We hypothesized that proximal tubular damage, which occurs in AKI and CKD, will decrease MIOX activity, causing MI accumulation. To explore this, we developed an LC-MS/MS assay to quantify plasma MI and assessed its potential in identifying AKI and CKD patients. METHODS: MI was quantified in plasma from 3 patient cohorts [normal kidney function (n = 105), CKD (n = 94), and AKI (n = 54)]. The correlations between MI and creatinine were determined using Deming regression and Pearson correlation and the impact of age, sex, and ethnicity on MI concentrations was assessed. Receiver operating characteristic curve analysis was employed to evaluate MI diagnostic performance. RESULTS: In volunteers with normal kidney function, the central 95th percentile range of plasma MI concentrations was 16.6 to 44.2 µM. Age, ethnicity, and sex showed minimal influence on MI. Patients with AKI and CKD exhibited higher median MI concentrations [71.1 (25th percentile: 38.2, 75th percentile: 115.4) and 102.4 (77, 139.5) µM], respectively. MI exhibited excellent sensitivity (98.9%) and specificity (100%) for diagnosing CKD. In patients with AKI, MI increased 32.9 (SD 16.8) h before creatinine. CONCLUSIONS: This study unveils MI as a potential renal biomarker, notably elevated in plasma during AKI and CKD. Plasma MI rises 33 h prior to serum creatinine, enabling early AKI detection. Further validation and exploration of MI quantitation in kidney disease diagnosis is warranted.

The Value of Clinical Photographs in the Management of Traumatic Dental Injuries.

Purpose: The purpose of this study was to explore the perceived value of clinical photographs for traumatic dental injuries (TDIs). Methods: A survey was sent to members of the American Academy of Pediatric Dentistry (AAPD). The survey collected respondents' responses to case-based questions with and without photographs, and opinions about the value of photography for TDI. Results: A total of 496 respondents (5.8 percent response) completed the survey. Overall, no significant difference in correct answers was observed between cases with and without a photograph (P=0.09). The majority of respondents (82.2 percent) agreed that photographs should be taken for the management of TDIs, with 88.7 percent stating that the photographs aided in the diagnosis of TDIs. The majority of respondents acknowledged the time-saving (80.9 percent) and legal importance (77.0 percent) of photographs. Conclusion: Photographs should be taken in the management of traumatic dental injuries when possible for history and documentation purposes.

Hierarchical tricarboxylic acid cycle regulation by hepatocyte arginase 2 links the urea cycle to oxidative metabolism.

Urea cycle impairment and its relationship to obesity and inflammation remained elusive, partly due to the dramatic clinical presentation of classical urea cycle defects. We generated mice with hepatocyte-specific arginase 2 deletion (Arg2LKO) and revealed a mild compensated urea cycle defect. Stable isotope tracing and respirometry revealed hepatocyte urea and TCA cycle flux defects, impaired mitochondrial oxidative metabolism, and glutamine anaplerosis despite normal energy and glucose homeostasis during early adulthood. Yet during middle adulthood, chow- and diet-induced obese Arg2LKO mice develop exaggerated glucose and lipid derangements, which are reversible by replacing the TCA cycle oxidative substrate nicotinamide adenine dinucleotide. Moreover, serum-based hallmarks of urea, TCA cycle, and mitochondrial derangements predict incident fibroinflammatory liver disease in 106,606 patients nearly a decade in advance. The data reveal hierarchical urea-TCA cycle control via ARG2 to drive oxidative metabolism. Moreover, perturbations in this circuit may causally link urea cycle compromise to fibroinflammatory liver disease.

Feasibility, reproducibility, and accuracy of echocardiographic right ventricular systolic function assessments in childhood cancer survivors at risk for heart failure.

PURPOSE: We sought to assess the feasibility, reproducibility, and accuracy of conventional and newer echocardiographic measures of right ventricular (RV) systolic function in adolescent and young adult childhood cancer survivors treated with anthracyclines. METHODS: Echocardiography and cardiac magnetic resonance imaging (CMR) were acquired ≤60 days apart in prospectively recruited survivors and RV functional measures were quantitated by blinded observers. Repeat quantitation was performed in a subset to evaluate reproducibility. For each echocardiographic measure, Spearman correlations with CMR measures were calculated, and values in participants with CMR RV ejection fraction (RVEF) ≥48% and RVEF <48% were compared using two sample Wilcoxon rank-sum tests. RESULTS: Among 58 participants, mean age was 18.2 years (range 13.1-25.2) and five participants had CMR RVEF <48%. Intra- and inter-observer coefficients of variation were 8.2%-10.1% and 10.5%-12.0% for adjusted automated strain measures, and 5.2%-8.7% and 2.7% for 3D RVEF, respectively. No echocardiographic measures were significantly correlated with CMR RVEF; only tricuspid annular plane systolic excursion was correlated with CMR RV stroke volume (r = .392, p = .003). Participants with RV dysfunction had worse automated global longitudinal strain (-20.3% vs. -23.9%, p = .007) and free wall longitudinal strain (-23.7% vs. -26.7%, p = .09). CONCLUSIONS: Echocardiographic strain and 3D RV function measurements were feasible and reproducible in at-risk childhood cancer survivors. Although not associated with CMR RVEF in this population with predominantly normal RV function, automated strain measurements were more abnormal in participants with RV dysfunction, suggesting potential clinical utility of these measures.

Synaptotagmins 3 and 7 mediate the majority of asynchronous release from synapses in the cerebellum and hippocampus.

Neurotransmitter release consists of rapid synchronous release followed by longer-lasting asynchronous release (AR). Although the presynaptic proteins that trigger synchronous release are well understood, the mechanisms for AR remain unclear. AR is sustained by low concentrations of intracellular Ca2+ and Sr2+, suggesting the involvement of sensors with high affinities for both ions. Synaptotagmin 7 (SYT7) partly mediates AR, but substantial AR persists in the absence of SYT7. The closely related SYT3 binds Ca2+ and Sr2+ with high affinity, making it a promising candidate to mediate AR. Here, we use knockout mice to study the contribution of SYT3 and SYT7 to AR at cerebellar and hippocampal synapses. AR is dramatically reduced when both isoforms are absent, which alters the number and timing of postsynaptic action potentials. Our results confirm the long-standing prediction that SYT3 mediates AR and show that SYT3 and SYT7 act as dominant mechanisms for AR at three central synapses.

De novo gene synthesis by an antiviral reverse transcriptase.

Defense-associated reverse transcriptase (DRT) systems perform DNA synthesis to protect bacteria against viral infection, but the identities and functions of their DNA products remain largely unknown. Here we show that DRT2 systems encode an unprecedented immune pathway that involves de novo gene synthesis via rolling circle reverse transcription of a non-coding RNA (ncRNA). Programmed template jumping on the ncRNA generates a concatemeric cDNA, which becomes double-stranded upon viral infection. Remarkably, this DNA product constitutes a protein-coding, nearly endless ORF (neo) gene whose expression leads to potent cell growth arrest, thereby restricting the viral infection. Our work highlights an elegant expansion of genome coding potential through RNA-templated gene creation, and challenges conventional paradigms of genetic information encoded along the one-dimensional axis of genomic DNA.

An evaluation of mitomycin-containing reverse thermal gel for the treatment of low-grade upper tract urothelial carcinoma.

INTRODUCTION: Endoscopic management of upper tract urothelial carcinoma (UTUC) is increasingly relevant with greater detection of low-grade disease and guidelines recommending kidney preservation for low-risk disease. Historically, laser or thermal ablation has served as the primary tool for endoscopic management of UTUC, however, chemoablation is rapidly being developed to serve as a primary or adjuvant treatment option, which warrants review. AREAS COVERED: The current literature was reviewed to compare the outcomes and clinical utility of endoscopic treatment modalities for low-grade UTUC, with a focus on mitomycin-containing reverse thermal gel (UGN-101). EXPERT OPINION: The overall outcomes of mitomycin-containing gel therapy are promising, but adverse effects such as ureteral stricture call for careful consideration when using this treatment. We believe it is reasonable to consider use of mitomycin-containing gel as an adjuvant chemotherapy with endoscopic laser resection of low-grade upper tract urothelial carcinoma.

Targeted proteomic approach for quantification of collagen type I and type III in formalin-fixed paraffin-embedded tissue.

Collagen is the most abundant protein in mammals and a major structural component of the extracellular matrix (ECM). Changes to ECM composition occur as a result of numerous physiological and pathophysiological causes, and a common means to evaluate these changes is the collagen 3 (Col3) to collagen 1 (Col1) ratio. Current methods to measure the Col3/1 ratio suffer from a lack of specificity and often under- or over-estimate collagen composition and quantity. This manuscript presents a targeted liquid chromatography tandem mass spectrometry (LC-MS/MS) method for quantification of Col3 and Col1 in FFPE tissues. Using surrogate peptides to generate calibration curves, Col3 and Col1 are readily quantified in FFPE tissue sections with high accuracy and precision. The method is applied to several tissue types from both human and reindeer sources, demonstrating its generalizability. In addition, the targeted LC-MS/MS method permits quantitation of the hydroxyprolinated form of Col3, which has significant implications for understanding not only the quantity of Col3 in tissue, but also understanding of the pathophysiology underlying many causes of ECM changes. This manuscript presents a straightforward, accurate, precise, and generalizable method for quantifying the Col3/1 ratio in a variety of tissue types and organisms.

High-throughput gene expression analysis with TempO-LINC sensitively resolves complex brain, lung and kidney heterogeneity at single-cell resolution.

We report the development and performance of a novel genomics platform, TempO-LINC, for conducting high-throughput transcriptomic analysis on single cells and nuclei. TempO-LINC works by adding cell-identifying molecular barcodes onto highly selective and high-sensitivity gene expression probes within fixed cells, without having to first generate cDNA. Using an instrument-free combinatorial-indexing approach, all probes within the same fixed cell receive an identical barcode, enabling the reconstruction of single-cell gene expression profiles across as few as several hundred cells and up to 100,000+ cells per run. The TempO-LINC approach is easily scalable based on the number of barcodes and rounds of barcoding performed; however, for the experiments reported in this study, the assay utilized over 5.3 million unique barcodes. TempO-LINC has a robust protocol for fixing and banking cells and displays high-sensitivity gene detection from multiple diverse sample types. We show that TempO-LINC has an observed multiplet rate of less than 1.1% and a cell capture rate of ~50%. Although the assay can accurately profile the whole transcriptome (19,683 human or 21,400 mouse genes), it can be targeted to measure only actionable/informative genes and molecular pathways of interest - thereby reducing sequencing requirements. In this study, we applied TempO-LINC to profile the transcriptomes of 89,722 cells across multiple sample types, including nuclei from mouse lung, kidney and brain tissues. The data demonstrated the ability to identify and annotate at least 50 unique cell populations and positively correlate expression of cell type-specific molecular markers within them. TempO-LINC is a robust new single-cell technology that is ideal for large-scale applications/studies across thousands of samples with high data quality.

Lecanemab and Vascular-Amyloid Deposition in Brains of People With Down Syndrome.

Importance: Anti-ß-amyloid immunotherapy using lecanemab is becoming increasingly available to patients with Alzheimer disease (AD). Individuals with Down syndrome (DS) develop AD neuropathology by age 40 years, representing a significant cohort of genetically determined AD. Objective: To investigate the binding properties of lecanemab in the brains of people with DS, in anticipation of their inclusion in clinical trials or access to antiamyloid immunotherapies. Design, Setting, Participants: The study included cases of postmortem brain tissue analysis from 15 individuals with DS aged 43 to 68 years that were acquired from Alzheimer Disease research centers at the University of California, Irvine and the University of Kentucky from 2008 to 2021. Data were analyzed from August 2023 through May 2024. Exposure: The binding properties of lecanemab were assessed in brain tissue. Main Outcome: The primary outcome was the extent of lecanemab binding to amyloid plaques and brain blood vessels. Results: Tissue from 15 people (8 were female [53%]) with DS ranging in age from 43 to 68 (mean, 56.6) years were included in the study. Lecanemab-labeled amyloid plaques appeared in all 15 DS cases studied, indicating potential target engagement. However, extensive binding of lecanemab to brain blood vessels in DS was observed, raising significant safety concerns. These findings underscore the necessity for clinical trials of lecanemab in people with DS to evaluate both safety and efficacy, particularly in individuals older than 43 years. Conclusions and Relevance: These findings suggest significant binding of lecanemab to cerebral amyloid angiopathy in DS. Lecanemab should be rigorously tested in clinical trials for AD in the DS population to determine its safety and efficacy, especially in those older than 43 years.

Functional network characteristics in anxiety- and mania-based subgroups of bipolar I disorder.

BACKGROUND: Bipolar disorder I (BD-I) is a heterogeneous disorder with a high prevalence of comorbid anxiety. The aim of this study was to investigate whether anxiety and mania symptoms define distinct subgroups within BD-I and to explore potential differences in functional network characteristics between these subgroups. METHODS: Subgroups were identified using scores from clinical anxiety and mania scales. After dimension reduction of these scores, data-driven clustering analysis with cross-validation was employed to reveal the existence of subgroups. Resting-state functional magnetic resonance imaging (rs-fMRI) scans were pre-processed using fMRIPrep. After parcellation and network construction, global and regional graph theoretical measures were calculated per subgroup. RESULTS: Clustering results revealed that, based on anxiety symptomatology, subjects fell into two distinct subgroups, whereas mania symptoms divided subjects into four unique subgroups. These subgroups varied notably on several symptom scales. Network assortativity was significantly associated with anxiety subgroups. Post-hoc pairwise comparisons did not reveal significant global functional network differences between the anxiety subgroups or between mania subgroups. Regional network differences between clinical subgroups were especially apparent for strength and degree in the temporal and frontal lobes. LIMITATIONS: Small sample size of some subgroups is a limitation of this study as is the categorical rather than continuous representation of anxiety and mania symptoms. CONCLUSIONS: BD-I populations may be stratified into robust subgroups based on anxiety and mania symptoms, showing differences in functional network connectivity. Our findings highlight new avenues of research for investigating heterogeneity in psychiatric populations.

Preventability of injury-related morbidity & mortality at four hospitals in Cameroon: A systematic approach to trauma quality improvement.

BACKGROUND: Adverse events reviews are a fundamental component of trauma quality improvement (QI) that facilitate the correction of systemic issues in care. Although injury-related mortality in Cameroon is substantial, to our knowledge, opportunities for QI have not been formally assessed. Thus, a formal review of adverse events in Cameroonian trauma patients was implemented as a first step toward identifying targets for systems modification. METHODS: A QI committee composed of multidisciplinary experts at four hospitals in Cameroon was formed to review adverse events including deaths among trauma patients from 2019 to 2021. Events were discussed at newly established morbidity and mortality conferences and committee meetings to identify contributing factors and overall preventability. RESULTS: During 50 meetings, 95 adverse events were reviewed, including 58 deaths (61%). Other adverse events were delays in diagnosis/treatment (22%) and surgical site infections (17%). Overall, 34 deaths (59%) were classified as preventable, 21% potentially preventable, and 21% not preventable. Over half (52%) of the 46 preventable or potentially preventable deaths occurred in the emergency department (ED); while brain injury (57%), respiratory failure (41%), and hemorrhage (39%) were the most frequent physiologic factors associated with mortality. Contributory factors identified include lack of a structured approach to patient management, absence of continuous training for personnel, and locally adapted protocols. CONCLUSIONS: Basic improvements in evaluation and management of life-threatening issues in the ED can significantly reduce the high rate of preventable trauma-related deaths across Cameroon. Formal trauma QI methods can be utilized in low-resource environments to determine mortality root causes and identify intervention targets.

The symbiotic alga Trebouxia fuels a coherent soil ecosystem on the landscape scale in the Atacama Desert.

Biocrusts represent associations of lichens, green algae, cyanobacteria, fungi and other microorganisms, colonizing soils in varying proportions of principally arid biomes. The so-called grit crust represents a recently discovered type of biocrust situated in the Coastal Range of the Atacama Desert (Chile) made of microorganisms growing on and in granitoid pebbles, resulting in a checkerboard pattern visible to the naked eye on the landscape scale. This specific microbiome fulfills a broad range of ecosystem services, all probably driven by fog and dew-induced photosynthetic activity of mainly micro-lichens. To understand its biodiversity and impact, we applied a polyphasic approach on the phototrophic microbiome of this biocrust, combining isolation and characterization of the lichen photobionts, multi-gene phylogeny of the photobionts and mycobionts based on a direct sequencing and microphotography approach, metabarcoding and determination of chlorophylla+b contents. Metabarcoding showed that yet undescribed lichens within the Caliciaceae dominated the biocrust together with Trebouxia as the most abundant eukaryote in all plots. Together with high mean chlorophylla+b contents exceeding 410 mg m-2, this distinguished the symbiotic algae Trebouxia as the main driver of the grit crust ecosystem. The trebouxioid photobionts could be assigned to the I (T. impressa/gelatinosa) and A (T. arboricola) clades and represented several lineages containing five potential species candidates, which were identified based on the unique phylogenetic position, morphological features, and developmental cycles of the corresponding isolates. These results designate the grit crust as the only known coherent soil layer with significant landscape covering impact of at least 440 km2, predominantly ruled by a single symbiotic algal genus.

The Proteogenomics of Prostate Cancer Radioresistance.

Prostate cancer is frequently treated with radiotherapy. Unfortunately, aggressive radioresistant relapses can arise, and the molecular underpinnings of radioresistance are unknown. Modern clinical radiotherapy is evolving to deliver higher doses of radiation in fewer fractions (hypofractionation). We therefore analyzed genomic, transcriptomic and proteomic data to characterize prostate cancer radioresistance in cells treated with both conventionally fractionated and hypofractionated radiotherapy. Independent of fractionation schedule, resistance to radiotherapy involved massive genomic instability and abrogation of DNA mismatch repair. Specific prostate cancer driver genes were modulated at the RNA and protein levels, with distinct protein subcellular responses to radiotherapy. Conventional fractionation led to a far more aggressive biomolecular response than hypofractionation. Testing pre-clinical candidates identified in cell lines, we revealed POLQ (DNA Polymerase Theta) as a radiosensitizer. POLQ-modulated radioresistance in model systems and was predictive of it in large patient cohorts. The molecular response to radiation is highly multi-modal, and sheds light on prostate cancer lethality.

γ-Secretase activity, clinical features, and biomarkers of autosomal dominant Alzheimer's disease: cross-sectional and longitudinal analysis of the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS).

BACKGROUND: Genetic variants that cause autosomal dominant Alzheimer's disease are highly penetrant but vary substantially regarding age at symptom onset (AAO), rates of cognitive decline, and biomarker changes. Most pathogenic variants that cause autosomal dominant Alzheimer's disease are in presenilin 1 (PSEN1), which encodes the catalytic core of γ-secretase, an enzyme complex that is crucial in production of amyloid ß. We aimed to investigate whether the heterogeneity in AAO and biomarker trajectories in carriers of PSEN1 pathogenic variants could be predicted on the basis of the effects of individual PSEN1 variants on γ-secretase activity and amyloid ß production. METHODS: For this cross-sectional and longitudinal analysis, we used data from participants enrolled in the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS) via the DIAN-OBS data freeze version 15 (data collected between Feb 29, 2008, and June 30, 2020). The data freeze included data from 20 study sites in research institutions, universities, hospitals, and clinics across Europe, North and South America, Asia, and Oceania. We included individuals with PSEN1 pathogenic variants for whom relevant genetic, clinical, imaging, and CSF data were available. PSEN1 pathogenic variants were characterised via genetically modified PSEN1 and PSEN2 double-knockout human embryonic kidney 293T cells and immunoassays for Aß37, Aß38, Aß40, Aß42, and Aß43. A summary measure of γ-secretase activity (γ-secretase composite [GSC]) was calculated for each variant and compared with clinical history-derived AAO using correlation analyses. We used linear mixed-effect models to assess associations between GSC scores and multimodal-biomarker and clinical data from DIAN-OBS. We used separate models to assess associations with Clinical Dementia Rating Sum of Boxes (CDR-SB), Mini-Mental State Examination (MMSE), and Wechsler Memory Scale-Revised (WMS-R) Logical Memory Delayed Recall, [11C]Pittsburgh compound B (PiB)-PET and brain glucose metabolism using [18F] fluorodeoxyglucose (FDG)-PET, CSF Aß42-to-Aß40 ratio (Aß42/40), CSF log10 (phosphorylated tau 181), CSF log10 (phosphorylated tau 217), and MRI-based hippocampal volume. FINDINGS: Data were included from 190 people carrying PSEN1 pathogenic variants, among whom median age was 39·0 years (IQR 32·0 to 48·0) and AAO was 44·5 years (40·6 to 51·4). 109 (57%) of 190 carriers were female and 81 (43%) were male. Lower GSC values (ie, lower γ-secretase activity than wild-type PSEN1) were associated with earlier AAO (r=0·58; p<0·0001). GSC was associated with MMSE (ß=0·08, SE 0·03; p=0·0043), CDR-SB (-0·05, 0·02; p=0·0027), and WMS-R Logical Memory Delayed Recall scores (0·09, 0·02; p=0·0006). Lower GSC values were associated with faster increase in PiB-PET signal (p=0·0054), more rapid decreases in hippocampal volume (4·19, 0·77; p<0·0001), MMSE (0·02, 0·01; p=0·0020), and WMS-R Logical Memory Delayed Recall (0·004, 0·001; p=0·0003). INTERPRETATION: Our findings suggest that clinical heterogeneity in people with autosomal dominant Alzheimer's disease can be at least partly explained by different effects of PSEN1 variants on γ-secretase activity and amyloid ß production. They support targeting γ-secretase as a therapeutic approach and suggest that cell-based models could be used to improve prediction of symptom onset. FUNDING: US National Institute on Aging, Alzheimer's Association, German Center for Neurodegenerative Diseases, Raul Carrea Institute for Neurological Research, Japan Agency for Medical Research and Development, Korea Health Industry Development Institute, South Korean Ministry of Health and Welfare, South Korean Ministry of Science and ICT, and Spanish Institute of Health Carlos III.

Accumulation of alkyl-lysophosphatidylcholines in Niemann-Pick disease type C1.

Lysosomal function is impaired in Niemann-Pick disease type C1 (NPC1), a rare and inherited neurodegenerative disorder, resulting in late endosomal/lysosomal accumulation of unesterified cholesterol. The precise pathogenic mechanism of NPC1 remains incompletely understood. In this study, we employed metabolomics to uncover secondary accumulated substances in NPC1. Our findings unveiled a substantial elevation in the levels of three alkyl-lysophosphatidylcholine [alkyl-LPC, also known as lyso-platelet activating factor (PAF)] species in NPC1 compared to controls across various tissues, including brain tissue from individuals with NPC1, liver, spleen, cerebrum, cerebellum, and brain stem from NPC1 mice, as well as in both brain and liver tissue from NPC1 cats. The three elevated alkyl-LPC species were as follows: LPC O-16:0, LPC O-18:1, and LPC O-18:0. However, the levels of PAF 16:0, PAF 18:1, and PAF 18:0 were not altered in NPC1. In the NPC1 feline model, the brain and liver alkyl-LPC levels were reduced following 2-hydroxypropyl-ß-cyclodextrin (HPßCD) treatment, suggesting that alkyl-LPCs are secondary storage metabolites in NPC1 disease. Unexpectedly, cerebrospinal fluid (CSF) levels of LPC O-16:0 and LPC O-18:1 were decreased in individuals with NPC1 compared to age-appropriate comparison samples, and their levels were increased in 80% of participants 2 years after intrathecal HPßCD treatment. The fold increases in CSF LPC O-16:0 and LPC O-18:1 levels were more pronounced in responders compared to nonresponders. This study identified alkyl-LPC species as secondary storage metabolites in NPC1 and indicates that LPC O-16:0 and LPC O-18:1, in particular, could serve as potential biomarkers for tracking treatment response in NPC1 patients.

Bimodal alteration of cognitive accuracy for spintronic artificial neural networks.

Spintronics-based artificial neural networks (ANNs) exhibiting nonvolatile, fast, and energy-efficient computing capabilities are promising neuromorphic hardware for performing complex cognitive tasks of artificial intelligence and machine learning. Early experimental efforts focused on multistate device concepts to enhance synaptic weight precisions, albeit compromising on cognitive accuracy due to their low magnetoresistance. Here, we propose a hybrid approach based on the tuning of tunnel magnetoresistance (TMR) and the number of states in the compound magnetic tunnel junctions (MTJs) to improve the cognitive performance of an all-spin ANN. A TMR variation of 33-78% is controlled by the free layer (FL) thickness wedge (1.6-2.6 nm) across the wafer. Meanwhile, the number of resistance states in the compound MTJ is manipulated by varying the number of constituent MTJ cells (n = 1-3), generating n + 1 states with a TMR difference between consecutive states of at least 21%. Using MNIST handwritten digit and fashion object databases, the test accuracy of the compound MTJ ANN is observed to increase with the number of intermediate states for a fixed FL thickness or TMR. Meanwhile, the test accuracy for a 1-cell MTJ increases linearly by 8.3% and 7.4% for handwritten digits and fashion objects, respectively, with increasing TMR. Interestingly, a multifarious TMR dependence of test accuracy is observed with the increasing synaptic complexity in the 2- and 3-cell MTJs. By leveraging on the bimodal tuning of multilevel and TMR, we establish viable paths for enhancing the cognitive performance of spintronic ANN for in-memory and neuromorphic computing.

Cognitive impairment in young adults following cerebellar stroke: Prevalence and longitudinal course.

INTRODUCTION: Cognitive impairment is a well-known result of a stroke, but for cerebellar stroke in young patients detailed knowledge on the nature and extent of cognitive deficits is limited. This study examined the prevalence and course of cognitive impairment in a large cohort of patients with cerebellar stroke. METHODS: Sixty young (18-49 years) cerebellar stroke patients completed extensive neuropsychological assessments in the subacute (<9 months post-stroke) and/or chronic phase (≥9 months post-stroke). Performance and course were assessed using standardized scores and Reliable Change Index analyses. Associations between cognitive deficits and lesion locations were explored using subtraction analyses, and associations with subjective cognitive complaints and fatigue were examined. RESULTS: Sixty patients (52% male) were included with a mean age at event of 43.1 years. Cognitive impairment was observed in 60.3% of patients in the subacute phase and 51.2% during the chronic phase. Deficits were most frequent for visuo-spatial skills and executive functioning (42.5-54.6%). Both improvement and decline were observed over time, in 17.9% and 41.0% of participants, respectively. Cognitive deficits seem to be associated with lesions in certain cerebellar regions, however, no distinct correlation was found for a specific subregion. Subjective cognitive complaints were present in the majority of participants (61-80.5%) and positively correlated with fatigue in both phases (ρ = -.661 and ρ = -.757, p < .001, respectively). DISCUSSION: Cognitive impairment in cerebellar stroke patients is common, with deficits most pronounced for visuo-spatial skills and executive functioning, as in line with the Cerebellar Cognitive Affective Syndrome. The course of cognitive performance was heterogenous, with cognitive decline despite the fact that no recurrent strokes occurred. No clear association between lesion location and cognitive deficits was observed. Subjective cognitive complaints and fatigue were prevalent and positively correlated. Clinicians could use this information to actively screen for and better inform patients about possible cognitive sequalae.

The underestimated fraction: diversity, challenges and novel insights into unicellular cyanobionts of lichens.

Lichens are remarkable and classic examples of symbiotic organisms that have fascinated scientists for centuries. Yet, it has only been for a couple of decades that significant advances have focused on the diversity of their green algal and/or cyanobacterial photobionts. Cyanolichens, which contain cyanobacteria as their photosynthetic partner, include up to 10% of all known lichens and, as such, studies on their cyanobionts are much rarer compared to their green algal counterparts. For the unicellular cyanobionts, i.e. cyanobacteria that do not form filaments, these studies are even scarcer. Nonetheless, these currently include at least 10 different genera in the cosmopolitan lichen order Lichinales. An international consortium (International Network of CyanoBionts; INCb) will tackle this lack of knowledge. In this article, we discuss the status of current unicellular cyanobiont research, compare the taxonomic resolution of photobionts from cyanolichens with those of green algal lichens (chlorolichens), and give a roadmap of research on how to recondition the underestimated fraction of symbiotic unicellular cyanobacteria in lichens.

The pathogenicity of PSEN2 variants is tied to Aß production and homology to PSEN1.

INTRODUCTION: Though recognized as a potential cause of Autosomal Dominant Alzheimer's Disease, the pathogenicity of many PSEN2 variants remains uncertain. We compared Aß production across all missense PSEN2 variants in the Alzforum database and, when possible, to corresponding PSEN1 variants. METHODS: We expressed 74 PSEN2 variants, 21 of which had homologous PSEN1 variants with the same amino acid substitution, in HEK293 cells lacking PSN1/2. Aß production was compared to age at symptom onset (AAO) and between homologous PSEN1/2 variants. RESULTS: Aß42/40 and Aß37/42 ratios were associated with AAO across PSEN2 variants, strongly driven by PSEN2 variants with PSEN1 homologs. PSEN2 AAO was 18.3 years later compared to PSEN1 homologs. Aß ratios from PSEN1 / 2 homologs were highly correlated, suggesting a similar mechanism of γ-secretase dysfunction. DISCUSSION: The existence of a PSEN1 homolog and patterns of Aß production are important considerations in assessing the pathogenicity of previously-reported and new PSEN2 variants.