Browse Articles

Derailed degradation: LRRK2-dependent exocytosis in Parkinson’s disease

Hierarchical luminescence center coupling enables time-dependent phosphorescence color from self-protective carbonized polymer dots

Enhancing the optoelectronic and mechanical response of MgXCl3 (X = Rb, Cl) for advance energy conversion applications

Detecting poststroke epilepsy in nationwide administrative data: A validation study using Swedish registers

Objective Healthcare administrative data often rely on the International Classification of Diseases (ICD) system, which lacks specific codes to identify etiological subgroups of epilepsy. Combining indicators for epilepsy and potential etiologies is possible, but such approaches require validation. This study aimed to validate methods for identifying poststroke epilepsy (PSE) in Swedish administrative data. Methods The algorithms were based on combinations of ICD-10 codes for stroke and seizures, with some also incorporating antiseizure medication prescriptions. We focused on positive predictive values (PPVs), using medical records as the reference standard. We identified individuals in the National Patient Register with a primary inpatient diagnostic code for stroke (I61 or I63) during 2005–2010 and a first-ever seizure-related code (G40, G41, or R56.8), occurring more than seven days post-stroke. To facilitate access to medical records, only patients who were deceased at data extraction (Jan 16, 2021) were eligible. A nationwide random sample of 500 patients was selected, with the intended sample for medical record review being 250. Medical records were reviewed before processing the administrative data. Results Records were obtained for 321 patients (median age 78; 56% males), with no significant differences in characteristics between those included and the rest of the sample. Across different algorithms, PPVs ranged from 84.1% (95% CI: 79.2–88.3) to 92.5% (95% CI: 87.3–96.1). Relative coverage ranged from 60% to 89% compared to the most inclusive algorithm. Significance Our findings demonstrate the potential of administrative data to reliably identify PSE cases, supporting the use of these algorithms for large-scale studies of treatment and outcomes. Stricter algorithms, limited to G40 codes for epilepsy or requiring ASM prescriptions, improve accuracy but at the cost of missing more cases. Limitations include the inability to calculate sensitivity due to study design, and the need for local validation before use in other healthcare systems.

The entities enabling scientific fraud at scale are large, resilient, and growing rapidly

Science is characterized by collaboration and cooperation, but also by uncertainty, competition, and inequality. While there has always been some concern that these pressures may compel some to defect from the scientific research ethos—i.e., fail to make genuine contributions to the production of knowledge or to the training of an expert workforce—the focus has largely been on the actions of lone individuals. Recently, however, reports of coordinated scientific fraud activities have increased. Some suggest that the ease of communication provided by the internet and open-access publishing have created the conditions for the emergence of entities—paper mills (i.e., sellers of mass-produced low quality and fabricated research), brokers (i.e., conduits between producers and publishers of fraudulent research), predatory journals, who do not conduct any quality controls on submissions—that facilitate systematic scientific fraud. Here, we demonstrate through case studies that i) individuals have cooperated to publish papers that were eventually retracted in a number of journals, ii) brokers have enabled publication in targeted journals at scale, and iii), within a field of science, not all subfields are equally targeted for scientific fraud. Our results reveal some of the strategies that enable the entities promoting scientific fraud to evade interventions. Our final analysis suggests that this ability to evade interventions is enabling the number of fraudulent publications to grow at a rate far outpacing that of legitimate science.

Targeted gene editing and near-universal cDNA insertion of CYBA and CYBB as a treatment for chronic granulomatous disease

Abstract Chronic granulomatous disease (CGD) is a severe inborn error of immunity caused by NADPH oxidase defects. Here, we develop CRISPR/Cas9-based gene editing strategies for correction of variants in the CYBA and CYBB genes causing CGD. For X-linked CGD, we also develop a near-universal gene editing strategy by targeted integration of a truncated CYBB cDNA in CD34+ hematopoietic stem and progenitor cells (HSPCs). Throughout, off-target editing and chromosomal translocations are evident, which negatively impact the ability of gene-edited HSPCs to engraft in immunodeficient mice. However, by employing a high-fidelity Cas9 to minimize off-target editing, we demonstrate restoration of the multilineage engraftment potential of gene-edited HSPCs. Moreover, to further improve safety, we develop a D10A Cas9n editing approach with no detectable off-target activity or chromosomal translocations. Collectively, through risk assessments of different gene editing approaches, we present a D10A Cas9n-based strategy with improved safety, offering a potentially curative treatment for CGD patients.

Spectral sensitivity and temporal resolution of the sexually dimorphic compound eyes of Electrogena lateralis

Abstract Several mayfly species have sexually dimorphic compound eyes. Female Electrogena lateralis have uniform eyes, while male eyes are split into ventral and dorsal regions. We compared the spectral sensitivity and temporal resolution of the male eye regions and female eyes using electroretinography. Larval spectral sensitivity was also measured. Temporal resolution was quantified by measuring the eye flicker fusion frequency. The male ventral eye region and female eye were most sensitive to the green spectral range, with major and minor peak sensitivities at 536 and 366 nm, respectively. The dorsal eye region of males was exclusively ultraviolet sensitive, with maximal sensitivity at 353 nm. Relative ultraviolet sensitivity of larvae was lower than that of adults, which could be explained with the transmittance of the exuvium. Flicker fusion frequency of the male dorsal eye region was significantly higher than that of the ventral region. Temporal resolution of female eyes was similar to that of the ventral eye region of males. The high temporal resolution of the dorsal eye region and the exclusive ultraviolet sensitivity in males might play a role in the detection of females during swarming, while the female eye and the ventral male eye region may serve general navigation.

Editorial Note: Effect of intrinsic foot muscles training on foot function and dynamic postural balance: A systematic review and meta-analysis

On-chip integration of achromatic metalens arrays

Seasonal variation of rare earth elements in Taraxacum officinale as an indicator of changes in urban pollution

Abstract Taraxacum officinale has been identified as a potential rare earth elements (REEs) accumulator, making it a promising bioindicator for urban environment. However, the influence of seasonal variation on the bioavailability, transport, and accumulation of REEs in plant tissues remains poorly understood. This knowledge gap is crucial, especially in the context of development of reliable bioindicators for urban pollution and managing urban ecosystems sustainably. The aim of this study was to evaluate seasonal changes in the content and distribution of Sc, Y and 14REEs in soils and dandelion roots and leaves from urban areas. Ten research sites typical for urbanised areas were designated and samples of soils and plants were collected in the spring and autumn season. The assessment of the level of studied elements combined with statistical analysis was performed. Variation in REEs accumulation in soil was found. Due to the lack of heavy industry in the city, the major source of REEs contamination in soils might be related to transportation and local agrotechnical and nutrition treatments. Our research on dandelion showed a decrease in REEs content in roots and leaves during autumn compared to spring. Slightly higher translocation efficiency was observed in autumn, possibly due to the plant’s age and tolerance mechanism.

Platelet count and coagulation profiles of adult hypertensive patients at Felege Hiwot comprehensive specialized hospital, Northwest Ethiopia: A comparative cross-sectional study

Background Hypertension is a global public health problem and associated with metabolic, cellular, and blood disturbances. Hematological and hemostatic disturbance have been documented in individuals with hypertension, playing a pivotal role in hypertension associated vascular complications. Despite this, there is a scarcity of evidence and reports regarding the coagulation profiles are contradicting among hypertensive patients. Thus, this study aimed to compare the platelet count and coagulation profiles of adult hypertensive patients with those of normotensive controls at Felege Hiwot Comprehensive Specialized Hospital in Northwest Ethiopia, from June to August, 2023. Methods A comparative cross-sectional study was conducted among a total of 180 study participants (120 hypertensive patients and 60 healthy individuals) recruited by consecutive sampling technique. Socio-demographic, clinical and anthropometric data were collected using structured questionnaires and checklist. A total of six milliliters of venous blood (3 ml in EDTA tube and 3 mL in citrate tube) was collected for platelet count and coagulation profile determination. Platelet count and coagulation profile were determined using Uni Cel DxH800 hematology analyzer and Huma cue due plus coagulation analyzer, respectively. One-way ANOVA, Kruskal Wallis test, and correlation analysis was used during data analysis. A p-value of <0.05 was considered statistically significant. Results In the present study, the median (interquartile range) age was 42.5 (36.0–50.0) years for newly diagnosed, 50.0 (45.0–65.0) years for treatment and 40.0 (35.0–45.7) years for the control group (P < 0.001). The overall hemostatic abnormality in hypertensive patient was 83 (69.2%), and significant difference was found in the median of activated partial thromboplastin time, prothrombin time and international normalized ratio between hypertensive patients as compared to control. Statistically significant difference was observed in the median (interquartile range) of activated partial thromboplastin time (P = 0.041), prothrombin time (P < 0.001), and international normalized ratio (P < 0.001) results between newly diagnosed hypertensive patients and healthy controls. Moreover, there was also a significant difference in activated partial thromboplastin time (P = 0.020), prothrombin time (P = 0.011), and international normalized ratio (P = 0.012) results between hypertensive patients undergoing treatment and healthy controls. Conclusions Hemostatic abnormality was observed in majority of hypertensive patients. Compered to healthy controls, the median values of activated partial thromboplastin time, prothrombin time and international normalized ratio were significantly higher in hypertensive patients. This finding highlights the importance of assessing coagulation parameters in hypertensive patients in order to prevent complications related to abnormal blood clotting. However, further longitudinal studies are necessary to gain better understanding of the changes in coagulation observed in hypertensive patients.

Protective antigen–mediated delivery of an anti-CRISPR protein for precision genome editing

Precise control over the dosage of Cas9-based technologies is essential because off-target effects, mosaicism, chromosomal aberrations, immunogenicity, and genotoxicity can arise with prolonged Cas9 activity. Type II anti-CRISPR proteins (Acrs) inhibit and control Cas9 but are generally impermeable to the cell membrane due to their size and anionic charge. Moreover, existing Acr delivery methods are long-lived and operate within hours (e.g., viral and nonviral vectors) or require external devices (e.g., electroporation), limiting therapeutic applications. To address these problems, we developed a protein-based anti-CRISPR delivery platform, LF N -Acr/PA, which delivers Acrs into cells within minutes. LF N -Acr/PA is a nontoxic, two-component protein system derived from anthrax toxin, where protective antigen (PA) proteins bind receptors widespread in human cells, forming a pH-triggered endosomal pore that an engineered Acr (LF N -Acr) binds and uses to enter the cell. In the presence of PA, LF N -Acr enters human cells (e.g., immortalized cell lines, embryonic stem cells, and 3D cell cultures) at concentrations as low as 2.5 pM to inhibit up to 95% of Cas9-mediated knockout, knock-in, transcriptional activation, and base editing. Timing LF N -Acr delivery reduces off-target base editing and increases Cas9 specificity by 41%. LF N -Acr/PA is the most potent known cell-permeable CRISPR-Cas inhibition system, significantly improving the utility of CRISPR for genome editing.

Time cell sequences during delay intervals are not dependent on brain state and do not support hippocampus-dependent working memory

Abstract Working memory (WM) is essential for performing cognitive tasks, and sequentially active hippocampal cells over many seconds (‘time cells’) have been observed during WM retention. Time cells predominantly occur when neural activity oscillates at theta frequency. To examine whether time cells during WM maintenance depend on ongoing theta oscillations, we controlled the persistence of theta during 10 s and 30 s delay intervals by either having rats run or rest, which resulted in conditions with and without persistent theta oscillations. In either condition, reliable time cells were limited to only the first few seconds of the delay interval while a second population of constitutively active cells emerged during the remainder of the delay period, neither of which were memory-related. Our results show that hippocampal sequential activity patterns are short-lasting and uninformative for WM, and that WM retention over more than ~5 s needs to include mechanisms other than hippocampal time cells.

Tyrosine phosphatase Shp2 accelerated the progression of dilated cardiomyopathy via upregulating NF-κB/Src/FAK signaling induced ROS and mitophagy

Quality of postnatal care for mothers and neonates in Mexico: Insights from the maternal eCohort study

Objective The study aimed to evaluate healthcare use during the postnatal period for mothers and their babies, the content of care received, mothers’ perceived quality of care, and the factors influencing these perceptions. Methods The study analyzed data from a postnatal survey conducted within the maternal eCohort at the Mexican Institute of Social Security (IMSS). The research involved 973 women aged 18–49 who were recruited following their first antenatal care visit with a family physician at 48 family medicine clinics across eight Mexican states. We described postnatal care (PNC) use, content of care and perceived quality and used Poisson multivariable regression analysis to investigate the factors influencing women’s perceptions of higher quality of care during PNC. Results 29.4% of women and 12.0% of infants had no postnatal care visits within the six weeks following hospital discharge. Among women who received PNC, 72.3% accessed services exclusively through IMSS, 17.7% utilized a combination of IMSS and other providers, and 10% relied solely on private providers. Infants received 82.4% of recommended content of care, compared to 66.7% for mothers. The median perceived quality of care among women was 25 points on a scale of 8–40. Key areas for improvement include enhancing awareness of the importance of postnatal consultations among health personnel and women, reducing waiting times, and improving the content and length of consultations. Factors associated with better perceived quality included being over 35, receiving better content of care for infants, and being treated by private providers, while lower education levels, prior pregnancies, and poor health were associated with lower perceived quality. Conclusion Improvements are needed to ensure all women and infants receive comprehensive postnatal care and to enhance patient-perceived quality.

Cryptic intronic transcriptional initiation generates efficient endogenous mRNA templates for C9orf72-associated RAN translation

Intronic GGGGCC hexanucleotide repeat expansions in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Despite its intronic location, this repeat avidly supports synthesis of pathogenic dipeptide repeat (DPR) proteins via repeat-associated non-AUG (RAN) translation. However, the template RNA species that undergoes RAN translation endogenously remains unclear. Using long-read based 5′ RNA ligase-mediated rapid amplification of cDNA ends (5′ Repeat-RLM-RACE), we identified C9orf72 transcripts initiating within intron 1 in a C9BAC mouse model, patient-derived iNeurons, and iNeuron-derived polysomes. These cryptic m 7 G-capped mRNAs are at least partially polyadenylated and are more abundant than transcripts derived from intron retention or circular intron lariats. In RAN translation reporter assays, intronic template transcripts–even those with short (32 nucleotide) leaders–exhibited robust expression compared to exon–intron and repeat-containing lariat reporters. To assess endogenous repeat-containing lariat RNA contributions to RAN translation, we enhanced endogenous lariat stability by knocking down the lariat debranching enzyme Dbr1. However, this modulation did not impact DPR production in patient-derived iNeurons. These findings identify cryptic, linear, m 7 G-capped intron-initiating C9orf72 mRNAs as an endogenous template for RAN translation and DPR production, with implications for disease pathogenesis and therapeutic development.

Epigenetic control of topoisomerase 1 activity presents a cancer vulnerability

Abstract DNA transactions introduce torsional constraints that pose an inherent risk to genome integrity. While topoisomerase 1 (TOP1) activity is essential for DNA supercoil removal, the aberrant stabilization of TOP1:DNA cleavage complexes (TOP1ccs) can result in cytotoxic DNA lesions. What protects genomic hot spots of topological stress from excessive TOP1cc accumulation remains unknown. Here, we identify chromatin context as an essential means to coordinate TOP1cc resolution. Through its ability to bind poly(ADP-ribose) (PAR), the histone variant macroH2A1.1 facilitates TOP1cc repair factor recruitment and lesion turnover, thereby preventing DNA damage in response to transcription-associated topological stress. The alternatively spliced macroH2A1.2 isoform is unable to bind PAR or protect from TOP1ccs. Impaired macroH2A1.1 splicing, a frequent cancer feature, was predictive of increased sensitivity to TOP1 poisons in a pharmaco-genomic screen in breast cancer cells, and macroH2A1.1 inactivation mirrored this effect. We propose macroH2A1 alternative splicing as an epigenetic modulator of TOP1-associated genome maintenance and a potential cancer vulnerability.

Automated violence monitoring system for real-time fistfight detection using deep learning-based temporal action localization

Association between pet ownership and physical function at discharge in hospitalized older adults: A retrospective observational study

Objectives Hospitalization can lead to a loss of physical function among older adults. While pet ownership has been reported to have beneficial effects on physical function, its impact on hospitalized patients remains unclear. We examined the association between pet ownership upon admission and physical function during hospitalization. Methods This single-center, retrospective, observational study was conducted between April 2013 and April 2023. Patients aged ≥65 years who were hospitalized for the first time due to pneumonia at our facility were included. Cases were identified through medical record searches using the keywords “pet”, “dog”, “cat”, “ownership”, and “keeping”. Patients with unclear pet ownership status in the medical records were excluded from the analysis. Patients were classified into two groups: Pet Owners (PO) and Non-Pet Owners (NPO) upon admission. The Barthel index (BI) gain (the difference between admission and discharge BI scores) and BI efficiency (BI gain divided by hospital stay) were compared. Logistic regression was performed for patients with a BI gain >0 and discharge BI scores >85, indicating independence without functional decline, after adjusting for covariates. Results A total of 248 patients were initially screened, we finally included 172 patients (69.4%) in the PO group and 46 patients (18.5%) in the NPO group. The median BI gain was 10 (0–30) and 2.5 (0.0–26.3) in the PO and NPO groups (p = 0.24), respectively. The median BI efficiency was 0.48 (0.00–1.87) and 0.16 (0.00–1.27) in the PO and NPO groups (p = 0.062), respectively. Current pet ownership was not associated with independence without functional decline, with an adjusted odds ratio of 0.68 (95% confidence interval, 0.15–3.94; p = 0.63). Conclusions This study found no association between current pet ownership and the maintenance of physical function in hospitalized older adults.

Progressively greater biological carbon storage in the deep Atlantic during glacial inception

Changes in oceanic circulation and carbon storage have been implicated as important drivers of atmospheric pCO 2 variability during the last glacial cycle (0 to 150 ka), though consensus on the mechanisms responsible remains elusive due to sparse marine carbonate chemistry reconstructions. Here, we present vertical profiles of carbonate ion concentration ([CO 3 2 − ]) from the Southwest Atlantic to investigate oceanic carbon sequestration during key intervals of atmospheric CO 2 change. During the first major decline in atmospheric CO 2 (115 to 109 ka), enhanced carbon storage occurred in the abyssal Atlantic (>3,500 m water depth). During the second decline in CO 2 (72 to 68 ka), enhanced carbon storage occurred throughout the deep Atlantic (>2,000 m water depth). Paired with δ 13 C and δ 18 O vertical profiles from the same locations, the [CO 3 2 − ] results suggest progressively greater sequestration of biological carbon occurred in the South Atlantic as the volume of Southern Source Water expanded during glacial inception. Shoaling of the carbonate ion saturation horizon during the second decline in pCO 2 resulted in seafloor calcium carbonate dissolution and enhanced alkalinity, likely contributing to further draw down of atmospheric CO 2 . We also document carbon release from the deep South Atlantic during glacial Terminations I and II when atmospheric CO 2 was rising. Overall, our results highlight the tight linkage between pCO 2 and deep Atlantic carbon storage over the last glacial cycle.