Genetic diseases can be caused by monogenic diseases, which result from a single gene mutation in the DNA sequence. Many innovative approaches have been developed to cure monogenic genetic diseases, namely by genome editing. A specific type of genomic editing, prime editing, has the potential advantage to edit the human genome without requiring double-strand breaks or donor DNA templates for editing. Additionally, prime editing does not require a precisely positioned protospacer adjacent motif (PAM) sequence, which offers flexible target and more precise genomic editing. Here we detail a novel construction of a prime editing extended guide RNA (pegRNA) to target mutated leptin receptors in B6.BKS(D)-Leprdb/J mice (db/db mice). The pegRNA was then injected into the flexor digitorum brevis (FDB) muscle of db/db mice to demonstrate in vivo efficacy, which resulted in pegRNA mediated base transversion at endogenous base transversion. Genomic DNA sequencing confirmed that prime editing could correct the mutation of leptin receptor gene in db/db mice. Furthermore, prime editing treated skeletal muscle exhibited enhanced leptin receptor signals. Thus, the current study showed in vivo efficacy of prime editing to correct mutant protein and rescue the physiology associated with functional protein.

A document by Samira Yeasmin. Click on the document to view its contents.

Document clustering plays a pivotal role in structuring and analyzing vast textual datasets. In this paper, we leverage the Bidirectional Encoder Representations from Transformers (BERT) algorithm, a cutting-edge natural language processing model, to perform document clustering on three distinct datasets: the 20News Group dataset, Reuters dataset, and BBC Sports dataset. BERT’s contextualized embeddings enable a deeper understanding of document semantics, enhancing the clustering process. The objective is to investigate the efficacy of BERT-based document clustering across diverse domains, shedding light on its performance and potential applications. We implement BERT for document clustering, utilizing its pre-trained contextual embeddings to capture intricate relationships within textual data. Our study aims to assess how well BERT adapts to the unique characteristics of each dataset, offering insights into the model’s generalizability and effectiveness across various domains.

Both ground based magnetometers and ionospheric radars at Earth have frequently detected Ultra Low Frequency (ULF) fluctuations at discrete frequencies extending below one mHz-range. Many dayside solar wind drivers have been convincingly demonstrated as driver mechanism. In this paper we investigate and propose an additional, nightside generation mechanism of a low frequency magnetic field fluctuation. We propose that the Moon may excite a magnetic field perturbation of the order of 1 nT at discrete frequencies when it travels through the Earth’s magnetotail $\approx$ 4-5 days every month. Our theoretical prediction is supported by simulations and a case study of ARTEMIS magnetic field measurements at the lunar orbit in the Earth’s magnetotail. ARTEMIS detects peaks in magnetic field fluctuation power at frequencies of 0.37 to 0.47 mHz that are not present in the solar wind.

A document by Qian Sun. Click on the document to view its contents.

Background and Purpose Thrombo-inflammation is a key feature of stroke pathophysiology and provides multiple candidate drug targets. Thrombin exerts coagulation-independent actions via protease-activated receptors (PAR), of which PAR1 has been implicated in stroke-associated neuro-inflammation. The role of PAR4 in this context is less clear. This study examined if the selective PAR4 antagonist ML354 provides neuroprotection in experimental stroke and explored the underlying mechanisms. Experimental Approach Mouse primary cortical neurons were exposed to oxygen-glucose deprivation (OGD) and simulated reperfusion ± ML354. For comparison, functional Ca2+-imaging was performed upon acute stimulation with a PAR4 activating peptide or glutamate. Male mice underwent sham operation or transient middle cerebral artery occlusion (tMCAO), with ML354 or vehicle treatment beginning at recanalization. A subset of mice received a platelet-depleting antibody. Stroke size and functional outcome were assessed. Abundance of target genes, proteins and cell markers was determined in cultured cells and tissues by qPCR, immunoblotting and immunofluorescence. Key Results Stroke upregulates PAR4 expression in cortical neurons in vitro and in vivo. OGD augments spontaneous and PAR4-mediated neuronal activity; ML354 suppresses OGD-induced neuronal excitotoxicity and apoptosis. ML354 applied in vivo after tMCAO reduces infarct size, apoptotic markers, macrophage accumulation and interleukin-1β expression. Platelet depletion did not affect infarct size in mice with tMCAO ± ML354. Conclusions and Implications Selective PAR4 inhibition during reperfusion improves infarct size and neurological function after experimental stroke by blunting neuronal excitability, apoptosis and local inflammation. PAR4 antagonists may provide additional neuroprotective benefits in patients with acute stroke beyond their canonical antiplatelet action.

Deep lakes are critical for freshwater storage, although they are struggling against major ecological issues from climate change and nutrient pollution. A comprehensive understanding of internal feedback mechanisms would be helpful for nutrient regulation within such lakes. A five-year consecutive study of the diatom community and its abiotic environment was conducted in Lake Fuxian, which is the largest deep freshwater lake in China and is currently heading toward a eutrophic state. The results indicate a shift in the diatom community from a stable state dominated by a single species to a rapid seasonal fluctuation, along with a significant increase in diatom biomass. Specifically, stable stratification and low nutrient concentrations are limiting the growth of diatom biomass and maintaining the dominance of Cyclotella. Nutrients in the hypolimnion were replenished in the epilimnion during the extreme cold of winter, triggering a shift in the diatom community. This shift may imply that future climate change will exacerbate the positive feedback of hypoxia-nutrient release of algal blooms, potentially triggering a regime shift in the ecosystem of the entire lake. This study underscores the fact that climate change alters the internal feedback mechanisms of deep lakes and reduces the stability of their ecosystems, and provides a scientific basis for further clarification of protection measures for deep lakes.

The ecological factors driving specialisation in species interaction networks along environmental gradients at large spatial scales are poorly understood. Although such drivers can have synergistic impacts, previous work has mainly assessed effects of network type and the abiotic environment separately. We conducted a meta-analysis of existing network data to assess the interactive effects and relative importance of these drivers of specialisation in ant-plant networks at global scales. We collated 74 ant plant networks from 1979–2023, categorised into four network types: plants that provide ants nesting sites (myrmecophytes); plants that provide only food sources (myrmecophiles); plants for which ants disperse seeds (myrmecochories); plants on which ants forage only (foraging). We explored how network specialisation varies between interaction types with elevation, latitude, and anthropogenic disturbance. We used a standard measure of network specialisation (H2’), tested whether standardising this against network null models influenced results (H2’ z-score), and measured phylogenetic network specialisation (dsi*). We found that H2’ was strongly affected by habitat disturbance, elevation and interaction type in a manner congruent with previous work, However, these effects disappeared once H2’ was standardised (H2’ z-score). The disappearance of these effects indicates that previous results may relate to variation in network structure rather than specialisation. This is supported by the existence of correlations between network species richness/weighted connectance and H2’. Phylogenetic network specialisation (dsi*) was greater for myrmecophytes than for other three network types. This probably relates to closer co-evolution between partners in myrmecophytic network. Phylogenetic network specialisation did not vary significantly with elevation, latitude or anthropogenic disturbance. Our results demonstrate that ant-plant network types, in this case relating to strength of mutualistic interaction, is the main driver of network specialisation, and that previously reported impacts of latitude, elevation and anthropogenic habitat disturbance are likely to have been mediated mediated via correlations with network size.

1. Climate change is projected to increase the likelihood of extreme heat events, but it may also alter humidity levels, leading to the potential for coupled thermal and hydric stress. While increasing frequency and intensity of extreme heat events have been well-documented for their negative effects on species and their interactions, how humidity modulates the impacts of heat waves is currently unknown. 2. We investigated how humidity interacted with heat waves of different timings and durations to affect the life histories in an insect host-parasitoid interaction, comprising the Indian meal moth, Plodia interpunctella, and its endoparasitoid wasp, Venturia canescens. Hosts parasitised as 4th instar larvae and unparasitized hosts were maintained in a high humid (60.8% RH) or low-humid (32.5% RH) environment at a constant temperature of 28℃. They were then exposed to 38℃ heatwaves with a duration of 6 or 72 hours in either the 4th or 5th instar. 3. Humidity and heat waves did not affect the adult emergence of unparasitized hosts, but longer heat waves and lower humidity increased the probability that host adults emerged from parasitized hosts, indicating the negative effect of these conditions on the survival of parasitoids. Furthermore, juvenile development time and body size of hosts and parasitoids responded differently to timing and duration of heat waves, and high humidity decreased larval development time of unparasitized hosts and increased the size of both hosts and parasitoids. In addition, humidity negatively interacted with larval stage and duration of heat waves to affect the size of unparasitized hosts, but this effect was not found in parasitoids. 4. Our results show that humidity modulates the life history of hosts and parasitoids, highlighting the importance of humidity in maintaining host-parasitoid interactions. Humidity should be considered when predicting the impact of temperature extremes on species’ population dynamics and their interactions.

Generation of green energy is critical for addressing the environmental pollution and saving aquatic life in future by reducing the greenhouse gas. Green energy is generated using sources like wind, water, sun, living plants etc. These sources are essential for long-term efforts to mitigate climate change. The large-scale use of green energies will contribute to sustainable development which ensure access to reliable, and chemical free energy to power up the portable devices. This research paper proposes design of Green rechargeable and regenerative battery for brighter future. The proposed battery is not only rechargeable and eco-friendly but also non-flammable and can survive at extreme weather conditions T=70 0 C (V=1.52 V, I=75.5 µA) and T=-65 0 C (V=1.2 V, I=55.2 µA). The electric current of the designed battery also depends on shaking/rotation. The proposed battery can charge 80-90% of its initial value within 30-40 minutes which makes it a favourable candidate where faster recharging is needed. The designed battery does not show any heating effect even at T=70 0 C. Since, battery is free from any chemical, it is therefore does not release any hazardous chemicals once dispose of.

Many populations near low-latitude range margins are declining in response to climate change, but most studies of trailing-edge populations have focused on single species. Using ten years (2014–2023) of avian survey data from a trailing-edge population hotspot in the Appalachian Mountains, USA, we tested the hypothesis that high-elevation communities would experience turnover through thermophilisation, as warm-adapted species near the center of their geographic ranges expand into regions formerly dominated by peripheral populations of cool-adapted species. Three of the nine cool-adapted populations decreased in abundance whereas six species exhibited little change. For warm-adapted populations, one of 16 decreased in abundance, 11 increased, and four exhibited no change. Our results indicate that warm-adapted species are expanding their ranges faster than the rate at which ranges of cool-adapted species are contracting, suggesting that community turnover will lag behind encroachment by warm-adapted species.

The study of alpha band oscillations in the brain is a popular topic in cognitive neuroscience. A fair amount of research in recent years has focused on the potential role these oscillations may play in the discrete sampling of continuous sensory information. In particular, the question of whether or not peak frequency in the alpha band is linked with the temporal resolution of visual perception is a topic of ongoing debate. Some studies have reported a correlation between the two, whereas others were unable to observe a link. It is unclear whether these conflicting findings are due to differing methodologies and/or low statistical power, or due to the absence of a true relationship. Replication studies are needed to gain better insight into this matter. In the current study, we replicated an experiment published in a 2015 paper by Samaha & Postle. Additionally, we expanded on this study by adding an extra behavioural task, the critical flicker fusion task, to investigate if any links with peak alpha frequency are generalizable across multiple measures for visual temporal resolution. We succeeded in replicating some, but not all of Samaha & Postle’s findings. Our partial replication suggests that there may be a link between visual temporal resolution and peak alpha frequency. However, this relationship may be very small and only apparent for specific stimulus parameters. The correlations found in our study did not generalize to other behavioural measures for visual temporal resolution.

A document by Muhammd Umair Khan. Click on the document to view its contents.

This study presents the fabrication of a cultivated meat prototype featuring a three-dimensional (3D) structure constructed from myoblast C2C12 cell sheets. The absence of blood vessels in dense structures poses a significant challenge to oxygen supply of the cells. To address this, simulations were conducted using the COMSOL Multiphysics package to estimate the maximum achievable size of the 3D constructs. Key model parameters, including the oxygen uptake rate, effective diffusion coefficient, structure porosity, and volumetric mass transfer coefficient, were experimentally determined to perform the simulation accurately. The simulation results revealed that, for the current construct, the maximum achievable structure diameter considering oxygen availability to the cells is 5 mm. To enhance the reliability of the simulation model, it underwent validation against experimental data. This approach represents a valuable strategy with potential applications in various meat cultivation platforms. Its adaptability allows for better control over the desired cell microenvironment and optimization of culture conditions, offering a promising avenue for advancing the field of cultivated meat production.

Background: Fungi are ubiquitous in horses’ environment. Their contribution to the pathophysiology of severe asthma (SA) is acknowledged, while controversies remain for mild-moderate asthma (MA). Objectives: We hypothesized that fungi were a risk factor for asthma. Our objective was to compare different combinations of analytical methods (cytology, culture) and sampling sites (tracheal wash (TW), bronchoalveolar lavage fluid (BALF)) in relation to clinical status (control, MA, SA). Study design: Prospective cross-sectional study. Methods: The study population included asymptomatic racing horses in the field and horses referred to the hospital for respiratory investigations. Fungi were detected by cytology and identified by mycology on TW and pooled BALF. Chi-square tests were used for prevalence comparison between groups and association with clinical investigations. Results: A total of 155 horses (85 MA, 35 SA and 35 controls) were included in the study. The overall proportions of fungal detection in TW ranged from 45.7% to 89.4% among groups. The prevalence of fungal detection in BALF was significantly lower by cytology for SA (5.7%) than MA horses (23.6%) and significantly higher by culture for MA horses (31.8%) than controls (8.6%). Fungal detection by culture in BALF was significantly associated with high tracheal mucus score, high neutrophil proportions in BALF and diagnosis of MA. Main limitations: Mycology was only performed in pooled BALF, and environment was not sampled. Conclusion and clinical importance: Fungi were significantly more prevalent in the airways of MA horses than SA and/or controls. Fungal detection on TW, either by cytology or culture, was uninformative in a clinical context. Fungal detection by culture (but not cytology) in BALF represents a risk factor for MA.

Case report

Key Clinical Message Identification of achalasia cardia in adolescents requires a high index of suspicion. We share our experience of managing a challenging case of achalasia in an adolescent female in which treatment was complicated by esophageal perforation following Heller cardiomyotomy.

Visible-light-induced difunctionalization of alkenes is a powerful strategy for constructing complex molecules. Herein, we disclose a three-component 1,2-alkylpyridylation of alkenes under mild and photosensitizers-free conditions. UV-vis absorption spectroscopy studies and NMR titration experiments indicate that the formation of an EDA complex between 4-alkyl-DHPs and 4-cyanopyridines. Primary, secondary, and tertiary C(sp3)-centered radicals were formed by homolytic cleavage of 4-alkyl-DHPs. Gram-scale synthesis and late-stage functionalization of medicinally relevant molecules showed the synthetic potential of our methodology.

A document by Kati Suominen. Click on the document to view its contents.

Background Flares of inflammatory bowel disease (IBD) and a few cases of new-onset IBD have been reported after mRNA-based COVID-19 vaccines. Reports are scarce with viral vector and inactivated COVID-19 vaccines. Methods Patients diagnosed with ‘flares’ and new-onset IBD after receiving ChAdox1-nCoV-19 and inactivated COVID-19 vaccines were recruited from April–July 2022 from the Gastroenterology department of a tertiary hospital of North India. Clinical presentation, colonoscopy findings, treatment, and outcomes were recorded. Results A total of 44 patients were identified. 28 patients had flares of IBD at a median interval of 8.1, 13.2, and 2 weeks since the first, second, and booster doses of COVID-19 vaccines respectively. 16 new-onset cases of IBD occurred at a median interval respectively of 4.8, 9, and 17.8 weeks after the first, second, and booster doses. The majority of the cases occurred after the second dose of ChAdOx1-nCoV-19. With oral amino-salicylic acid (ASA), ASA enema, and systemic steroids, improvement was seen in the majority at a median follow-up of 26-30 weeks. 14 patients had persistent health issues (median follow-up of 73-75 weeks). Conclusion New-onset IBD and exacerbations can occur after 1-3 months of COVID-19 vaccines. Extended surveillance of vaccinated individuals is required to understand the incidence and course of late-onset adverse events and molecular studies are warranted to understand their immunological basis.

The synthesis of N-glycosides has received significant attention due to their crucial role in carbohydrate chemistry. Despite considerable advancements were developed in the construction of N-glycosides, methods for the stereoselective construction of 2-deoxy-α-N-glycosides are still limited. Herein, we disclosed a nickel-catalyzed hydroamination of glycals under mild conditions. This transformation could allow for the stereoselective synthesis of an array of 2-deoxy-α-N-glycosides with excellent α-stereoselectivity. Nickel-catalyzed glycosylation reactions, particularly those involving anomeric C(sp3)-metal bond formation, have proven to be an effec-tive and stereoselective strategy for producing various N-glycosides. Additionally, with highlight the application of this reaction, γ-sugar amino acid derivatives were synthesized by one step.

Transformation of an abnormal karyotype to acute erythroid leukemia in a pediatric patient with Fanconi anemia: a case reportCorresponding Author: Lauren Hernandez, D.O.Pediatric Hematology/Oncology FellowUniversity of North Carolina at Chapel Hill170 Manning Drive1185A Houpt Physicians’ Office BuildingChapel Hill, NC 27599-7236Email: lauren.hernandez@unc.eduPhone: 321-501-4891 | Fax: 919-966-7629Thomas B. Alexander, M.D., M.P.H.Assistant Professor of PediatricsDivision of Pediatric Hematology and OncologyUniversity of North Carolina at Chapel HillJonathan Galeotti, M.D.Assistant Professor of HematopathologyDepartment of Pathology and Laboratory MedicineUniversity of North Carolina at Chapel HillStuart Gold, M.D.Distinguished Professor of PediatricsDivision of Pediatric Hematology and OncologyUniversity of North Carolina at Chapel HillWord count: 842Figures: 1Keywords: acute erythroid leukemia, pediatric, Fanconi anemia, monosomy 7Abbreviations:

Environmental change is becoming synchronous across sites with frequent emergence of extremes in recent years, with potential impacts on species’ synchronous abundance over large scales. Analyzing 41 years of breeding bird survey data across North America, we observed that some birds showed mostly lower tail-dependent spatial synchrony (i.e., synchrony across sites at low abundances), while others showed mostly upper tail-dependent spatial synchrony (i.e., synchrony across sites at high abundances). We found that spatial synchrony in climate extremes (i.e., tail-dependence in climate), not the dispersal trait (hand-wing index), drove the spatial synchrony in abundance extremes (i.e., tail-dependence in abundance) up to 250 Km. Tail-dependence in high (or low, respectively) temperature across sites caused lower (or upper, respectively) tail-dependent spatial synchrony in abundance. In a rapidly changing environment, these findings highlight the importance of considering synchronized climatic extremes to assess species’ tail-dependent spatial synchrony across large scales.

Introduction: