Dynamics of subsurface chlorophyll maxima in the northern Indian Ocean.

Subsurface chlorophyll maxima (SCM) significantly contributes to oceanic primary productivity, emphasizing the need to study its dynamics and governing mechanisms. We used datasets from various platforms to investigate relationships between the SCM characteristics (SCM depth (ZSCM), SCM magnitude (Chlmax), SCM thickness (TSCM)) and environmental variables modulated by various physical processes in the Northern Indian Ocean (NIO). In the Arabian Sea (western NIO), seasonal processes like convective mixing and upwelling, primarily regulated the SCM characteristics. In the Bay of Bengal (eastern NIO), SCM characteristics were jointly influenced by fresh water influx, barrier layer formation, presence of eddies, and the propagation of Kelvin and Rossby waves. Any changes in these oceanic processes, potentially driven by climate change, could therefore impact oceanic primary production. Additionally, a positive association obtained between Chlmax and downward CO2 flux, while a shallower ZSCM, associated with higher concentrations of DMS, indicated SCM's role in regulating atmospheric gases.

Origin of Dopant-Carrier Exchange Coupling and Excitonic Zeeman Splitting in Mn2+-Doped Lead Halide Perovskite Nanocrystals.

Low-dimensional metal halide perovskites have unique optical and electrical properties that render them attractive for the design of diluted magnetic semiconductors. However, the nature of dopant-exciton exchange interactions that result in spin-polarization of host-lattice charge carriers as a basis for spintronics remains unexplored. Here, we investigate Mn2+-doped CsPbCl3 nanocrystals using magnetic circular dichroism spectroscopy and show that Mn2+ dopants induce excitonic Zeeman splitting which is strongly dependent on the nature of the band-edge structure. We demonstrate that the largest splitting corresponds to exchange interactions involving the excited state at the M-point along the spin-orbit split-off conduction band edge. This splitting gives rise to an absorption-like C-term excitonic MCD signal, with the estimated effective g-factor (geff) of ca. 70. The results of this work help resolve the assignment of absorption transitions observed for metal halide perovskite nanocrystals and allow for a design of new diluted magnetic semiconductor materials for spintronics applications.

Anterior Cingulate Cortex Contributes to the Hyperlocomotion under Nitrogen Narcosis.

Nitrogen narcosis is a neurological syndrome that manifests when humans or animals encounter hyperbaric nitrogen, resulting in a range of motor, emotional, and cognitive abnormalities. The anterior cingulate cortex (ACC) is known for its significant involvement in regulating motivation, cognition, and action. However, its specific contribution to nitrogen narcosis-induced hyperlocomotion and the underlying mechanisms remain poorly understood. Here we report that exposure to hyperbaric nitrogen notably increased the locomotor activity of mice in a pressure-dependent manner. Concurrently, this exposure induced heightened activation among neurons in both the ACC and dorsal medial striatum (DMS). Notably, chemogenetic inhibition of ACC neurons effectively suppressed hyperlocomotion. Conversely, chemogenetic excitation lowered the hyperbaric pressure threshold required to induce hyperlocomotion. Moreover, both chemogenetic inhibition and genetic ablation of activity-dependent neurons within the ACC reduced the hyperlocomotion. Further investigation revealed that ACC neurons project to the DMS, and chemogenetic inhibition of ACC-DMS projections resulted in a reduction in hyperlocomotion. Finally, nitrogen narcosis led to an increase in local field potentials in the theta frequency band and a decrease in the alpha frequency band in both the ACC and DMS. These results collectively suggest that excitatory neurons within the ACC, along with their projections to the DMS, play a pivotal role in regulating the hyperlocomotion induced by exposure to hyperbaric nitrogen.

Auranofin inhibition of thioredoxin reductase sensitizes lung neuroendocrine tumor cells (NETs) and small cell lung cancer (SCLC) cells to sorafenib as well as inhibiting SCLC xenograft growth.

Thioredoxin Reductase (TrxR) functions to recycle thioredoxin (Trx) during hydroperoxide metabolism mediated by peroxiredoxins and is currently being targeted using the FDA-approved anti-rheumatic drug, auranofin (AF), to selectively sensitize cancer cells to therapy. AF treatment decreased TrxR activity and clonogenic survival in small cell lung cancer (SCLC) cell lines (DMS273 and DMS53) as well as the H727 atypical lung carcinoid cell line. AF treatment also significantly sensitized DMS273 and H727 cell lines in vitro to sorafenib, an FDA-approved multi-kinase inhibitor that depleted intracellular glutathione (GSH). The pharmacokinetic, pharmacodynamic, and safety profile of AF was examined in nude mice with DMS273 xenografts administered AF intraperitoneally at 2 mg/kg or 4 mg/kg (IP) once (QD) or twice daily (BID) for 1-5 d. Plasma levels of AF were 10-20 µM (determined by mass spectrometry of gold), and the optimal inhibition of TrxR activity was obtained at 4 mg/kg once daily, with no effect on glutathione peroxidase 1 activity. This AF treatment extended for 14 d, inhibited TrxR (>75%), and resulted in a significant prolongation of median overall survival from 19 to 23 d (p = .04, N = 30 controls, 28 AF). In this experiment, there were no observed changes in animal bodyweight, complete blood counts (CBCs), bone marrow toxicity, blood urea nitrogen, or creatinine. These results support the hypothesis that AF effectively inhibits TrxR both in vitro and in vivo in SCLC, sensitizes NETs and SCLC to sorafenib, and could be repurposed as an adjuvant therapy with targeted agents that induce disruptions in thiol metabolism.

Distinctive chemotactic responses of three marine herbivore protists to DMSP and related compounds.

Marine planktonic predator-prey interactions occur in microscale seascapes, where diffusing chemicals may act either as chemotactic cues that enhance or arrest predation, or as elemental resources that are complementary to prey ingestion. The phytoplankton osmolyte dimethylsulfoniopropionate (DMSP) and its degradation products dimethylsulfide (DMS) and acrylate are pervasive compounds with high chemotactic potential, but there is a longstanding controversy over whether they act as grazing enhancers or deterrents. Here, we investigated the chemotactic responses of three herbivorous dinoflagellates to point-sourced, microscale gradients of dissolved DMSP, DMS, and acrylate. We found no evidence for acrylate being a chemotactic repellent and observed a weak attractor role of DMS. DMSP behaved as a strong chemoattractor whose potential for grazing facilitation through effects on swimming patterns and aggregation depends on the grazer's feeding mode and ability to incorporate DMSP. Our study reveals that predation models will fail to predict grazing impacts unless they incorporate chemotaxis-driven searching and finding of prey.

Abolished frameshifting for predicted structure-stabilizing SARS-CoV-2 mutants: Implications to alternative conformations and their statistical structural analyses.

The SARS-CoV-2 frameshifting element (FSE) has been intensely studied and explored as a therapeutic target for coronavirus diseases including COVID-19. Besides the intriguing virology, this small RNA is known to adopt many length-dependent conformations, as verified by multiple experimental and computational approaches. However, the role these alternative conformations play in the frameshifting mechanism and how to quantify this structural abundance has been an ongoing challenge. Here, we show by DMS and dual-luciferase functional assays that previously predicted FSE mutants (using the RAG graph theory approach) suppress structural transitions and abolish frameshifting. Furthermore, correlated mutation analysis of DMS data by three programs (DREEM, DRACO, and DANCE-MaP) reveals important differences in their estimation of specific RNA conformations, suggesting caution in the interpretation of such complex conformational landscapes. Overall, the abolished frameshifting in three different mutants confirms that all alternative conformations play a role in the pathways of ribosomal transition.

Hfq mediates transcriptome-wide RNA structurome reprogramming under virulence-inducing conditions in a phytopathogen.

Although RNA structures play important roles in regulating gene expression, the mechanism and function of mRNA folding in plant bacterial pathogens remain elusive. Therefore, we perform dimethyl sulfate sequencing (DMS-seq) on the Pseudomonas syringae under nutrition-rich and -deficient conditions, revealing that the mRNA structure changes substantially in the minimal medium (MM) that tunes global translation efficiency (TE), thereby inducing virulence. This process is led by the increased expression of hfq, which is directly activated by transcription regulators RpoS and CysB. The co-occurrence of Hfq and RpoS in diverse bacteria and the deep conservation of Hfq Y25 is critical for RNA-mediated regulation and implicates the wider biological importance of mRNA structure and feedback loops in the control of global gene expression.

Biofiltration of gaseous mixtures of dimethyl sulfide, dimethyl disulfide and dimethyl trisulfide: Effect of operational conditions and microbial analysis.

The efficient removal of volatile sulfur compounds (VSCs), such as dimethyl sulfide (DMS), dimethyl disulfide (DMDS) and dimethyl trisulfide (DMTS), is crucial due to their foul odor and corrosive potential in sewer systems. Biofilters (BFs) offer promise for VSCs removal, but face challenges related to pH control and changing conditions at full scale. Two BFs, operated under acidophilic conditions for 78 days, were evaluated for their performance at varying inlet concentrations and empty bed residence times (EBRTs). BF1, incorporating 4-6 mm marble limestone for pH control, outperformed BF2, which used NaHCO3 in the nutrient solution. BF1 displayed better resilience, maintained a stable pH of 4.6 ± 0.6, and achieved higher maximum elimination capacities (ECmax, 41 mg DMS m-3 h-1 (RE 38.3%), 146 mg DMDS m-3 h-1 (RE 83.1%), 47 mg DMTS m-3 h-1 (RE 93.1%)) at an EBRT of 56 s compared to BF2 (9 mg DMS m-3 h-1 (RE 7.1%), 9 mg DMDS m-3 h-1 (RE 4.8%) and 11 mg DMTS m-3 h-1 (RE 26.6%)). BF2 exhibited pH stratification and decreased performance after feeding interruptions. The biodegradability of VSCs followed the order DMTS > DMDS > DMS, and several microorganisms were identified contributing to VSCs degradation in BF1, including Bacillus (14%), Mycobacterium (11%), Acidiphilium (7%), and Acidobacterium (3%).

An Improved Method to Compute the Mutual Capacitance between Interdigital Transducers in Radio Frequency Surface Acoustic Wave Filters.

This paper proposes an improved method to calculate the mutual capacitance between interdigital transducer (IDT) electrodes to enhance the accuracy of the traditional coupling-of-modes (COM) model, which is commonly used to simulate surface acoustic wave (SAW) filters and duplexers. In this method, the boundary element method (BEM) is adopted to obtain the capacitance per unit length in a layered medium, while the partial capacitance (PC) method is used to derive the effective relative permittivity of the multi-layered IDT. Numerical results from commercially available software are provided for comparison with the results calculated using the proposed method. The consistent results verify the validity and accuracy of this method, which also demonstrates significantly faster calculation speed compared to commercially available software. Precise electrical response prediction of a dual-mode SAW (DMS) filter can be achieved by applying this method to the COM model, and this ultra-fast calculation method can also be included in filter design optimization.

PRKN-linked familial Parkinson's disease: cellular and molecular mechanisms of disease-linked variants.

Parkinson's disease (PD) is a common and incurable neurodegenerative disorder that arises from the loss of dopaminergic neurons in the substantia nigra and is mainly characterized by progressive loss of motor function. Monogenic familial PD is associated with highly penetrant variants in specific genes, notably the PRKN gene, where homozygous or compound heterozygous loss-of-function variants predominate. PRKN encodes Parkin, an E3 ubiquitin-protein ligase important for protein ubiquitination and mitophagy of damaged mitochondria. Accordingly, Parkin plays a central role in mitochondrial quality control but is itself also subject to a strict protein quality control system that rapidly eliminates certain disease-linked Parkin variants. Here, we summarize the cellular and molecular functions of Parkin, highlighting the various mechanisms by which PRKN gene variants result in loss-of-function. We emphasize the importance of high-throughput assays and computational tools for the clinical classification of PRKN gene variants and how detailed insights into the pathogenic mechanisms of PRKN gene variants may impact the development of personalized therapeutics.

Neuroinflammation Plays a Potential Role in the Medulla Oblongata After Moderate Traumatic Brain Injury in Mice as Revealed by Nontargeted Metabonomics Analysis.

Moderate traumatic brain injury (mTBI) involves a series of complex pathophysiological processes in not only the area in direct contact with mechanical violence but also in other brain regions far from the injury site, which may be important factors influencing subsequent neurological dysfunction or death. The medulla oblongata (MO) is a key area for the maintenance of basic respiratory and circulatory functions, whereas the pathophysiological processes after mTBI have rarely drawn the attention of researchers. In this study, we established a closed-head cortical contusion injury model, identified 6 different time points that covered the acute, subacute, and chronic phases, and then used nontargeted metabolomics to identify and analyze the changes in differential metabolites (DMs) and metabolic pathways in the MO region. Our results showed that the metabolic profile of the MO region underwent specific changes over time: harmaline, riboflavin, and dephospho-coenzyme A were identified as the key DMs and play important roles in reducing inflammation, enhancing antioxidation, and maintaining homeostasis. Choline and glycerophospholipid metabolism was identified as the key pathway related to the changes in MO metabolism at different phases. In addition, we confirmed increases in the levels of inflammatory factors and the activation of astrocytes and microglia by Western blot and immunofluorescence staining, and these findings were consistent with the nontargeted metabolomic results. These findings suggest that neuroinflammation plays a central role in MO neuropathology after mTBI and provide new insights into the complex pathophysiologic mechanisms involved after mTBI.

A Performance Analysis of Security Protocols for Distributed Measurement Systems Based on Internet of Things with Constrained Hardware and Open Source Infrastructures.

The widespread adoption of Internet of Things (IoT) devices in home, industrial, and business environments has made available the deployment of innovative distributed measurement systems (DMS). This paper takes into account constrained hardware and a security-oriented virtual local area network (VLAN) approach that utilizes local message queuing telemetry transport (MQTT) brokers, transport layer security (TLS) tunnels for local sensor data, and secure socket layer (SSL) tunnels to transmit TLS-encrypted data to a cloud-based central broker. On the other hand, the recent literature has shown a correlated exponential increase in cyber attacks, mainly devoted to destroying critical infrastructure and creating hazards or retrieving sensitive data about individuals, industrial or business companies, and many other entities. Much progress has been made to develop security protocols and guarantee quality of service (QoS), but they are prone to reducing the network throughput. From a measurement science perspective, lower throughput can lead to a reduced frequency with which the phenomena can be observed, generating, again, misevaluation. This paper does not give a new approach to protect measurement data but tests the network performance of the typically used ones that can run on constrained hardware. This is a more general scenario typical for IoT-based DMS. The proposal takes into account a security-oriented VLAN approach for hardware-constrained solutions. Since it is a worst-case scenario, this permits the generalization of the achieved results. In particular, in the paper, all OpenSSL cipher suites are considered for compatibility with the Mosquitto server. The most used key metrics are evaluated for each cipher suite and QoS level, such as the total ratio, total runtime, average runtime, message time, average bandwidth, and total bandwidth. Numerical and experimental results confirm the proposal's effectiveness in foreseeing the minimum network throughput concerning the selected QoS and security. Operating systems yield diverse performance metric values based on various configurations. The primary objective is identifying algorithms to ensure suitable data transmission and encryption ratios. Another aim is to explore algorithms that ensure wider compatibility with existing infrastructures supporting MQTT technology, facilitating secure connections for geographically dispersed DMS IoT networks, particularly in challenging environments like suburban or rural areas. Additionally, leveraging open firmware on constrained devices compatible with various MQTT protocols enables the customization of the software components, a crucial necessity for DMS.

Characterizing glucokinase variant mechanisms using a multiplexed abundance assay.

BACKGROUND: Amino acid substitutions can perturb protein activity in multiple ways. Understanding their mechanistic basis may pinpoint how residues contribute to protein function. Here, we characterize the mechanisms underlying variant effects in human glucokinase (GCK) variants, building on our previous comprehensive study on GCK variant activity. RESULTS: Using a yeast growth-based assay, we score the abundance of 95% of GCK missense and nonsense variants. When combining the abundance scores with our previously determined activity scores, we find that 43% of hypoactive variants also decrease cellular protein abundance. The low-abundance variants are enriched in the large domain, while residues in the small domain are tolerant to mutations with respect to abundance. Instead, many variants in the small domain perturb GCK conformational dynamics which are essential for appropriate activity. CONCLUSIONS: In this study, we identify residues important for GCK metabolic stability and conformational dynamics. These residues could be targeted to modulate GCK activity, and thereby affect glucose homeostasis.

Minimum information and guidelines for reporting a multiplexed assay of variant effect.

Multiplexed assays of variant effect (MAVEs) have emerged as a powerful approach for interrogating thousands of genetic variants in a single experiment. The flexibility and widespread adoption of these techniques across diverse disciplines have led to a heterogeneous mix of data formats and descriptions, which complicates the downstream use of the resulting datasets. To address these issues and promote reproducibility and reuse of MAVE data, we define a set of minimum information standards for MAVE data and metadata and outline a controlled vocabulary aligned with established biomedical ontologies for describing these experimental designs.

Biodegradable Microspheres for Transarterial Chemoembolization in Malignant Liver Disease.

Transarterial chemoembolization (TACE) has revolutionized the treatment landscape for malignant liver disease, offering localized therapy with reduced systemic toxicity. This manuscript delves into the use of degradable microspheres (DMS) in TACE, exploring its potential advantages and clinical applications. DMS-TACE emerges as a promising strategy, offering temporary vessel occlusion and optimized drug delivery. The manuscript reviews the existing literature on DMS-TACE, emphasizing its tolerability, toxicity, and efficacy. Notably, DMS-TACE demonstrates versatility in patient selection, being suitable for both intermediate and advanced stages. The unique properties of DMS provide advantages over traditional embolic agents. The manuscript discusses the DMS-TACE procedure, adverse events, and tumor response rates in HCC, ICC, and metastases.

GLP-1 receptor agonists alleviate colonic inflammation by modulating intestinal microbiota and the function of group 3 innate lymphoid cells.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs), which are drugs used for treating type 2 diabetes, have been reported to exert anti-inflammatory effects on inflammatory bowel disease (IBD), the mechanism of which remains elusive. Here, we report that GLP-1RAs ameliorate dextran sulfate sodium (DSS)-induced colitis in both wild-type and T/B-cell-deficient mice through modulating group 3 innate lymphoid cells (ILC3s), a subset of innate lymphoid cells that regulate intestinal immunity. GLP-1RAs promote IL-22 production by ILC3, and the protective effect of GLP-1RAs on DSS-induced colitis was abrogated in ILC3-deficient RORgtgfp/gfp mice. Furthermore, the treatment effect of GLP-RAs on colitis, as well as the generation of IL-22-producing ILC3s by GLP-RAs, is dependent on the gut microbiota. GLP-1RAs increase the abundance of Firmicutes and Proteobacteria in the gut, particularly beneficial bacteria such as Lactobacillus reuteri, and decrease the abundance of enteropathogenic Staphylococcus bacteria. The untargeted gas chromatography (GC)/liquid chromatography (LC)-mass spectrometry (MS) of faecal metabolites further revealed enrichment of N,N-dimethylsphingosine (DMS), an endogenous metabolite derived from sphingosine, in the GLP-1RA-treated group. Strikingly, DMS ameliorates colitis while promoting intestinal IL-22-producing ILC3s. Taken together, our findings show that GLP-1RAs exert a therapeutic effect on colitis possibly by regulating the microbiota-DMS-IL-22+ILC3 axis, highlighting the potential beneficial role of GLP-RAs in inflammatory intestinal disorders with diabetes complications.

Rugged fitness landscapes minimize promiscuity in the evolution of transcriptional repressors.

How a protein's function influences the shape of its fitness landscape, smooth or rugged, is a fundamental question in evolutionary biochemistry. Smooth landscapes arise when incremental mutational steps lead to a progressive change in function, as commonly seen in enzymes and binding proteins. On the other hand, rugged landscapes are poorly understood because of the inherent unpredictability of how sequence changes affect function. Here, we experimentally characterize the entire sequence phylogeny, comprising 1,158 extant and ancestral sequences, of the DNA-binding domain (DBD) of the LacI/GalR transcriptional repressor family. Our analysis revealed an extremely rugged landscape with rapid switching of specificity, even between adjacent nodes. Further, the ruggedness arises due to the necessity of the repressor to simultaneously evolve specificity for asymmetric operators and disfavors potentially adverse regulatory crosstalk. Our study provides fundamental insight into evolutionary, molecular, and biophysical rules of genetic regulation through the lens of fitness landscapes.

Structured 3' UTRs destabilize mRNAs in plants.

BACKGROUND: RNA secondary structure (RSS) can influence the regulation of transcription, RNA processing, and protein synthesis, among other processes. 3' untranslated regions (3' UTRs) of mRNA also hold the key for many aspects of gene regulation. However, there are often contradictory results regarding the roles of RSS in 3' UTRs in gene expression in different organisms and/or contexts. RESULTS: Here, we incidentally observe that the primary substrate of miR159a (pri-miR159a), when embedded in a 3' UTR, could promote mRNA accumulation. The enhanced expression is attributed to the earlier polyadenylation of the transcript within the hybrid pri-miR159a-3' UTR and, resultantly, a poorly structured 3' UTR. RNA decay assays indicate that poorly structured 3' UTRs could promote mRNA stability, whereas highly structured 3' UTRs destabilize mRNA in vivo. Genome-wide DMS-MaPseq also reveals the prevailing inverse relationship between 3' UTRs' RSS and transcript accumulation in the transcriptomes of Arabidopsis, rice, and even human. Mechanistically, transcripts with highly structured 3' UTRs are preferentially degraded by 3'-5' exoribonuclease SOV and 5'-3' exoribonuclease XRN4, leading to decreased expression in Arabidopsis. Finally, we engineer different structured 3' UTRs to an endogenous FT gene and alter the FT-regulated flowering time in Arabidopsis. CONCLUSIONS: We conclude that highly structured 3' UTRs typically cause reduced accumulation of the harbored transcripts in Arabidopsis. This pattern extends to rice and even mammals. Furthermore, our study provides a new strategy of engineering the 3' UTRs' RSS to modify plant traits in agricultural production and mRNA stability in biotechnology.

Test procedure for the evaluation of partially automated driving HMI including driver monitoring systems in driving simulation.

The proposed test procedure presents an approach for the evaluation of the usability of partial automated driving HMI including driver monitoring systems in driving simulation. This procedure is based on a definition of requirements that a Level 2 HMI and its included driver monitoring system must fulfill in order to guarantee that the drivers understand their responsibilities of continuously monitoring the driving environment and the status of the partial automated driving system. These requirements are used to define the evaluation criteria that have to be validated in the test as well as the use cases in which these criteria can be assessed. The result is a detailed and comprehensive test guide including the specification of the test drives, the necessary instructions, the test environment and the recruiting criteria for the test sample.•Evaluation of usability aspects of level 2 automated driving HMI including driver monitoring systems•Based on the definition of requirements for L2 HMI•Test guide including the definition of use cases, evaluation criteria and testing conditions in driving simulation.

Revealing the Marine Cycles of Volatile Sulfur Compounds and Their Biogeochemical Controls: A Case of the Western North Pacific.

Volatile sulfur compounds, such as dimethyl sulfide (DMS), carbonyl sulfide (OCS), and carbon disulfide (CS2), have significant implications for both atmospheric chemistry and climate change. Despite the crucial role of oceans in regulating their atmospheric budgets, our comprehension of their cycles in seawater remains insufficient. To address this gap, a field investigation was conducted in the western North Pacific to clarify the sources, sinks, and biogeochemical controls of these gases in two different marine environments, including relatively eutrophic Kuroshio-Oyashio extension (KOE) and oligotrophic North Pacific subtropical gyre. Our findings revealed higher concentrations of these gases in both seawater and the atmosphere in the KOE compared to the subtropical gyre. In the KOE, nutrient-rich upwelling stimulated rapid DMS biological production, while reduced seawater temperatures hindered the removal of OCS and CS2, leading to their accumulation. Furthermore, we have quantitatively evaluated the relative contribution of each pathway to the source and sink of DMS, OCS, and CS2 within the mixed layer and identified vertical exchange as a potential sink in most cases, transporting substantial amounts of these gases from the mixed layer to deeper waters. This research advances our understanding of sulfur gas source-sink dynamics in seawater, contributing to the assessment of their marine emissions and atmospheric budgets.