Network Topology Evaluation and Transitive Alignments for Molecular Networking.

Untargeted tandem mass spectrometry (MS/MS) is an essential technique in modern analytical chemistry, providing a comprehensive snapshot of chemical entities in complex samples and identifying unknowns through their fragmentation patterns. This high-throughput approach generates large data sets that can be challenging to interpret. Molecular Networks (MNs) have been developed as a computational tool to aid in the organization and visualization of complex chemical space in untargeted mass spectrometry data, thereby supporting comprehensive data analysis and interpretation. MNs group related compounds with potentially similar structures from MS/MS data by calculating all pairwise MS/MS similarities and filtering these connections to produce a MN. Such networks are instrumental in metabolomics for identifying novel metabolites, elucidating metabolic pathways, and even discovering biomarkers for disease. While MS/MS similarity metrics have been explored in the literature, the influence of network topology approaches on MN construction remains unexplored. This manuscript introduces metrics for evaluating MN construction, benchmarks state-of-the-art approaches, and proposes the Transitive Alignments approach to improve MN construction. The Transitive Alignment technique leverages the MN topology to realign MS/MS spectra of related compounds that differ by multiple structural modifications. Combining this Transitive Alignments approach with pseudoclique finding, a method for identifying highly connected groups of nodes in a network, resulted in more complete and higher-quality molecular families. Finally, we also introduce a targeted network construction technique called induced transitive alignments where we demonstrate effectiveness on a real world natural product discovery application. We release this transitive alignment technique as a high-throughput workflow that can be used by the wider research community.

Feasibility and Favorable Responses Following Investigational CAR T-Cell Therapy for Relapsed and Refractory Infant ALL.

Infants with B-cell acute lymphoblastic leukemia (B-ALL) continue to have significantly worse outcomes compared to older children with B-ALL, and those with relapsed or refractory (R/R) infant ALL have especially dismal outcomes with conventional treatment. CD19-targeting chimeric antigen receptor (CAR) T-cell therapy has demonstrated remarkable success in the treatment of R/R childhood B-ALL, though the majority of reports have been in non-infant patients. Barriers to the successful implementation of CAR T-cell therapy in infant B-ALL include challenges related to apheresis, product manufacturing and disease-specific considerations such as lineage switch. We describe our experience utilizing two experimental CD19-CAR T-cell products, SCRI-CAR19 or SCRI-CAR19x22, for 19 patients with R/R infant B-ALL enrolled on three clinical trials. CAR T-cell products were successfully manufactured in 18/19 (94.7%) patients, with a median age of 22.5 months at enrollment (range, 14.5-40.1 months). Sixteen of 17 (94.1%) treated patients achieved a complete remission without detectable minimal residual disease. The 1-year leukemia free survival was 75% and 1-year overall survival was 76.5%, with a median follow up time of 35.8 months (range, 1.7-83.6 months). Cytokine release syndrome (CRS) occurred in 14/17 (82.4%) patients, with only 1 patient experiencing Grade 3 CRS. Neurotoxicity occurred in 2/17 (11.8%) patients with all events ≤ Grade 2. With the successful early clinical experience of CAR T-cell therapy in this population, more systematic evaluation specific to infant ALL is warranted.

Speeding up the recovery of coastal habitats through management interventions that address constraints on dispersal and recruitment.

Plans for habitat restoration will benefit from predictions of timescales for recovery. Theoretical models have been a powerful tool for informing practical guidelines in planning marine protected areas, suggesting restoration planning could also benefit from a theoretical framework. We developed a model that can predict recovery times following restoration action, under dispersal, recruitment and connectivity constraints. We apply the model to a case study of seagrass restoration and find recovery times following restoration action can vary greatly, from <1 to >20 years. The model also shows how recovery can be accelerated when restoration actions are matched to the constraints on recovery. For example, spreading of propagules can be used when connectivity is the critical restriction. The recovery constraints we articulated mathematically also apply to the restoration of coral reefs, mangroves, saltmarsh, shellfish reefs and macroalgal forests, so our model provides a general framework for choosing restoration actions that accelerate coastal habitat recovery.

Single gene analysis in yeast suggests nonequilibrium regulatory dynamics for transcription.

Fluctuations in the initiation rate of transcription, the first step in gene expression, ensue from the stochastic behavior of the molecular process that controls transcription. In steady state, the regulatory process is often assumed to operate reversibly, i.e., in equilibrium. However, reversibility imposes fundamental limits to information processing. For instance, the assumption of equilibrium is difficult to square with the precision with which the regulatory process executes its task in eukaryotes. Here we provide evidence - from microscopic analyses of the transcription dynamics at a single gene copy of yeast - that the regulatory process for transcription is cyclic and irreversible (out of equilibrium). The necessary coupling to reservoirs of free energy occurs via sequence-specific transcriptional activators and the recruitment, in part, of ATP-dependent chromatin remodelers. Our findings may help explain how eukaryotic cells reconcile the dual but opposing requirements for fast regulatory kinetics and high regulatory specificity.

Total synthesis of dissectol A, using an enediolate-based Tsuji-Trost reaction.

Dissectol A is a rearranged terpene glycoside isolated from several flowering plants. Starting from glucose, the densely functionalized bicyclic structure has been prepared via site-selective oxidation and an intramolecular allylic alkylation reaction with an enediolate as the nucleophile. Despite earlier reports, dissectol A is not effective at inhibiting DevRS signaling in whole-cell Mycobacterium tuberculosis and does not inhibit growth of the bacterium.

Effectiveness of Platelet-Rich Plasma in Reducing Pain and Increasing Function After Acute Lateral Ankle Sprain: A Critically Appraised Topic.

CLINICAL SCENARIO: Ankle sprains are one of the most common injuries in athletics, and many lead to recurrent sprains, chronic ankle instability, and persistent symptoms. Treatment improvements are needed. Platelet-rich plasma (PRP) involves formulating autologous plasma with higher platelet concentration to be injected in the desired tissue. There is currently high-quality evidence supporting the use of PRP with lateral epicondylitis and knee osteoarthritis to accelerate the healing process and decrease pain. CLINICAL QUESTION: Does the injection of PRP relieve pain faster and improve function compared with no injection or placebo in patients with a lateral ankle sprain? SUMMARY OF KEY FINDINGS: A computerized search yielded 191 studies; of these, 3 studies fit the inclusion and exclusion criteria. PRP injection reduces pain and increases function after lateral ankle sprain 5 to 8 weeks after intervention. CLINICAL BOTTOM LINE: The use of PRP after lateral ankle sprain to decrease pain and increase function is supported with moderate evidence. STRENGTH OF RECOMMENDATION: Based on the Strength of Recommendation Taxonomy, evidence from the included studies is considered as level B, reflecting limited quality patient-oriented evidence.

COVID-19 Disruptions to Social Care Delivery: A Qualitative Study in Two Large, Safety-Net Primary Care Clinics.

BACKGROUND: Social care integration refers to the incorporation of activities into health systems that assist patients with health-related social needs (HRSNs) that negatively impact the health outcomes of their patients, such as food insecurity or homelessness. Social care integration initiatives are becoming more common. The COVID-19 pandemic strained health systems while simultaneously increasing levels of unmet social needs. OBJECTIVE: To describe the effects of the COVID-19 pandemic on established social care delivery in a primary care setting. DESIGN: We used qualitative semi-structured interviews of stakeholders to assess barriers and facilitators to social care delivery in the primary care setting during the COVID-19 health emergency. Data was analyzed using a hybrid inductive/deductive thematic analysis approach with both the Consolidated Framework for Implementation Research (CFIR) and the Screen-Navigate-Connect-Address-Evaluate model of social care integration. SETTING: Two safety-net, hospital-based primary care clinics with established screening for food insecurity, homelessness, and legal needs. PARTICIPANTS: Six physicians, six nurses, six members of the social work team (clinical social workers and medical case workers), six community health workers, and six patients (total N = 30) completed interviews. RESULTS: Four major themes were identified. (1) A strained workforce experienced challenges confronting increased levels of HRSNs. (2) Vulnerable populations experienced a disproportionate negative impact in coping with effects of the COVID-19 pandemic on HRSNs. (3) COVID-19 protections compounded social isolation but did not extinguish the sense of community. (4) Fluctuations in the social service landscape led to variable experiences. CONCLUSIONS: The COVID-19 pandemic disrupted established social care delivery in a primary care setting. Many of the lessons learned about challenges to social care delivery when health systems are strained are important considerations that can inform efforts to expand social care delivery.

A Framework for Response Escalation and Emergency Response Asset Management.

The Centers for Disease Control and Prevention (CDC) responds to public health emergencies at various levels within its organization. Overtime, CDC's response capabilities have matured across the organization due to years of emergency management investment and experience across the agency. In 2019, CDC began to implement the Graduated Response Framework to formalize an approach for managing public health emergencies that recognizes its response capabilities and meets the evolving needs of the country. This brief report summarizes CDC's Graduated Response Framework structure, and how response management escalates and de-escalates according to resource needs and complexity.

Quantum pathways for charged track finding in high-energy collisions.

In high-energy particle collisions, charged track finding is a complex yet crucial endeavor. We propose a quantum algorithm, specifically quantum template matching, to enhance the accuracy and efficiency of track finding. Abstracting the Quantum Amplitude Amplification routine by introducing a data register, and utilizing a novel oracle construction, allows data to be parsed to the circuit and matched with a hit-pattern template, without prior knowledge of the input data. Furthermore, we address the challenges posed by missing hit data, demonstrating the ability of the quantum template matching algorithm to successfully identify charged-particle tracks from hit patterns with missing hits. Our findings therefore propose quantum methodologies tailored for real-world applications and underline the potential of quantum computing in collider physics.

Automatic segmentation of medial temporal lobe subregions in multi-scanner, multi-modality MRI of variable quality.

Background: Volumetry of subregions in the medial temporal lobe (MTL) computed from automatic segmentation in MRI can track neurodegeneration in Alzheimer's disease. However, image quality may vary in MRI. Poor quality MR images can lead to unreliable segmentation of MTL subregions. Considering that different MRI contrast mechanisms and field strengths (jointly referred to as "modalities" here) offer distinct advantages in imaging different parts of the MTL, we developed a muti-modality segmentation model using both 7 tesla (7T) and 3 tesla (3T) structural MRI to obtain robust segmentation in poor-quality images. Method: MRI modalities including 3T T1-weighted, 3T T2-weighted, 7T T1-weighted and 7T T2-weighted (7T-T2w) of 197 participants were collected from a longitudinal aging study at the Penn Alzheimer's Disease Research Center. Among them, 7T-T2w was used as the primary modality, and all other modalities were rigidly registered to the 7T-T2w. A model derived from nnU-Net took these registered modalities as input and outputted subregion segmentation in 7T-T2w space. 7T-T2w images most of which had high quality from 25 selected training participants were manually segmented to train the multi-modality model. Modality augmentation, which randomly replaced certain modalities with Gaussian noise, was applied during training to guide the model to extract information from all modalities. To compare our proposed model with a baseline single-modality model in the full dataset with mixed high/poor image quality, we evaluated the ability of derived volume/thickness measures to discriminate Amyloid+ mild cognitive impairment (A+MCI) and Amyloid- cognitively unimpaired (A-CU) groups, as well as the stability of these measurements in longitudinal data. Results: The multi-modality model delivered good performance regardless of 7T-T2w quality, while the single-modality model under-segmented subregions in poor-quality images. The multi-modality model generally demonstrated stronger discrimination of A+MCI versus A-CU. Intra-class correlation and Bland-Altman plots demonstrate that the multi-modality model had higher longitudinal segmentation consistency in all subregions while the single-modality model had low consistency in poor-quality images. Conclusion: The multi-modality MRI segmentation model provides an improved biomarker for neurodegeneration in the MTL that is robust to image quality. It also provides a framework for other studies which may benefit from multimodal imaging.

Nested non-covalent interactions expand the functions of supramolecular polymer networks.

Supramolecular polymer networks contain non-covalent cross-links that enable access to broadly tunable mechanical properties and stimuli-responsive behaviors; the incorporation of multiple unique non-covalent cross-links within such materials further expands their mechanical responses and functionality. To date, however, the design of such materials has been accomplished through discrete combinations of distinct interaction types in series, limiting materials design logic. Here we introduce the concept of leveraging "nested" supramolecular crosslinks, wherein two distinct types of non-covalent interactions exist in parallel, to control bulk material functions. To demonstrate this concept, we use polymer-linked Pd2L4 metal-organic cage (polyMOC) gels that form hollow metal-organic cage junctions through metal-ligand coordination and can exhibit well-defined host-guest binding within their cavity. In these "nested" supramolecular network junctions, the thermodynamics of host-guest interactions within the junctions affect the metal-ligand interactions that form those junctions, ultimately translating to substantial guest-dependent changes in bulk material properties that could not be achieved in traditional supramolecular networks with multiple interactions in series.

Two 3D Fractal-Based Approaches for Topographical Characterization: Richardson Patchwork versus Sdr.

Various methods exist for multiscale characterization of surface topographies, each offering unique insights and applications. The study focuses on fractal-based approaches, distinguishing themselves by leveraging fractals to analyze surface complexity. Specifically, the Richardson Patchwork method, used in the ASME B46.1 and ISO 25178 standards, is compared to the Sdr parameter derived from ISO 25178-2, with a low-pass Gaussian filter for multiscale characterization. The comparison is performed from the relative area calculated on topographies of TA6V samples grit blasted with different pressures and blasting materials (media). The surfaces obtained by grit blasting have fractal-like characteristics over the scales studied, enabling the analysis of area development at multiple levels based on pressure and media. The relative area is similar for both methods, regardless of the complexity of the topographies. The relevance scale for each calculation method that significantly represents the effect of grit blasting pressure on the increased value of the relative area is a tiling of 7657.64 µm² of triangle area for the Patchwork method and a 124.6 µm cut-off for the low-pass Gaussian filter of the Sdr method. These results could facilitate a standard, friendly, new fractal method for multiscale characterization of the relative area.

A systematic review of quantitative EEG findings in Fibromyalgia, Chronic Fatigue Syndrome and Long COVID.

Fibromyalgia Syndrome (FMS), Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long COVID (LC) are similar multisymptom clinical syndromes but with difference in dominant symptoms in each individual. There is existing and emerging literature on possible functional alterations of the central nervous system in these conditions. This review aims to synthesise and appraise the literature on resting-state quantitative EEG (qEEG) in FMS, ME/CFS and LC, drawing on previous research on FMS and ME/CFS to help understand neuropathophysiology of the new condition LC. A systematic search of MEDLINE, Embase, CINHAL, PsycINFO and Web of Science databases for articles published between December 1994 and September 2023 was performed. Out of the initial 2510 studies identified, 17 articles were retrieved that met all the predetermined selection criteria, particularly of assessing qEEG changes in one of the three conditions compared to healthy controls. All studies scored moderate to high quality on the Newcastle-Ottawa scale. There was a general trend for decreased low-frequency EEG band activity (delta, theta, and alpha) and increased high-frequency EEG beta activity in FMS, differing to that found in ME/CFS. The limited LC studies included in this review focused mainly on cognitive impairments and showed mixed findings not consistent with patterns observed in FMS and ME/CFS. Our findings suggest different patterns of qEEG brainwave activity in FMS and ME/CFS. Further research is required to explore whether there are phenotypes within LC that have EEG signatures similar to FMS or ME/CFS. This could inform identification of reliable diagnostic markers and possible targets for neuromodulation therapies tailored to each clinical syndrome.

U.S. Preparedness and Response to Increasing Clade I Mpox Cases in the Democratic Republic of the Congo - United States, 2024.

Clade I monkeypox virus (MPXV), which can cause severe illness in more people than clade II MPXVs, is endemic in the Democratic Republic of the Congo (DRC), but the country has experienced an increase in suspected cases during 2023-2024. In light of the 2022 global outbreak of clade II mpox, the increase in suspected clade I cases in DRC raises concerns that the virus could spread to other countries and underscores the importance of coordinated, urgent global action to support DRC's efforts to contain the virus. To date, no cases of clade I mpox have been detected outside of countries in Central Africa where the virus is endemic. CDC and other partners are working to support DRC's response. In addition, CDC is enhancing U.S. preparedness by raising awareness, strengthening surveillance, expanding diagnostic testing capacity for clade I MPXV, ensuring appropriate specimen handling and waste management, emphasizing the importance of appropriate medical treatment, and communicating guidance on the recommended contact tracing, containment, behavior modification, and vaccination strategies.

Medial temporal lobe gray matter microstructure in preclinical Alzheimer's disease.

INTRODUCTION: Typical MRI measures of neurodegeneration have limited sensitivity in early disease stages. Diffusion MRI (dMRI) microstructural measures may allow for detection in preclinical stages. METHODS: Participants had dMRI and either beta-amyloid PET or plasma biomarkers of Alzheimer's pathology within 18 months of MRI. Microstructure was measured in portions of the medial temporal lobe (MTL) with high neurofibrillary tangle (NFT) burden based on a previously developed post mortem 3D-map. Regressions examined relationships between microstructure and markers of Alzheimer's pathology in preclinical disease and then across disease stages. RESULTS: There was higher isometric volume fraction in amyloid-positive compared to amyloid-negative cognitively unimpaired individuals in high tangle MTL regions. Similarly, plasma biomarkers and 18F-flortaucipir were associated with microstructural changes in preclinical disease. Additional microstructural effects were seen across disease stages. DISCUSSION: Combining a post mortem atlas of NFT pathology with microstructural measures allows for detection of neurodegeneration in preclinical Alzheimer's disease. Highlights Typical markers of neurodegeneration are not sensitive in preclinical Alzheimer's. dMRI measured microstructure in regions with high NFT. Microstructural changes occur in medial temporal regions in preclinical disease. Microstructural changes occur in other typical Alzheimer's regions in later stages. Combining post mortem pathology atlases with in vivo MRI is a powerful framework.

Integrating socioeconomic and ecological data into restoration practice.

Driven by the United Nations Decade on Restoration and international funding initiatives, such as the Mangrove Breakthrough, investment in mangrove restoration is expected to increase. Yet, mangrove restoration efforts frequently fail, usually because of ad hoc site-selection processes that do not consider mangrove ecology and the socioeconomic context. Using decision analysis, we developed an approach that accounts for socioeconomic and ecological data to identify sites with the highest likelihood of mangrove restoration success. We applied our approach in the Biosphere Reserve Marismas Nacionales Nayarit, Mexico, an area that recently received funding for implementing mangrove restoration actions. We identified 468 potential restoration sites, assessed their restorability potential based on socioeconomic and ecological metrics, and ranked sites for implementation with spatial optimization. The metrics we used included favorable conditions for propagules to establish and survive under sea-level rise, provision of ecosystem services, and community dynamics. Sites that were selected based on socioeconomic or ecological metrics alone had lower likelihood of mangrove restoration success than sites that were selected based on integrated socioeconomic and ecological metrics. For example, selecting sites based on only socioeconomic metrics captured 16% of the maximum attainable value of functioning mangroves able to provide propagules to potential restoration sites, whereas selecting sites based on ecological and socioeconomic metrics captured 46% of functioning mangroves. Our approach was developed as part of a collaboration between nongovernmental organizations, local government, and academics under rapid delivery time lines given preexisting mangrove restoration implementation commitments. The systematic decision process we used integrated socioeconomic and ecological considerations even under short delivery deadlines, and our approach can be adapted to help mangrove restoration site-selection decisions elsewhere.

Integración de datos socioeconómicos y ecológicos en las prácticas de restauración Resumen Se espera que la inversión en la restauración de los manglares incremente debido a la Década de Restauración de las Naciones Unidad y las iniciativas internacionales de financiamiento, como The Mangrove Breakthrough. Sin embargo, los esfuerzos de restauración de manglares fallan con frecuencia, generalmente por los procesos de selección de sitios ad­hoc que no consideran la ecología del manglar y el contexto socioeconómico. Usamos el análisis de decisiones para desarrollar una estrategia que considera los datos socioeconómicos y ecológicos para identificar los sitios con mayor probabilidad de éxito de restauración. Aplicamos nuestra estrategia en la Reserva de la Biósfera Marismas Nacionales Nayarit, México, un área que recibió financiamiento reciente para la restauración del manglar. Identificamos 468 sitios potencialmente restaurables, evaluamos su potencial de restauración con base en medidas ecológicas y socioeconómicas y clasificamos los sitios para la implementación con la optimización espacial. Las medidas que usamos incluían las condiciones favorables para que los propágulos se establezcan y sobrevivan con el incremento en el nivel del mar, el suministro de servicios ambientales y las dinámicas de la comunidad. Los sitios seleccionados sólo con base en las medidas ecológicas o socioeconómicas tuvieron una menor probabilidad de éxito de restauración que los sitios que se seleccionaron con base en medidas socioeconómicas y ecológicas integradas. Por ejemplo, la selección de sitios con base sólo en las medidas socioeconómicas capturó el 16% del máximo valor alcanzable de manglares funcionales capaces de proporcionar propágulos a los sitios potenciales de restauración, mientras que la selección basada en medidas ecológicas y socioeconómicas capturó el 46% de los manglares funcionales. Desarrollamos nuestra estrategia como parte de una colaboración entre organizaciones no gubernamentales, el gobierno local y académicos sujetos a una fecha pronta de entrega debido a los compromisos preexistentes para la restauración de manglares. El proceso de decisión sistemática que usamos integró las consideraciones ecológicas y socioeconómicas incluso con plazos cortos de entrega. Nuestra estrategia puede adaptarse para apoyar en la selección de sitios de restauración de manglares en otros sitios.

Palmitoylation regulates norepinephrine transporter trafficking and expression and is potentially involved in the pathogenesis of postural orthostatic tachycardia syndrome.

Postural orthostatic tachycardia syndrome (POTS) is an adrenergic signaling disorder characterized by excessive plasma norepinephrine, postural tachycardia, and syncope. The norepinephrine transporter (NET) modulates adrenergic homeostasis via reuptake of extracellular catecholamines and is implicated in the pathogenesis of adrenergic and neurological disorders. Previous research has outlined that NET activity and trafficking is modulated via reversible post-translational modifications like phosphorylation and ubiquitylation. S-palmitoylation, or the addition of a 16-carbon saturated fatty acid, is another post-translational modification responsible for numerous biological mechanisms. In this study, we reveal that NET is dynamically palmitoylated and inhibition of this modification with the palmitoyl acyltransferase (DHHC) inhibitor, 2-bromopalmitate (2BP), results in decreased NET palmitoylation within 90 min of treatment. This result was followed closely with a reduction in transport capacity, cell surface, and total cellular NET expression after 120 min of treatment. Increasing 2BP concentrations and treatment time revealed a nearly complete loss of total NET protein. Co-expression with individual DHHCs revealed a single DHHC enzyme, DHHC1, promoted WT hNET palmitoylation and elevated NET protein levels. The POTS associated NET mutant, A457P, exhibits dramatically decreased transport capacity and cell surface levels which we have confirmed in the current study. In an attempt to recover A457P NET expression we co-expressed the A457P variant with DHHC1 to drive expression as seen with the WT protein but instead saw an increase in NET N-terminal immuno-detectable fragments. Further investigation of A457P NET palmitoylation and surface expression is necessary, but our preliminary novel findings reveal palmitoylation as a mechanism of NET regulation and suggest that dysregulation of this process may contribute to the pathogenesis of POTS.