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Lasso peptides are an increasingly relevant class of peptide natural products with diverse biological activities, intriguing physical properties, and unique chemical structures. Most characterized lasso peptides have been from Actinobacteria and Proteobacteria, despite bioinformatic analyses suggesting that other bacterial taxa, particularly those from Firmicutes, are rich in biosynthetic gene clusters (BGCs) encoding lasso peptides. Herein, we report the bioinformatic identification of a lasso peptide BGC from Paenibacillus taiwanensis DSM18679 which we termed pats. We used a bioinformatics-guided isolation approach and high-resolution tandem mass spectrometry (HRMS/MS) to isolate and subsequently characterize a new lasso peptide produced from the pats BGC, which we named trilenodin, after the tri-isoleucine motif present in its primary sequence. This tri-isoleucine motif is unique among currently characterized lasso peptides. We confirmed the connection between the pats BGC and trilenodin production by establishing the first Bacillus subtilis 168-based heterologous expression system for expressing Firmicutes lasso peptides. We finally determined that trilenodin exhibits potent antimicrobial activity against B. subtilis and Klebsiella pneumoniae, making trilenodin the first characterized biologically active lasso peptide from Firmicutes. Collectively, we demonstrate that bacteria from Firmicutes can serve as high-potential sources of chemically and biologically diverse lasso peptides.
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Immediate breast reconstruction (IBR) following a mastectomy, combined with radiotherapy, presents a multifaceted approach to breast cancer treatment, balancing oncological safety and aesthetic outcomes. IBR, typically involving the use of implants or autologous tissue, aims to restore breast morphology directly after a mastectomy, minimizing the psychological and physical impacts. However, integrating radiotherapy with IBR is complex due to the potential adverse effects on reconstructed tissues. Radiotherapy, essential for reducing local recurrence, can induce fibrosis, capsular contracture, and compromised aesthetic results. This narrative review covers the current trends in the sequencing of breast reconstruction and radiotherapy. We discuss patient selection, timing of radiotherapy, and reconstructive techniques, with special attention paid to quality-of-life outcomes that are increasingly reported in clinical trials. Emerging evidence supports the feasibility of IBR with careful patient selection and tailored therapeutic approaches, although ongoing research is necessary to refine protocols and enhance outcomes. Overall, IBR in the context of radiotherapy remains a promising but intricate treatment modality, requiring a nuanced balance between cancer control and aesthetic restoration.
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CASE: A 30-year-old man with a history of advanced HIV disease (AHD) presented with bilateral equinocavus, leg, and foot muscle paresis, Brooker grade 4 heterotopic ossification of hips and knee stiffness, and was unable to sit upright, stand independently, or walk. Electromyography showed demyelinating sensorimotor and axonal polyneuropathy of lower extremities. Multiple surgeries of bilateral hips, ankles, and feet enabled joint mobility, plantigrade feet, and independent ambulation. CONCLUSION: Patients with AHD may develop multijoint pathologies, secondary to HIV, antiretroviral therapy, or prolonged immobility, resulting in loss of ambulation and independence. Restoring ambulation may necessitate multiple surgeries, with potential for success.
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Infecciones por VIH , Humanos , Masculino , Adulto , Infecciones por VIH/complicaciones , Osificación Heterotópica/diagnóstico por imagen , Osificación Heterotópica/cirugía , Osificación Heterotópica/etiologíaRESUMEN
OBJECTIVES: Programmatic assessment approaches can be extended to the design of allied health professions training, to enhance the learning of trainees. The Australasian College of Physical Scientists and Engineers in Medicine worked with assessment specialists at the Australian Council for Educational Research and Amplexa Consulting, to revise their medical physics and radiopharmaceutical science training programs. One of the central aims of the revisions was to produce a training program that provides standardized training support to their registrars throughout the 3 years, better supporting their registrars to successfully complete the program in the time frame through providing timely and constructive feedback on the registrar's progression. METHODS: We used the principles of programmatic assessment to revise the assessment methods and progression decisions in the three training programs. RESULTS: We revised the 3-year training programs for diagnostic imaging medical physics, radiation oncology medical physics and radiopharmaceutical science in Australia and New Zealand, incorporating clear stages of training and associated progression points. CONCLUSIONS: We discuss the advantages and difficulties that have arisen with this implementation. We found 5 key elements necessary for implementing programmatic assessment in these specialized contexts: embracing blurred boundaries between assessment of and for learning, adapting the approach to each specialized context, change management, engaging subject matter experts, and clear communication to registrars/trainees.
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INTRODUCTION: Pancreatic cancer is a significant public health concern and a leading cause of cancer-related deaths worldwide. This study aimed to investigate pancreatic cancer mortality trends and disparities in the United States (US) from 1999 to 2020. METHODS: Data were obtained from the Centers for Disease Control (CDC) Wide-Ranging Online Data for Epidemiologic Research database. Mortality rates were age-adjusted and standardized to the year 2000 US population. Joinpoint regression was used to analyze temporal trends in age-adjusted mortality rates (AAMRs) by sociodemographic and geographic variables. RESULTS: Between 1999 and 2020, pancreatic cancer led to a total of 810,628 deaths in the US, an average mortality of nearly 39,000 deaths per year. The AAMR slightly increased from 10.6 in 1999 to 11.1 in 2020, with an associated annual percent change (APC) of 0.2. Mortality rates were highest among individuals aged 65 and older. Black individuals experienced the highest overall pancreatic cancer-related AAMR at 13.8. Despite this, Black individuals experienced a decreasing mortality trend over time (APC -0.2) while White individuals experienced an increasing trend in mortality (APC 0.4). Additionally, individuals residing in rural areas experienced steeper rates of mortality increase than those living in urban areas (APC 0.6 for rural vs -0.2 for urban). White individuals in urban and rural populations experienced an increase in mortality, while Black individuals in urban environments experienced a decrease in mortality, and Black individuals in rural environments experienced stable mortality trends. CONCLUSIONS: Mortality from pancreatic cancer continues to increase in the US, with racial and regional disparities identified in minorities and rural-dwelling individuals. These disparate findings highlight the importance of ongoing efforts to understand and address pancreatic cancer treatment and outcomes disparities in the US, and future studies should further investigate the underlying etiologies of these disparities and potential for novel therapies to reduce the mortality.
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Social isolation is a common problem faced by individuals with serious mental illness (SMI), and current intervention approaches have limited effectiveness. This paper presents a blended intervention approach, called mobile Social Interaction Therapy by Exposure (mSITE), to address social isolation in individuals with serious mental illness. The approach combines brief in-person cognitive-behavioral therapy (CBT) with context-triggered mobile CBT interventions that are personalized using mobile sensing data. Our approach targets social behavior and is the first context-aware intervention for improving social outcomes in serious mental illness.
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MoodCapture presents a novel approach that assesses depression based on images automatically captured from the front-facing camera of smartphones as people go about their daily lives. We collect over 125,000 photos in the wild from N=177 participants diagnosed with major depressive disorder for 90 days. Images are captured naturalistically while participants respond to the PHQ-8 depression survey question: "I have felt down, depressed, or hopeless". Our analysis explores important image attributes, such as angle, dominant colors, location, objects, and lighting. We show that a random forest trained with face landmarks can classify samples as depressed or non-depressed and predict raw PHQ-8 scores effectively. Our post-hoc analysis provides several insights through an ablation study, feature importance analysis, and bias assessment. Importantly, we evaluate user concerns about using MoodCapture to detect depression based on sharing photos, providing critical insights into privacy concerns that inform the future design of in-the-wild image-based mental health assessment tools.
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Understanding the dynamics of mental health among undergraduate students across the college years is of critical importance, particularly during a global pandemic. In our study, we track two cohorts of first-year students at Dartmouth College for four years, both on and off campus, creating the longest longitudinal mobile sensing study to date. Using passive sensor data, surveys, and interviews, we capture changing behaviors before, during, and after the COVID-19 pandemic subsides. Our findings reveal the pandemic's impact on students' mental health, gender based behavioral differences, impact of changing living conditions and evidence of persistent behavioral patterns as the pandemic subsides. We observe that while some behaviors return to normal, others remain elevated. Tracking over 200 undergraduate students from high school to graduation, our study provides invaluable insights into changing behaviors, resilience and mental health in college life. Conducting a long-term study with frequent phone OS updates poses significant challenges for mobile sensing apps, data completeness and compliance. Our results offer new insights for Human-Computer Interaction researchers, educators and administrators regarding college life pressures. We also detail the public release of the de-identified College Experience Study dataset used in this paper and discuss a number of open research questions that could be studied using the public dataset.
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BACKGROUND: Major depressive disorder (MDD) and borderline personality disorder (BPD) often co-occur, with 20 % of adults with MDD meeting criteria for BPD. While MDD is typically diagnosed by symptoms persisting for several weeks, research suggests a dynamic pattern of symptom changes occurring over shorter durations. Given the diagnostic focus on affective states in MDD and BPD, with BPD characterized by instability, we expected heightened instability of MDD symptoms among depressed adults with BPD traits. The current study examined whether BPD symptoms predicted instability in depression symptoms, measured by ecological momentary assessments (EMAs). METHODS: The sample included 207 adults with MDD (76 % White, 82 % women) recruited from across the United States. At the start of the study, participants completed a battery of mental health screens including BPD severity and neuroticism. Participants completed EMAs tracking their depression symptoms three times a day over a 90-day period. RESULTS: Using self-report scores assessing borderline personality disorder (BPD) traits along with neuroticism scores and sociodemographic data, Bayesian and frequentist linear regression models consistently indicated that BPD severity was not associated with depression symptom change through time. LIMITATIONS: Diagnostic sensitivity and specificity may be restricted by use of a self-report screening tool for capturing BPD severity. Additionally, this clinical sample of depressed adults lacks a comparison group to determine whether subclinical depressive symptoms present differently among individuals with BPD only. CONCLUSIONS: The unexpected findings shed light on the interplay between these disorders, emphasizing the need for further research to understand their association.
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Trastorno de Personalidad Limítrofe , Trastorno Depresivo Mayor , Evaluación Ecológica Momentánea , Humanos , Trastorno de Personalidad Limítrofe/psicología , Trastorno de Personalidad Limítrofe/epidemiología , Trastorno de Personalidad Limítrofe/diagnóstico , Femenino , Trastorno Depresivo Mayor/psicología , Trastorno Depresivo Mayor/epidemiología , Adulto , Masculino , Persona de Mediana Edad , Adulto Joven , Neuroticismo , Autoinforme , Escalas de Valoración Psiquiátrica , Depresión/psicología , Depresión/epidemiología , Estudios Longitudinales , Teorema de Bayes , Índice de Severidad de la Enfermedad , ComorbilidadRESUMEN
MindScape aims to study the benefits of integrating time series behavioral patterns (e.g., conversational engagement, sleep, location) with Large Language Models (LLMs) to create a new form of contextual AI journaling, promoting self-reflection and well-being. We argue that integrating behavioral sensing in LLMs will likely lead to a new frontier in AI. In this Late-Breaking Work paper, we discuss the MindScape contextual journal App design that uses LLMs and behavioral sensing to generate contextual and personalized journaling prompts crafted to encourage self-reflection and emotional development. We also discuss the MindScape study of college students based on a preliminary user study and our upcoming study to assess the effectiveness of contextual AI journaling in promoting better well-being on college campuses. MindScape represents a new application class that embeds behavioral intelligence in AI.
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ABSTRACT: Children and adults with sickle cell disease (SCD) have increases in morbidity and mortality with COVID-19 infections. The American Society of Hematology Research Collaborative Sickle Cell Disease Research Network performed a prospective COVID-19 vaccine study to assess antibody responses and analyze whether messenger RNA (mRNA) vaccination precipitated any adverse effects unique to individuals with SCD. Forty-one participants received 2 doses of the Pfizer-BioNTech vaccine and provided baseline blood samples before vaccination and 2 months after the initial vaccination for analysis of immunoglobulin G (IgG) reactivity against the receptor binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 spike protein. Six-month IgG reactivity against the viral RBD was also available in 37 patients. Postvaccination reactogenicity was common and similar to the general population. There were no fevers that required inpatient admission. Vaso-occlusive pain within 2 to 3 days of first or second vaccination was reported by 5 participants (12%) including 4 (10%) who sought medical care. Twenty-seven participants (66%) were seropositive at baseline, and all 14 initially seronegative participants (34%) converted to seropositive after vaccination. Overall, mRNA vaccination had a good risk-benefit profile in individuals with SCD. This mRNA vaccine study also marks the first evaluation of vaccine safety and antibody response in very young children with SCD. This trial was registered at www.ClinicalTrials.gov as #NCT05139992.
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Anemia de Células Falciformes , Vacunas contra la COVID-19 , COVID-19 , SARS-CoV-2 , Vacunación , Adolescente , Adulto , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Anemia de Células Falciformes/sangre , Anemia de Células Falciformes/inmunología , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , COVID-19/prevención & control , COVID-19/inmunología , Vacunas contra la COVID-19/efectos adversos , Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/administración & dosificación , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Vacunas de ARNm/administración & dosificación , Vacunas de ARNm/efectos adversos , Vacunas de ARNm/inmunología , Estudios Prospectivos , SARS-CoV-2/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , PreescolarRESUMEN
Anhedonia and depressed mood are two cardinal symptoms of major depressive disorder (MDD). Prior work has demonstrated that cannabis consumers often endorse anhedonia and depressed mood, which may contribute to greater cannabis use (CU) over time. However, it is unclear (1) how the unique influence of anhedonia and depressed mood affect CU and (2) how these symptoms predict CU over more proximal periods of time, including the next day or week (rather than proceeding weeks or months). The current study used data collected from ecological momentary assessment (EMA) in a sample with MDD (N = 55) and employed mixed effects models to detect and predict weekly and daily CU from anhedonia and depressed mood over 90 days. Results indicated that anhedonia and depressed mood were significantly associated with CU, yet varied at daily and weekly scales. Moreover, these associations varied in both strength and directionality. In weekly models, less anhedonia and greater depressed mood were associated with greater CU, and directionality of associations were reversed in the models looking at any CU (compared to none). Findings provide evidence that anhedonia and depressed mood demonstrate complex associations with CU and emphasize leveraging EMA-based studies to understand these associations with more fine-grained detail.
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Afecto , Anhedonia , Depresión , Trastorno Depresivo Mayor , Evaluación Ecológica Momentánea , Humanos , Anhedonia/fisiología , Masculino , Femenino , Adulto , Trastorno Depresivo Mayor/psicología , Afecto/fisiología , Depresión/psicología , Persona de Mediana Edad , Adulto Joven , Uso de la Marihuana/psicologíaRESUMEN
INTRODUCTION: Melanoma, a deadly form of skin cancer, has witnessed a notable increase in incidence over the past decades. Despite advancements in treatment, it remains a significant cause of cancer mortality. Understanding demographic trends and variations in melanoma mortality is crucial for addressing disparities and implementing effective interventions. METHODS: Using the Centers for Disease Control Wide Ranging Online Data for Epidemiologic Research (CDC WONDER) database, we analyzed melanoma mortality data in the United States from 1999 to 2020. Data were stratified by demographic and regional variables, and age-adjusted mortality rates were calculated. Descriptive analysis was performed and Joinpoint regression analysis was employed to identify temporal trends. RESULTS: Between 1999 and 2020, there were 184,416 melanoma-related deaths in the United States Overall, the age-adjusted mortality rate declined from 2.7 to 2.0 per 100,000 people at a rate of -1.3% annually, with significant variations across demographic groups and regions. Men, non-Hispanic White individuals, and those aged > 65 experienced higher mortality rates. Non-Hispanic White individuals noted the steepest decrease in AAMR after 2013 at a rate of -6.1% annually. Disparities were seen by geographic density, with rural populations exhibiting higher mortality compared to their urban and suburban counterparts. CONCLUSION: The study highlights a significant reduction in melanoma mortality in the U.S. since 2013, potentially attributed to advancements in diagnostic techniques such as dermoscopy and the introduction of immune checkpoint inhibitors. Disparities persist, particularly among rural populations. Targeted interventions focusing on increased screening and education are warranted to further mitigate melanoma mortality and address demographic disparities.
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Melanoma , Neoplasias Cutáneas , Humanos , Melanoma/mortalidad , Melanoma/epidemiología , Estados Unidos/epidemiología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Adulto , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/epidemiología , Adulto Joven , Adolescente , Mortalidad/tendencias , Incidencia , Anciano de 80 o más Años , Población Rural/estadística & datos numéricosRESUMEN
Genetic alterations that affect the function of p53 tumor suppressor have been extensively investigated in myeloid neoplasms, revealing their significant impact on disease progression, treatment response, and patient outcomes. The identification and characterization of TP53 mutations play pivotal roles in subclassifying myeloid neoplasms and guiding treatment decisions. Starting with the presentation of a typical case, this review highlights the complicated nature of genetic alterations involving TP53 and provides a comprehensive analysis of TP53 mutations and other alterations in myeloid neoplasms. Currently available methods used in clinical laboratories to identify TP53 mutations are discussed, focusing on the importance of establishing a robust testing protocol within clinical laboratories to ensure the delivery of accurate and reliable results. The treatment implications of TP53 mutations in myeloid neoplasms and clinical trial options are reviewed. Ultimately, we hope that this review provides valuable insights into the patterns of TP53 alterations in myeloid neoplasms and offers guidance to establish practical laboratory testing protocols to support the best practices of precision oncology.
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The synthesis of drug-loaded PLGA nanoparticles through nanoprecipitation in solvent/antisolvent mixtures is well reported but lacks clarity in explaining drug loading mechanisms and the prediction of efficiency of drug entrapment. Various methods using physical parameters such as log P and solid-state drug-polymer solubility aim to predict the intensity of drug-polymer interactions but lack precision. In particular, the zero-enthalpy method for drug/polymer solubility may be intrinsically inaccurate, as we demonstrate. Conventional measurement of loading capacity (LC), expressed in weight ratios, can be misleading for comparing different drugs and we stress the importance of using molar units. This research aims to provide new insights and critically evaluate the established methodologies for drug loading of PLGA nanoparticles. The study employs four model drugs with varying solubilities in solvent/antisolvent mixtures, log P values, and solid-state solubility in PLGA: ketoprofen (KPN), indomethacin (IND), sorafenib (SFN), and clofazimine (CFZ). This study highlights that drug loading efficiency is primarily influenced by the drug's solubilities within the solvent system. We emphasise that both kinetic and thermodynamic factors play a role in the behaviour of the system by considering the changes in drug solubility during mixing. The study introduces a pseudo-constant K* to characterise drug-polymer interactions, with CFZ and SFN showing the highest K* values. Interestingly, while IND and KPN have lower K* values, they achieve higher loading capacities due to their greater solubilities, indicating the key role of solubility in determining LC.
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Combining discrete and continuous data is an important capability for generative models. We present Discrete Flow Models (DFMs), a new flow-based model of discrete data that provides the missing link in enabling flow-based generative models to be applied to multimodal continuous and discrete data problems. Our key insight is that the discrete equivalent of continuous space flow matching can be realized using Continuous Time Markov Chains. DFMs benefit from a simple derivation that includes discrete diffusion models as a specific instance while allowing improved performance over existing diffusion-based approaches. We utilize our DFMs method to build a multimodal flow-based modeling framework. We apply this capability to the task of protein co-design, wherein we learn a model for jointly generating protein structure and sequence. Our approach achieves state-of-the-art co-design performance while allowing the same multimodal model to be used for flexible generation of the sequence or structure.
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Targeting the estrogen receptor alpha (ERα) pathway is validated in the clinic as an effective means to treat ER+ breast cancers. Here we present the development of a VHL-targeting and orally bioavailable proteolysis-targeting chimera (PROTAC) degrader of ERα. In vitro studies with this PROTAC demonstrate excellent ERα degradation and ER antagonism in ER+ breast cancer cell lines. However, upon dosing the compound in vivo we observe an in vitro-in vivo disconnect. ERα degradation is lower in vivo than expected based on the in vitro data. Investigation into potential causes for the reduced maximal degradation reveals that metabolic instability of the PROTAC linker generates metabolites that compete for binding to ERα with the full PROTAC, limiting degradation. This observation highlights the requirement for metabolically stable PROTACs to ensure maximal efficacy and thus optimisation of the linker should be a key consideration when designing PROTACs.
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Receptor alfa de Estrógeno , Proteolisis , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau , Humanos , Receptor alfa de Estrógeno/metabolismo , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/metabolismo , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genética , Femenino , Proteolisis/efectos de los fármacos , Animales , Administración Oral , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Ratones , Antineoplásicos/farmacología , Antineoplásicos/administración & dosificaciónRESUMEN
Carbonates are important carbon-bearing phases in the mantle. While their role in upper mantle petrologic processes has been well studied, their effect on phase relations, melting, and transport properties in the lower mantle is less understood. The stability of carbonates in the mantle depends on a host of factors, including pressure, temperature, oxygen fugacity, and reactions with surrounding mantle phases. To understand the stability of carbonates in the presence of metal in the lower mantle, carbonate-metal reaction experiments on the Fe-Si-Ca-Mg-C-O system were conducted up to 124 GPa and 3200 K. We find that carbonates react with iron alloys to form silicates, iron carbides, and oxides. However, the temperature at which these reactions occur increases with pressure, indicating that along a geotherm in the lowermost mantle carbonates are the stable carbon-bearing phase. Carbon is found to be less siderophilic at high-pressure compared to silicon.
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We describe an overweight but otherwise previously healthy 17-year-old female who presented with altered mental status and rapidly progressive weakness. She was ultimately diagnosed with Wernicke encephalopathy and wet beriberi resulting from severe thiamine deficiency. She required admission to the pediatric ICU because of hypoventilation with progressive weakness and worsening encephalopathy and was found to have impaired cardiac function as assessed by echocardiography. Her heart function and encephalopathy improved on initiation of thiamine repletion. She remained in inpatient rehabilitation for 10 months but still remained weak at discharge. Thiamine deficiency is not commonly considered in the United States as a diagnosis other than in patients with severe alcohol use disorder. However, thiamine may be depleted in as little as 2 weeks if nutrition is inadequate. In such a setting, thiamine deficiency is an important etiology to consider early in the pediatric patient with altered mentation especially because it can be readily and safely treated.