Adaptive multi-epitope targeting and avidity-enhanced nanobody platform for ultrapotent, durable antiviral therapy.

Pathogens constantly evolve and can develop mutations that evade host immunity and treatment. Addressing these escape mechanisms requires targeting evolutionarily conserved vulnerabilities, as mutations in these regions often impose fitness costs. We introduce adaptive multi-epitope targeting with enhanced avidity (AMETA), a modular and multivalent nanobody platform that conjugates potent bispecific nanobodies to a human immunoglobulin M (IgM) scaffold. AMETA can display 20+ nanobodies, enabling superior avidity binding to multiple conserved and neutralizing epitopes. By leveraging multi-epitope SARS-CoV-2 nanobodies and structure-guided design, AMETA constructs exponentially enhance antiviral potency, surpassing monomeric nanobodies by over a million-fold. These constructs demonstrate ultrapotent, broad, and durable efficacy against pathogenic sarbecoviruses, including Omicron sublineages, with robust preclinical results. Structural analysis through cryoelectron microscopy and modeling has uncovered multiple antiviral mechanisms within a single construct. At picomolar to nanomolar concentrations, AMETA efficiently induces inter-spike and inter-virus cross-linking, promoting spike post-fusion and striking viral disarmament. AMETA's modularity enables rapid, cost-effective production and adaptation to evolving pathogens.

SARS-CoV-2 variants evolve convergent strategies to remodel the host response.

SARS-CoV-2 variants of concern (VOCs) emerged during the COVID-19 pandemic. Here, we used unbiased systems approaches to study the host-selective forces driving VOC evolution. We discovered that VOCs evolved convergent strategies to remodel the host by modulating viral RNA and protein levels, altering viral and host protein phosphorylation, and rewiring virus-host protein-protein interactions. Integrative computational analyses revealed that although Alpha, Beta, Gamma, and Delta ultimately converged to suppress interferon-stimulated genes (ISGs), Omicron BA.1 did not. ISG suppression correlated with the expression of viral innate immune antagonist proteins, including Orf6, N, and Orf9b, which we mapped to specific mutations. Later Omicron subvariants BA.4 and BA.5 more potently suppressed innate immunity than early subvariant BA.1, which correlated with Orf6 levels, although muted in BA.4 by a mutation that disrupts the Orf6-nuclear pore interaction. Our findings suggest that SARS-CoV-2 convergent evolution overcame human adaptive and innate immune barriers, laying the groundwork to tackle future pandemics.

SUCNR1 controls an anti-inflammatory program in macrophages to regulate the metabolic response to obesity.

Succinate is a signaling metabolite sensed extracellularly by succinate receptor 1 (SUNCR1). The accumulation of succinate in macrophages is known to activate a pro-inflammatory program; however, the contribution of SUCNR1 to macrophage phenotype and function has remained unclear. Here we found that activation of SUCNR1 had a critical role in the anti-inflammatory responses in macrophages. Myeloid-specific deficiency in SUCNR1 promoted a local pro-inflammatory phenotype, disrupted glucose homeostasis in mice fed a normal chow diet, exacerbated the metabolic consequences of diet-induced obesity and impaired adipose-tissue browning in response to cold exposure. Activation of SUCNR1 promoted an anti-inflammatory phenotype in macrophages and boosted the response of these cells to type 2 cytokines, including interleukin-4. Succinate decreased the expression of inflammatory markers in adipose tissue from lean human subjects but not that from obese subjects, who had lower expression of SUCNR1 in adipose-tissue-resident macrophages. Our findings highlight the importance of succinate-SUCNR1 signaling in determining macrophage polarization and assign a role to succinate in limiting inflammation.

Structures of SARS-CoV-2 N7-methyltransferase with DOT1L and PRMT7 inhibitors provide a platform for new antivirals.

The RNA N7-methyltransferase (MTase) activity of SARS-CoV-2's nsp14 protein is essential for viral replication and is a target for the development of new antivirals. Nsp14 uses S-adenosyl methionine (SAM) as the methyl donor to cap the 5' end of the SARS-CoV-2 mRNA and generates S-adenosyl homocysteine (SAH) as the reaction byproduct. Due to the central role of histone MTases in cancer, many SAM/SAH analogs with properties of cell permeability have recently been developed for the inhibition of these MTases. We have succeeded in identifying two such compounds (SGC0946 and SGC8158) that display significant antiviral activity and bind to the SARS-CoV-2 nsp14 N7-MTase core. Unexpectedly, crystal structures of SGC0946 and SGC8158 with the SARS-CoV-2 nsp14 N7-MTase core identify them as bi-substrate inhibitors of the viral MTase, co-occupying both the SAM and RNA binding sites; positing novel features that can be derivatized for increased potency and selectivity for SARS-CoV-2 nsp14. Taken together, the high-resolution structures and the accompanying biophysical and viral replication data provide a new avenue for developing analogs of SGC0946 and SGC8158 as antivirals.

Home-Based Trimodal Prehabilitation in Patients with Peritoneal Carcinomatosis Undergoing Cytoreductive Surgery: Effect on Functional Walking Capacity and Skeletal Muscle Mass.

BACKGROUND: Patients with peritoneal carcinomatosis often suffer from loss of skeletal muscle mass and require extensive surgery. Multimodal prehabilitation may improve physical status but its benefits for these specific patients remain unknown. This study aimed to evaluate the effect of prehabilitation on functional walking capacity and skeletal muscle mass, as well as its association with postoperative complications. PATIENTS AND METHODS: A prospective study of patients with peritoneal carcinomatosis following a home-based trimodal prehabilitation program was carried out. Functional walking capacity was assessed with the 6-min walk test (T6MWT), and by the appendicular skeletal muscle index (ASMI) estimated by bioelectrical impedance analysis. Data were collected at the first medical appointment and on the day before surgery. A 90-day postoperative morbidity was registered according to the Clavien-Dindo classification. RESULTS: A total of 62 patients were included in the analysis. Women were more prevalent (77.4%) and peritoneal metastasis from ovarian origin accounted for 48.4%. Clavien II-V grades occurred in 30 (57.7%) patients. After prehabilitation, functional walking capacity improved by 42.2 m (39.62-44.72 m) compared with baseline data (p < 0.001), but no improvement was observed in the ASMI (p = 0.301). Patients able to walk at least 360 m after prehabilitation suffered fewer Clavien-Dindo II-V postoperative complications (p = 0.016). A T6MWT of less than 360 m was identified as an independent risk factor in the multivariable analysis (OR 3.99; 1.01-15.79 p = 0.048). CONCLUSIONS: This home-based trimodal prehabilitation program improved functional walking capacity but not ASMI scores in patients with peritoneal metastasis before surgery. A T6MWT of less than 360 m was found to be a risk factor for postoperative complications.

Coherent states of the Laguerre-Gauss modes.

Large quantum photonic systems hold promise for surpassing classical computational limits, yet their state preparation remains a challenge. We propose an alternative approach to study multiparticle dynamics by mapping the excitation mode of these systems to physical properties of the Laguerre-Gauss modes. We construct coherent states establishing a direct link between excitation number dynamics and the evolution of the Laguerre-Gauss modes. This highlights the photon transverse spatial degree of freedom as a versatile platform for testing the fundamental aspects of quantum multiparticle systems.

Control of Iron(II)-Tris(2,2'-Bipyridine) Light-Induced Excited-State Trapping via External Electromagnetic Fields.

Light-induced excited spin-state trapping reactions in iron pyridinic complexes allow the iron's low-to-high spin transition in a sub-picosecond timescale. Employing a recently developed model for [Fe(2,2'-bipyridine)3]2+ photochemical spin-crossover reaction in conjunction with quantum wavepacket dynamics, we explore the possibility of controlling the reaction through external electromagnetic fields, aiming at stabilizing the initial metal-to-ligand charge transfer states. We show that simple Gaussian-shaped electromagnetic fields have a minor effect on the population kinetics. However, introducing vibrationally excited initial wavepacket representations allows for maintaining the population trapped in the metal-to-ligand charge transfer states. Using optimal control theory, we propose an electromagnetic field shape that increases the lifetime of metal-to-ligand charge transfer states. These results open the route for controlling the iron photochemistry through the action of external electric fields.

The role of time to positive blood cultures in enhancing the predictive capability of DENOVA score for diagnosing infective endocarditis in patients with Enterococcus faecalis bacteremia.

DENOVA-score is useful to stratify the risk of infective endocarditis (IE) in Enterococcus faecalis bacteremia. Recently, time to positive (TTP) of blood cultures has also been related with a higher risk of IE. The objective was to evaluate DENOVA- score with TTP to improve its specificity. We performed a retrospective, case-control study in adult patients with E. faecalis bacteremia. Thirty-nine patients with definite E. faecalis IE and 82 with E. faecalis bacteremia were included. The addition of a TTP ≤ 8 h to DENOVA-score did not improve the diagnostic accuracy of this score.

The Role of Inflammation in Depression and Beyond: A Primer for Clinicians.

PURPOSE OF REVIEW: We evaluate available evidence for the role of inflammation in depression. We reappraise literature involving systemic inflammation, neuroinflammation and neurotransmission and their association with depression. We review the connection between depression, autoimmunity and infectious diseases. We revise anti-inflammatory treatments used in depression. RECENT FINDINGS: Peripheral inflammatory markers are present in a subset of patients with depression and can alter common neurotransmitters in this population but there is no clear causality between depression and systemic inflammation. Infectious conditions and autoimmune illnesses do not have a clear correlation with depression. Certain medications have positive evidence as adjunctive treatments in depression but studies are heterogenic, hence they are sparsely used in clinical settings. The current evidence does not fully support inflammation, infections or autoimmunity as possible etiologies of depression. The available studies have numerous confounders that obscure the findings. Anti-inflammatory agents may have potential for treatment of depression, but further research is needed to clarify their usefulness in routine clinical practice.

Upper storage-capacity limit and multiple occupancy phenomena in H2-hydroquinone clathrates using Monte Carlo and DFT simulations.

The upper hydrogen-storage capacity limit of the ß-hydroquinone clathrate has been investigated using hybrid Grand-Canonical Monte Carlo/Molecular Dynamics simulations, for temperatures ranging from 77 K to 300 K. The evolution with pressure of the cage occupancies has been monitored in detail, describing the progressive nature of the uptake process. It is found that the storage capacity of the pure ß-HQ + H2 clathrate could reach 0.6 wt% (weight percentage) only for pressures above 1400 bar, at ambient temperature. The enhancement of the storage capacities by the multiple occupancy phenomenom was accordingly shown to be very limited by the need for extreme conditions. Following this observation, an unmodified version of the van der Waals & Platteeuw theory was applied allowing for the prediction of experimentally accessible formation pressures. Density functional theory calculations were addittionnaly performed to comprehensively characterize the hydrogen diffusion process within the clathrate crystalline structure, considering different occupancy scenarios.

Are farmers motivated to select for heat tolerance? Linking attitudinal factors, perceived climate change impacts, and social trust to farmers' breeding desires.

This study provides an understanding of dairy farmers' willingness to include heat tolerance in breeding goals and the modulating effect of sociopsychological factors and farm profile. A survey instrument including a choice experiment was designed to specifically address the trade-off between heat tolerance and milk production level. A total of 122 farmers across cattle, goat, and sheep farms were surveyed face-to-face. The results of the experiment show that most farmers perceive that heat stress and climate change are increasingly important problems, and that farming communities should invest more in generating knowledge and resources on mitigation strategies. However, we found limited initial support for selection for heat tolerance. This attitude changed when farmers were presented with objective information on the benefits and limitations of the different breeding choices, after which most farmers supported selection for heat tolerance, but only if doing so would compromise milk production gains to a small extent. Our results show that farmers' selection choices are driven by the interactions between heat stress risk perception, attitudes toward breeding tools, social trust, the species reared, and farm production level. In general, farmers willing to support selection of heat-tolerant animals are those with positive attitudes toward genetic values and genomic information and a strong perception of climate change and heat stress impacts on farms. On the contrary, negative support for selection for heat tolerance is found among farmers with high milk production levels; high trust in farming magazines, livestock farmers' associations, and veterinarians; and low trust in environmental and animalist groups.

Impact of mediterranean diet promotion on environmental sustainability: a longitudinal analysis.

OBJECTIVE: This article aims to estimate the differences in environmental impact (greenhouse gas [GHG] emissions, land use, energy used, acidification and potential eutrophication) after one year of promoting a Mediterranean diet (MD). METHODS: Baseline and 1-year follow-up data from 5800 participants in the PREDIMED-Plus study were used. Each participant's food intake was estimated using validated semi-quantitative food frequency questionnaires, and the adherence to MD using the Dietary Score. The influence of diet on environmental impact was assessed through the EAT-Lancet Commission tables. The influence of diet on environmental impact was assessed through the EAT-Lancet Commission tables. The association between MD adherence and its environmental impact was calculated using adjusted multivariate linear regression models. RESULTS: After one year of intervention, the kcal/day consumed was significantly reduced (-125,1 kcal/day), adherence to a MD pattern was improved (+0,9) and the environmental impact due to the diet was significantly reduced (GHG: -361 g/CO2-eq; Acidification:-11,5 g SO2-eq; Eutrophication:-4,7 g PO4-eq; Energy use:-842,7 kJ; and Land use:-2,2 m2). Higher adherence to MD (high vs. low) was significantly associated with lower environmental impact both at baseline and one year follow-up. Meat products had the greatest environmental impact in all the factors analysed, both at baseline and at one-year follow-up, in spite of the reduction observed in their consumption. CONCLUSIONS: A program promoting a MD, after one year of intervention, significantly reduced the environmental impact in all the factors analysed. Meat products had the greatest environmental impact in all the dimensions analysed.

Early complications and quality of life in patients with immediately loaded implant-supported maxillary partial rehabilitations: A prospective cohort study.

BACKGROUND: Immediate loading of dental implants is considered an excellent option to reestablish function and aesthetics in a short period of time, thereby reducing the psychological impact of edentulism. The aim of this study was to describe the incidence of complications in immediately loaded implant-supported single or partial maxillary provisional rehabilitations; to assess changes in patient quality of life (QoL); to evaluate patient overall satisfaction; and to determine whether the occurrence of complications affects these outcomes. MATERIAL AND METHODS: Patients requiring partial rehabilitation with implants in the maxilla were included in a prospective cohort study. In all cases, implant-based restoration with an immediate loading protocol was indicated. A provisional restoration was placed within 72 hours after implant placement. Patient QoL was measured at the first appointment and just before placing the final restoration, using two validated questionnaires. All mechanical and biological complications occurring up until placement of the final restoration were documented. A descriptive and bivariate analysis of the data was performed. RESULTS: Thirty-five patients with 40 prostheses supported by 60 implants were analyzed. Three implant failures were observed, yielding a 95% survival rate. Five provisional prosthesis fractures and two prosthetic screw loosenings were recorded in four patients. A significant reduction in OHIP-14 score was observed. Likewise, significant differences were found in the results of the QoLFAST-10, with a mean difference in score of 7.3 between the initial and final evaluation. CONCLUSIONS: Patients receiving immediately loaded implant-supported single or partial maxillary provisional rehabilitations seem to have a low risk of developing early mechanical (13.3%) or biological complications (5%). These patients appear to experience significant improvement in QoL and report excellent overall satisfaction with the treatment received - though the occurrence of complications seems to affect these outcomes.

AEDV Expert Consensus for the Management of Syphilis. / Documento de expertos de la AEDV para el manejo de la sífilis.

Syphilis -the "great simulator" for classical venereologists-is re-emerging in Western countries despite adequate treatment; several contributing factors have been identified, including changes in sexual behaviour, which won't be the topic of this article though. In 2021, a total of 6613 new cases of syphilis were reported in Spain, representing an incidence of 13.9×100 000 inhabitants (90.5%, men). Rates have increased progressively since 2000. The clinical presentation of syphilis is heterogeneous. Although chancroid, syphilitic roseola and syphilitic nails are typical lesions, other forms of the disease can be present such as non-ulcerative primary lesions like Follmann balanitis, chancres in the oral cavity, patchy secondary lingual lesions, or enanthema on the palate and uvula, among many others. Regarding diagnosis, molecular assays such as PCR have been replacing dark-field microscopy in ulcerative lesions while automated treponemal tests (EIA, CLIA) are being used in serological tests, along with classical tests (such as RPR and HAART) for confirmation and follow-up purposes. The interpretation of these tests should be assessed in the epidemiological and clinical context of the patient. HIV serology and STI screening should be requested for anyone with syphilis. Follow-up of patients under treatment is important to ensure healing and detect reinfection. Serological response to treatment should be assessed with the same non-treponemal test (RPR/VDRL); 3-, 6-, 12-, and 24-month follow-up is a common practice in people living with HIV (PLHIV). Sexual contacts should be assessed and treated as appropriate. Screening is advised for pregnant women within the first trimester of pregnancy. Pregnant women with an abortion after week 20 should all be tested for syphilis. The treatment of choice for all forms of syphilis, including pregnant women and PLHIV, is penicillin. Macrolides are ill-advised because of potential resistance.

[Translated article] AEDV Expert Consensus for the Management of Syphilis.

Syphilis -the "great simulator" for classical venereologists-is re-emerging in Western countries despite adequate treatment; several contributing factors have been identified, including changes in sexual behaviour, which won't be the topic of this article though. In 2021, a total of 6613 new cases of syphilis were reported in Spain, representing an incidence of 13.9×100 000 inhabitants (90.5%, men). Rates have increased progressively since 2000. The clinical presentation of syphilis is heterogeneous. Although chancroid, syphilitic roseola and syphilitic nails are typical lesions, other forms of the disease can be present such as non-ulcerative primary lesions like Follmann balanitis, chancres in the oral cavity, patchy secondary lingual lesions, or enanthema on the palate and uvula, among many others. Regarding diagnosis, molecular assays such as PCR have been replacing dark-field microscopy in ulcerative lesions while automated treponemal tests (EIA, CLIA) are being used in serological tests, along with classical tests (such as RPR and HAART) for confirmation and follow-up purposes. The interpretation of these tests should be assessed in the epidemiological and clinical context of the patient. HIV serology and STI screening should be requested for anyone with syphilis. Follow-up of patients under treatment is important to ensure healing and detect reinfection. Serological response to treatment should be assessed with the same non-treponemal test (RPR/VDRL); 3-, 6-, 12-, and 24-month follow-up is a common practice in people living with HIV (PLHIV). Sexual contacts should be assessed and treated as appropriate. Screening is advised for pregnant women within the first trimester of pregnancy. Pregnant women with an abortion after week 20 should all be tested for syphilis. The treatment of choice for all forms of syphilis, including pregnant women and PLHIV, is penicillin. Macrolides are ill-advised because of potential resistance.

Different Mutational Profiles of Subcutaneous Panniculitis-like T-cell Lymphoma and Lupus Panniculitis: An Additional Case Series.

BACKGROUND: Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare cytotoxic T-cell lymphoma with indolent behavior, mostly present in women and associated with immunological diseases whose pathogenic background is still poorly understood. SPTCL is associated with lupus erythematosus panniculitis (LEP) and histologically misdiagnosed. OBJECTIVES: The aim of our study was to identify mutations affecting the pathogenesis of both SPTCL and LEP. MATERIALS AND METHODS: We studied a total of 10 SPTCL and 10 LEP patients using targeted next-generation sequencing and pyrosequencing. Differences in gene expression between molecular subgroups were investigated using NanoString technology. Clinical data were collected, and correlations sought with the molecular data obtained. RESULTS: The mutational profile of SPTCL and LEP is different. We identified fewer pathogenic mutations than previously reported in SPTCL, noting a single HAVCR2-mutated SPTCL case. Interestingly, 40% of our SPTCL cases showed the pathogenic TP53 (p.Pro72Arg) (P72R) variant. Although cases showing HAVCR2 mutations or the TP53 (P72R) variant had more severe symptomatic disease, none developed hemophagocytic syndrome (HPS). Furthermore, TP53 (P72R)-positive cases were characterized by a lower metabolic signaling pathway and higher levels of CD28 expression and Treg signaling genes. In addition, 30% of our cases featured the same mutation (T735C) of the epigenetic modificatory gene DNMT3A. None of the LEP cases showed mutations in any of the studied genes. CONCLUSIONS: The mutational landscape of SPTCL is broader than previously anticipated. We describe, for the first time, the involvement of the TP53 (P72R) pathogenic variant in this subgroup of tumors, consider the possible role of different genetic backgrounds in the development of SPTCL, and conclude that LEP does not follow the same pathogenic pathway as SPTCL.

Upscaling the effect of traits in response to drought: The relative importance of safety-efficiency and acquisitive-conservation functional axes.

We tested the idea that functional trade-offs that underlie species tolerance to drought-driven shifts in community composition via their effects on demographic processes and subsequently on shifts in species' abundance. Using data from 298 tree species from tropical dry forests during the extreme ENSO-2015, we scaled-up the effects of trait trade-offs from individuals to communities. Conservative wood and leaf traits favoured slow tree growth, increased tree survival and positively impacted species abundance and dominance at the community-level. Safe hydraulic traits, on the other hand, were related to demography but did not affect species abundance and communities. The persistent effects of the conservative-acquisitive trade-off across organizational levels is promising for generalization and predictability of tree communities. However, the safety-efficient trade-off showed more intricate effects on performance. Our results demonstrated the complex pathways in which traits scale up to communities, highlighting the importance of considering a wide range of traits and performance processes.

Immune thrombotic thrombocytopenic purpura in older patients: Results from the Spanish TTP Registry (REPTT).

Immune thrombotic thrombocytopenic purpura (iTTP) is an ultra-rare disease that seldom occurs in the elderly. Few reports have studied the clinical course of iTTP in older patients. In this study, we have analysed the clinical characteristics at presentation and response to therapy in a series of 44 patients with iTTP ≥60 years at diagnosis from the Spanish TTP Registry and compared them with 209 patients with <60 years at diagnosis from the same Registry. Similar symptoms and laboratory results were described in both groups, except for a higher incidence of renal dysfunction among older patients (23% vs. 43.1%; p = 0.008). Front-line treatment in patients ≥60 years was like that administered in younger patients. Also, no evidence of a difference in clinical response and overall survival was seen in both groups. Of note, 14 and 25 patients ≥60 years received treatment with caplacizumab and rituximab, respectively, showing a favourable safety and efficacy profile, like that observed in patients <60 years.

Food for all? Wildfire ash fuels growth of diverse eukaryotic plankton.

In December 2017, one of the largest wildfires in California history, the Thomas Fire, created a large smoke and ash plume that extended over the northeastern Pacific Ocean. Here, we explore the impact of Thomas Fire ash deposition on seawater chemistry and the growth and composition of natural microbial communities. Experiments conducted in coastal California waters during the Thomas Fire revealed that leaching of ash in seawater resulted in significant additions of dissolved nutrients including inorganic nitrogen (nitrate, nitrite and ammonium), silicic acid, metals (iron, nickel, cobalt and copper), organic nitrogen and organic carbon. After exposure to ash leachate at high (0.25 g ash l-1) and low (0.08 g ash l-1) concentrations for 4 days, natural microbial communities had 59-154% higher particulate organic carbon concentrations than communities without ash leachate additions. Additionally, a diverse assemblage of eukaryotic microbes (protists) responded to the ash leachate with taxa from 11 different taxonomic divisions increasing in relative abundance compared with control treatments. Our results suggest that large fire events can be important atmospheric sources of nutrients (particularly nitrogen) to coastal marine systems, where, through leaching of various nutrients, ash may act as a 'food for all' in protist communities.

Functional neuroimaging of resilience to trauma: convergent evidence and challenges for future research.

Resilience is broadly defined as the ability to adapt successfully following stressful life events. Here, we review functional MRI studies that investigated key psychological factors that have been consistently linked to resilience to severe adversity and trauma exposure. These domains include emotion regulation (including cognitive reappraisal), reward responsivity, and cognitive control. Further, we briefly review functional imaging evidence related to emerging areas of study that may potentially facilitate resilience: namely social cognition, active coping, and successful fear extinction. Finally, we also touch upon ongoing issues in neuroimaging study design that will need to be addressed to enable us to harness insight from such studies to improve treatments for - or, ideally, guard against the development of - debilitating post-traumatic stress syndromes.