Navigating causal reasoning in sustainability science.

When reasoning about causes of sustainability problems and possible solutions, sustainability scientists rely on disciplinary-based understanding of cause-effect relations. These disciplinary assumptions enable and constrain how causal knowledge is generated, yet they are rarely made explicit. In a multidisciplinary field like sustainability science, lack of understanding differences in causal reasoning impedes our ability to address complex sustainability problems. To support navigating the diversity of causal reasoning, we articulate when and how during a research process researchers engage in causal reasoning and discuss four common ideas about causation that direct it. This articulation provides guidance for researchers to make their own assumptions and choices transparent and to interpret other researchers' approaches. Understanding how causal claims are made and justified enables sustainability researchers to evaluate the diversity of causal claims, to build collaborations across disciplines, and to assess whether proposed solutions are suitable for a given problem.

Combination of Indomethacin with Nanostructured Lipid Carriers for Effective Anticancer Therapy.

Purpose: The anticancer potential of indomethacin and other nonsteroidal anti-inflammatory drugs (NSAIDs) in vitro, in vivo, and in clinical trials is well known and widely reported in the literature, along with their side effects, which are mainly observed in the gastrointestinal tract. Here, we present a strategy for the application of the old drug indomethacin as an anticancer agent by encapsulating it in nanostructured lipid carriers (NLC). We describe the production method of IND-NLC, their physicochemical parameters, and the results of their antiproliferative activity against selected cancer cell lines, which were found to be higher compared to the activity of free indomethacin. Methods: IND-NLC were fabricated using the hot high-pressure homogenization method. The nanocarriers were physicochemically characterized, and their biopharmaceutical behaviour and therapeutic efficacy were evaluated in vitro. Results: Lipid nanoparticles IND-NLC exhibited a particle size of 168.1 nm, a negative surface charge (-30.1 mV), low polydispersity index (PDI of 0.139), and high encapsulation efficiency (over 99%). IND-NLC were stable for over 60 days and retained integrity during storage at 4 °C and 25 °C. The potential therapeutic benefits of IND-NLC were screened using in vitro cancer models, where nanocarriers with encapsulated drug effectively inhibited the growth of breast cancer cell line MDA-MB-468 at dosage 15.7 µM. Conclusion: We successfully developed IND-NLC for delivery of indomethacin to cancer cells and confirmed their antitumoral efficacy in in vitro studies. The results suggest that indomethacin encapsulated in lipid nanoparticles possesses high anticancer potential. Moreover, the presented strategy is highly promising and may offer a new alternative for future therapeutic drug innovations.

Reliability of Tear Meniscus Height Measurements in Contact Lens Wearers and Its Relationship With Discomfort Symptoms.

OBJECTIVES: To evaluate the reliability and agreement of tear meniscus height (TMH) measurements performed with a corneal analyzer and optical coherence tomography (OCT) technology in contact lens (CL) wearers and its correlation with contact lens discomfort symptoms. METHODS: Asymptomatic and symptomatic CL wearers classified through the Contact Lens Dry Eye Questionnaire-8 were evaluated with the Corneal Analyzer (Topcon CA-800) and OCT technology (Topcon 3D OCT-2000). The repeatability and intraclass correlation coefficient (ICC) were calculated. The agreement between devices was calculated using the Bland-Altman method. The relationship between TMH measurements and the Contact Lens Dry Eye Questionnaire-8 and Contact Lens Discomfort Index scores was assessed through the Spearman correlation coefficient. RESULTS: Seventy-nine asymptomatic and 42 symptomatic CL wearers aged 34.24±12.50 years were enrolled. The repeatability values obtained for the CA-800 were 0.07 mm in all cases, and the ICC was 0.93 for the whole sample. The CA-800 provided significantly (P<0.01) higher TMH values than the OCT for the whole sample (0.22±0.08 vs. 0.17±0.06 mm). A weak indirect correlation (ρ=-0.22) between the OCT TMH measurement and Contact Lens Discomfort Index scores was found (P≤0.04). CONCLUSION: The CA-800 provides reliable TMH measurements during CL wear; however, they might not be interchangeable with OCT ones. Tear meniscus height measurements might be useful as a complementary sign to detect CL discomfort, but it cannot be used alone as a diagnostic tool.

Short- and medium-term effects of a single session of pain neuroscience education on pain and psychological factors in patients with chronic low back pain. A single-blind randomized clinical trial.

INTRODUCTION: Biopsychosocial approach in patients suffering chronic low back pain (CLBP) promotes pain self-management strategies. Current evidence recommends high dose of Pain Neuroscience Education (PNE) for clinically significant differences. However, the workload and time constraints experienced by healthcare providers impede the application of the recommended treatment regimen. In fact, Back School with a biomechanical model is the main approach to manage CLBP in public systems. OBJECTIVE: The objective of this study is to explore the effect of a 60 min single session of PNE as an adjunct to back school on pain intensity and psychological variables patients with CLBP. METHODS: A double-blind, two-arm randomized controlled clinical trial was conducted in patients with CLBP who attended back school sessions held in a Spanish public hospital. A total of 121 patients were randomized into control group, who received the Back School program during 5 weeks, and intervention group, who additionally received a single session of PNE. Patient-reported outcomes were the Numerical Pain Rating Scale, Central Sensitization Inventory, Pain Catastrophizing Scale, and Tampa Scale of Kinesiophobia, with a 12-week follow-up. RESULTS: A total of 113 patients were analysed. Intervention and control group presented similar effects on pain and kinesiophobia. At follow-up, intervention group exhibited reduced sensitization and catastrophism scores compared with control, including the subscales. Additionally, PNE reduced the percentage of participants classified as having central sensitization compared with control. CONCLUSIONS: Adding a single PNE session in the back school program did not reduce pain but improved psychological factors as central sensitization and pain catastrophizing at medium-term. This study highlights the potential of PNE to optimize treatment strategies for CLBP, especially in public health centres where time resources are scarce. SIGNIFICANCE STATEMENT: Adding a single PNE session in the back school program did not reduce pain but improved psychological factors as central sensitization and pain catastrophism at medium-term.

Efficacy and safety of bendamustine-containing bridging therapy in R/R LBCL patients receiving CD19 CAR T-cells.

Bridging therapy (BT) after leukapheresis is required in most relapsed/refractory (R/R) large B-cell lymphoma (LBCL) patients receiving chimeric antigen receptor (CAR) T cells. Bendamustine-containing regimens are a potential BT option. We aimed to assess if this agent had a negative impact on CAR-T outcomes when it was administered as BT. We included R/R LBCL patients from six centers who received systemic BT after leukapheresis from February 2019 to September 2022; patients who only received steroids or had pre-apheresis bendamustine exposure were excluded. Patients were divided into two BT groups, with and without bendamustine. Separate safety and efficacy analyses were carried out for axi-cel and tisa-cel. Of 243 patients who received BT, bendamustine (benda) was included in 62 (26%). There was a higher rate of BT progressors in the non-benda group (62% vs. 45%, p = 0.02). Concerning CAR-T efficacy, complete responses were comparable for benda versus non-benda BT cohorts with axi-cel (70% vs. 53%, p = 0.12) and tisa-cel (44% vs. 36%, p = 0.70). Also, 12-month progression-free and overall survival were not significantly different between BT groups with axi-cel (56% vs. 43% and 71% vs. 63%) and tisa-cel (25% vs. 26% and 52% vs. 48%); there were no differences when BT response was considered. CAR T-cell expansion for each construct was similar between BT groups. Regarding safety, CRS G ≥3 (6% vs. 6%, p = 0.79), ICANS G ≥3 (15% vs. 17%, p = 0.68), severe infections, and neutropenia post-infusion were comparable among BT regimens. BT with bendamustine-containing regimens is safe for patients requiring disease control during CAR T-cell manufacturing.

[4]Rhombene: Solution-Phase Synthesis and Application for Distributed Feedback Lasers With Emission Beyond 830 nm.

Graphene-like molecules with multiple zigzag edges are emerging as promising gain materials for organic lasers. Their emission wavelengths can vary widely, ranging from visible to near-infrared (NIR), as molecular size increases. Specifically, rhombus-shaped molecular graphenes with two pairs of parallel zigzag edges, known as [n]rhombenes, are excellent candidates for NIR lasers due to their small energy gaps. However, synthesizing large-size rhombenes with emission beyond 800 nm in solution remains a significant challenge. In this study, we present a straightforward synthesis of an aryl-substituted [4]rhombene derivative, [4]RB-Ar, using a method that combines intramolecular radical-radical coupling with Bi(OTf)3-mediated cyclization of vinyl ethers. The structure of [4]RB-Ar was confirmed through X-ray crystallographic analysis. Bond length analysis and theoretical calculations indicate that aromatic sextets are predominantly localized along the molecule's long axis. Significantly, [4]RB-Ar demonstrates narrow amplified spontaneous emission at around 834 nm when dispersed in polystyrene thin films. Moreover, solution-processed distributed feedback lasers employing [4]RB-Ar as the active gain material display tunable narrow emissions in the range of 830 to 844 nm.

Pseudoaneurysm as an unusual complication in bone lengthening.

One of the risks of distraction osteogenesis-based techniques is the development of vascular complications, such as pseudoaneurysms associated with the osteotomies performed or the fixation elements of the external fixator used in the procedure. Pseudoaneurysm are formed when the tunica adventitia of the artery is injured, resulting in a gradual and persistent blood extravasation into the surrounding tissues that is encapsulated and connected to the arterial lumen. This report describes a rare case of a late-presentation pseudoaneurysm in the anterior tibial artery resulting from a tibial lengthening procedure aimed at addressing a leg length discrepancy in a 57-year-old female with severe peripheral neuropathy resulting from long-standing poorly controlled diabetes mellitus. We describe the diagnostic process, the treatment options and confirm how the shape of the bony callus can be a reliable indicator of this pathology, as has already been described in the literature.

Risk factors for bloodstream infections due to carbapenem-resistant Enterobacterales: a nested case-control-control study.

BACKGROUND: Carbapenem-resistant Enterobacterales (CRE) bloodstream infections (BSIs) are a major threat to patients. To date, data on risk factors have been limited, with low internal and external validity. In this multicentre study, risk factors for CRE BSI were determined by comparison with two control groups: patients with carbapenem-susceptible Enterobacterales (CSE) BSI, and patients without Enterobacterales infection (uninfected patients). METHODS: A multicentre, case-control-control study was nested in a European prospective cohort study on CRE (EURECA). CRE BSI:CSE BSI matching was 1:1, CRE BSI:Uninfected patients matching was 1:3, based on hospital, ward and length of stay. Conditional logistic regression was applied. RESULTS: From March 2016 to November 2018, 73 CRE BSIs, 73 CSE BSIs and 219 uninfected patients were included from 18 European hospitals. For CRE versus CSE BSI, previous CRE colonization/infection [incidence rate ratio (IRR) 7.32; 95% CI 1.65-32.38) increased the risk. For CRE versus uninfected controls, independent risk factors included: older age (IRR 1.03; 95% CI 1.01-1.06), patient referral (long-term care facility: IRR 7.19; 95% CI 1.51-34.24; acute care hospital: IRR 5.26; 95% CI 1.61-17.11), previous colonization/infection with other MDR organisms (MDROs) (IRR 9.71; 95% CI 2.33-40.56), haemodialysis (IRR 8.59; 95% CI 1.82-40.53), invasive procedures (IRR 5.66; 95% CI 2.11-15.16), and ß-lactam/ß-lactamase inhibitor combinations (IRR 3.92; 95% CI 1.68-9.13) or third/fourth generation cephalosporin (IRR 2.75; 95% CI 1.06-7.11) exposure within 3 months before enrolment. CONCLUSIONS: Evidence of previous CRE colonization/infection was a major risk factor for carbapenem resistance among Enterobacterales BSI. Compared with uninfected patients, evidence of previous MDRO colonization/infection and healthcare exposure were important risk factors for CRE BSI. Targeted screening, infection prevention and antimicrobial stewardship should focus on these high-risk patients.

Forecasting daily total pollen concentrations on a global scale.

BACKGROUND: There is evidence that global anthropogenic climate change may be impacting floral phenology and the temporal and spatial characteristics of aero-allergenic pollen. Given the extent of current and future climate uncertainty, there is a need to strengthen predictive pollen forecasts. METHODS: The study aims to use CatBoost (CB) and deep learning (DL) models for predicting the daily total pollen concentration up to 14 days in advance for 23 cities, covering all five continents. The model includes the projected environmental parameters, recent concentrations (1, 2 and 4 weeks), and the past environmental explanatory variables, and their future values. RESULTS: The best pollen forecasts include Mexico City (R2(DL_7) ≈ .7), and Santiago (R2(DL_7) ≈ .8) for the 7th forecast day, respectively; while the weakest pollen forecasts are made for Brisbane (R2(DL_7) ≈ .4) and Seoul (R2(DL_7) ≈ .1) for the 7th forecast day. The global order of the five most important environmental variables in determining the daily total pollen concentrations is, in decreasing order: the past daily total pollen concentration, future 2 m temperature, past 2 m temperature, past soil temperature in 28-100 cm depth, and past soil temperature in 0-7 cm depth. City-related clusters of the most similar distribution of feature importance values of the environmental variables only slightly change on consecutive forecast days for Caxias do Sul, Cape Town, Brisbane, and Mexico City, while they often change for Sydney, Santiago, and Busan. CONCLUSIONS: This new knowledge of the ecological relationships of the most remarkable variables importance for pollen forecast models according to clusters, cities and forecast days is important for developing and improving the accuracy of airborne pollen forecasts.

Correction: A Straightforward Access to New Families of Lipophilic Polyphenols by Using Lipolytic Bacteria.

[This corrects the article DOI: 10.1371/journal.pone.0166561.].

The Influence of Accommodative Demand on Ocular Aberrations: A Study of Zernike Coefficients Repeatability and Variability.

PURPOSE: To evaluate the repeatability of the Zernike coefficients in healthy eyes when monocular accommodation was stimulated at different vergences demands. METHODS: A total of 36 right eyes from healthy volunteers were prospectively and consecutively recruited for this study. Wavefront aberrometry was conducted to objectively characterize the ocular optical quality during accommodation, from the individual's far point to a 5 D accommodation demand in steps of 0.5 D. The repeatability of Zernike coefficients up to the fourth order was assessed by calculating the within-eye repeatability (Sw), the coefficient of repeatability (CR), the coefficient of variation (CV), and the intraclass correlation coefficient (ICC) as an indicator of measurement reliability. RESULTS: Correlation among repeated measurements showed high reliability (ICC > 0.513) for all parameters measured except some fourth-order Zernike coefficients, C(4, -4) (ICC < 0.766), C(4, -2) (ICC < 0.875), C(4, 2) (ICC < 0.778) and C(4, 4) (ICC < 0.811). Greater repeatability and less variability were obtained for high-order Zernike coefficients (CR < 0.154), although an increase in CR in the coefficients analyzed was observed with increasing accommodative demand. No clear trend was evident in CV; however, it was observed that the low-order Zernike coefficients exhibit lower CV (CV < 1.93) compared to the high-order Zernike coefficients (CV > 0). CONCLUSIONS: The reliability of Zernike coefficients up to the fourth order in healthy young individuals demonstrated a strong consistency in measuring terms up to the fourth order, with more variability observed for high-order terms. The Zernike coefficients up to the third order exhibited the highest level of repeatability.

A meta-analysis approach for annotation and identification of lncRNAs controlling perirenal fat deposition in suckling lambs.

Long non-coding RNAs (lncRNAs) are being studied in farm animals due to their association with traits of economic interest, such as fat deposition. Based on the analysis of perirenal fat transcriptomes, this research explored the relevance of these regulatory elements to fat deposition in suckling lambs. To that end, meta-analysis techniques have been implemented to efficiently characterize and detect differentially expressed transcripts from two different RNA-seq datasets, one including samples of two sheep breeds that differ in fat deposition features, Churra and Assaf (n = 14), and one generated from Assaf suckling lambs with different fat deposition levels (n = 8). The joint analysis of the 22 perirenal fat RNA-seq samples with the FEELnc software allowed the detection of 3953 novel lncRNAs. After the meta-analysis, 251 differentially expressed genes were identified, 21 of which were novel lncRNAs. Additionally, a co-expression analysis revealed that, in suckling lambs, lncRNAs may play a role in controlling angiogenesis and thermogenesis, processes highlighted in relation to high and low fat deposition levels, respectively. Overall, while providing information that could be applied for the improvement of suckling lamb carcass traits, this study offers insights into the biology of perirenal fat deposition regulation in mammals.

The association between the size of adipocyte-derived extracellular vesicles and fasting serum triglyceride-glucose index as proxy measures of adipose tissue insulin resistance in a rat model of early-stage obesity.

Introduction: Obesity is a complex disease that predisposes individuals to cardiometabolic alterations. It leads to adipose tissue (AT) dysfunction, which triggers insulin resistance (IR). This suggests that people with obesity develop local IR first and systemic IR later. AT secretes extracellular vesicles, which may be physiopathologically associated with the development of IR. Our aim was to evaluate the effect of a high-fat diet on different parameters of adiposity in a rat model of early-stage obesity and to determine if these parameters are associated with markers of systemic IR. In addition, we sought to explore the relationship between fasting blood measures of IR (Triglycerides/High Density Lipoprotein-cholesterol [TAG/HDL-c] and Triglycerides-Glucose Index [TyG Index]) with the size of adipocyte-derived extracellular vesicles (adEV). Methods: We used a model of diet-induced obesity for ten weeks in Wistar rats exposed to a high-fat diet. Final weight gain was analyzed by Dual X-ray absorptiometry. Visceral obesity was measured as epididymal AT weight. IR was evaluated with fasting TyG Index & TAG/HDL-c, and adEV were isolated from mature adipocytes on ceiling culture. Results: In the high-fat diet group, glucose and triglyceride blood concentrations were higher in comparison to the control group (Log2FC, 0.5 and 1.5 times higher, respectively). The values for TyG Index and adEV size were different between the control animals and the high-fat diet group. Multiple linear regression analyses showed that adEV size can be significantly associated with the TyG Index value, when controlling for epididymal AT weight. Conclusion: Our results show that lipid and glucose metabolism, as well as the size and zeta potential of adEV are already altered in early-stage obesity and that adEV size can be significantly associated with liver and systemic IR, estimated by TyG Index.

COVID-19 in patients with haematologic malignancies: effect of RNAemia on clinical outcome in vaccinated patients.

OBJECTIVES: Patients with haematologic malignancies (HM) COVID-19 have more severe disease, with increased risk of mortality. Therefore, this study aimed to evaluate the effect of SARS-CoV-2 RNAemia and the specific humoral immune responses on the clinical outcomes of patients with HM and COVID-19. METHODS: Interferon-α/γ (IFN-α/IFN-γ) serum levels, neutralizing antibodies (NAb), and RNAemia at COVID-19 diagnosis, and persistent RNAemia during the follow-up were evaluated. RESULTS: Overall, 63 (58.9%) out of 107 patients had RNAemia, which was persistent in 26 (41.3%) patients. RNAemia at diagnosis and persistent RNAemia were associated with the need for high-flow nasal oxygen therapy during admission. Persistent RNAemia, age >70 years, and CURB-65 score ≥2 in patients with pneumonia were associated with increased 90-day mortality (p = 0.009, p = 0.030, and p = 0.001, respectively). The 90-day overall survival was lower (p = 0.006) in patients with persistent RNAemia. In addition, dexamethasone administration was associated with a COVID-19 episode with persistent RNAemia. CONCLUSIONS: Our results suggest that in patients with HM, RNAemia at the time of COVID-19 diagnosis and during the follow-up can be used to stratify patients with HM according to their clinical evolution and to guide clinical decisions tailored to the specific needs of each patient.

An international multicentre study of SwiTching from Intravenous to subcutaneous inflixiMab and vEdolizumab in inflammatory bowel diseases: The TIME study.

BACKGROUND AND AIMS: Subcutaneous (SC) formulations of infliximab (IFX) and vedolizumab (VDZ) are approved for the treatment of inflammatory bowel diseases (IBDs). Our aim was to evaluate the effectiveness of switching from intravenous (IV) to SC formulations of IFX and VDZ in IBDs. METHODS: This multicentre, retrospective study collected data of adult patients with Crohn's disease (CD) or ulcerative colitis (UC) switched to SC IFX or VDZ. The primary endpoint was clinical remission at 12 months stratified based on timing of switch. A composite endpoint consisting of therapy discontinuation, reverse-switch, need for steroids, and drug optimization was evaluated. A multivariate analysis investigated the association between patients' characteristics and outcomes. RESULTS: Two hundred and thirty-one patients (59% UC, 53% male, mean age 44 ± 15 years, 68% IFX) from 13 centres were included. The switch occurred at Week 6 in a third of cases (36%). Median time to switch was 13 months. Most patients switched to SC IFX and VDZ were in clinical remission at 3 (87% and 77%), 6 (86% and 83%) and 12 (63% and 60%) months. In the multivariate analysis, there was no difference in clinical remission rate at 12 months; however, patients switched at Week 6 had a higher rate of experiencing any therapeutic changes at 3 (false discovery rate (FDR) = .002), 6 (FDR <1 × 10-10) or 12 months (FDR = .08). Clinical disease activity at baseline (only in UC) (FDR = .07) and previous exposure to biologics (FDR = .001) were risk factors for composite endpoint at 6 and 12 months. CONCLUSION: SC IFX and VDZ are effective in daily clinical practice in IBD patients. Switching patients in remission reduces the risk of negative outcomes.

Effectiveness of psychological interventions for reducing depressive symptomatology and overload and improving quality of life in informal caregivers of non-institutionalized dependent elderly: a systematic review.

Introduction: The phenomenon of aging is distinguished by profound life transformations, with the most dependent group being constituted by elderly individuals. The responsibility for their care primarily falls on the figure of the informal caregiver. The scarcity of time, the stress associated with caregiving, the financial, work-related, and personal difficulties it entails, make it a collective with high probabilities of experiencing various psychological disorders. Interventions that have shown the best results are those of multiple components, composed of various techniques that seek to adapt to the reality of the informal caregiver. Method: The purpose of this study is a systematic review of effective interventions on depressive symptoms, emotional wellbeing, burden, or quality of life in informal caregivers of non-institutionalized dependents from 2018 to the present. A search was conducted in November 2023, on Pubmed, Pubmed Central, Proquest, and Scielo. The final review was conducted on 11 articles. Results: The results indicate that multiple component interventions including cognitive behavioral techniques and psychoeducation in combination with stress coping techniques and social support are more effective on depressive symptoms, burden, quality of life, and increasing the social support network. Discussion: Results on web-based programs demonstrate their efficacy and effectiveness, but require a greater number of trials to adjust their methodological quality and content to the idiosyncrasies of the informal caregiver.

Executive Summary of the Spanish Guidelines for the Diagnosis and Management of Imported Febrile Illnesses from the Spanish Society of Tropical Medicine and International Health (SEMTSI), the Imported Pathology Group of the Spanish Society of Infectious Diseases and Clinical Microbiology (GEPI-SEIMC), the Spanish Society of Family and Community Medicine (SEMFYC), the Spanish Society of Primary Care Physicians (SEMERGEN) and the Spanish Society of Emergency Medicine (SEMES).

The Spanish Society of Tropical Medicine and International Health (SEMTSI), the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC), the Spanish Society of Emergency Medicine (SEMES), the Spanish Society of Primary Care Physicians (SEMERGEN) and the Spanish Society of Family and Community Medicine (SEMFYC) have prepared a consensus statement on the diagnosis and management of patients with imported febrile illnesses. Twenty authors with different backgrounds and representing different healthcare perspectives (ambulatory primary care, travel and tropical medicine specialists, emergency medicine, hospital care, microbiology and parasitology and public health), identified 39 relevant questions, which were organised in 7 thematic blocks. After a systematic review of the literature and a thoughtful discussion, the authors prepared 125 recommendations, as well as several tables and figures to be used as a consulting tool. The present executive summary shows a selection of some of the most relevant questions and recommendations included in the guidelines.

PD-1/LAG-3 co-signaling profiling uncovers CBL ubiquitin ligases as key immunotherapy targets.

Many cancer patients do not benefit from PD-L1/PD-1 blockade immunotherapies. PD-1 and LAG-3 co-upregulation in T-cells is one of the major mechanisms of resistance by establishing a highly dysfunctional state in T-cells. To identify shared features associated to PD-1/LAG-3 dysfunctionality in human cancers and T-cells, multiomic expression profiles were obtained for all TCGA cancers immune infiltrates. A PD-1/LAG-3 dysfunctional signature was found which regulated immune, metabolic, genetic, and epigenetic pathways, but especially a reinforced negative regulation of the TCR signalosome. These results were validated in T-cell lines with constitutively active PD-1, LAG-3 pathways and their combination. A differential analysis of the proteome of PD-1/LAG-3 T-cells showed a specific enrichment in ubiquitin ligases participating in E3 ubiquitination pathways. PD-1/LAG-3 co-blockade inhibited CBL-B expression, while the use of a bispecific drug in clinical development also repressed C-CBL expression, which reverted T-cell dysfunctionality in lung cancer patients resistant to PD-L1/PD-1 blockade. The combination of CBL-B-specific small molecule inhibitors with anti-PD-1/anti-LAG-3 immunotherapies demonstrated notable therapeutic efficacy in models of lung cancer refractory to immunotherapies, overcoming PD-1/LAG-3 mediated resistance.

Soil fertility and plant nutrition in an organic olive orchard after 5 years of amendment with compost, biochar or their blend.

The agronomic use of compost and biochar as soil amendments may exhibit contrasting results in terms of soil fertility and plant nutrition. The effects of the biennial application of biochar, compost and a blend of compost:biochar (90:10; % dw:dw) on the agronomical performance of an organically managed and well established 25-year-old olive orchard was assessed 5 years after the initial application. The agronomical evaluation was based on the assessment of the soil physical, chemical, and biological characteristics, and the assessment of the soil fertility by both crop production and nutritional status of the orchard, and the bioassay with olive plantlets. Biochar mainly benefited the physical properties (bulk density, total porosity, aeration, water retention capacity) of soil, especially in the top 0-5 cm. Compost and its blend with biochar improved microbial activity, soil nutritional status (increasing the content of soluble organic C, N, and P) and favoured the formation of aggregates in soil. The bioassay conducted with young plantlets confirmed the enhanced soil fertility status in the three amended treatments, particularly in the case of biochar and its blend with compost. However, this effect was not significantly observed in the adult plants after 5 years of application, reflecting the slow response of adult olive trees to changes in fertilization. Based on these results, alongside the desirable long-residence time of biochar in soil and the ready availability of compost, the blend of biochar with compost assayed in this study is defined as a valid strategy for preparing high quality soil organic amendments.