Background: Macrophages, as one of the most abundant immune cells in the lung, has drawn great attention in allergic asthma. Currently, most studies emphasize on M2 polarization bias. However, the function of macrophages in allergic asthma is still controversial. IL-9 contributes to the development and pathogenesis of allergic airway inflammation. We sought to investigate the IL-9-producing macrophage subset and its role in allergic asthma. Methods: The model of OVA-induced allergic airway inflammation was employed to evaluate IL-9 production in macrophages of lung tissues. We used 22 cytokines or stimuli to screen for IL-9-producing mouse macrophage subset in vitro, and real-time PCR, flow cytometry, ELISA, immunofluorescence and RNA-seq to explore the M(IL-33+IL-2) subset. Mice with Lyz-IL-33 receptor conditional knockout and adoptive transfer M(IL-33+IL-2) were used to characterize the potential roles of M(IL-33+IL-2) in allergic airway inflammation. Results: We identified a unique pathogenic IL-9-producing macrophage subset in OVA-induced allergic airway inflammation. We found that only IL-33 significantly induced IL-9 production in mouse macrophages, and IL-2 collaborated with IL-33 to promote macrophages to produce IL-9, referred to as M(IL-33+IL-2). Importantly, human monocyte-derived macrophages produced IL-9 after IL-33 and IL-2 stimulation. Using mice with Lyz-IL-33 receptor conditional knockout and adoptive transfer of M(IL-33+IL-2), we found that M(IL-33+IL-2) significantly promoted pathogenesis in OVA-induced allergic airway inflammation. M(IL-33+IL-2) subset has a distinctive gene expression profile with high expression of cytokines and M(IL-33+IL2) polarization is dependent on JAK2-STAT3-IRF1 pathway. Conclusions: The identification of M(IL-33+IL-2) subset extends the diversity and heterogeneity of macrophage subsets, and may offer novel therapeutic strategies for treatment of allergic inflammation.

A document by Camilla Grenga. Click on the document to view its contents.

Key clinical message

Title PageManuscript type Case Report

In a world where habitats are degrading and the climate is warming and becoming increasingly unpredictable, biodiversity conservation efforts and funding remain grossly inadequate. There is a clear need to shift from preserving small, remnant populations to a model of genetically connecting populations that recreate larger and more diverse populations in climate-secure environments. This is crucial to harness key evolutionary processes to promote species’ ability to adapt to changing environments and to increase the likelihood of population persistence. Here, we use the endangered Macquarie perch (Macquaria australasica) as a case study to develop a genetic strategy for metapopulation management aimed at promoting population growth and persistence. Macquarie perch habitat has been highly fragmented and remaining habitat is at risk of catastrophic degradation due to climate change. We integrate results of new and existing genetic analyses to illustrate how genetically depauperate populations can benefit from admixture, and how the outcomes of management interventions can be quantified through genetic monitoring. We also develop the pipeline JeDi (https://github.com/drobledoruiz/JeDi) for estimating unbiased genetic heterozygosity for individuals and populations (nucleotide diversity) from reduced-representation genome sequencing data. We use this pipeline to estimate baseline data for monitoring of Macquarie perch populations and show that combining two genetic sources of migrants during population restoration resulted in doubling of nucleotide diversity compared to either source. Genetic diversity estimated using our pipeline is comparable across studies, datasets and species, and suitable for evaluating the rate of global biodiversity change.

Biofilms are found in diverse environmental settings and are considered to be responsible for various recalcitrant infections. One characteristic feature of biofilms is resistance to antibiotics, which is the leading cause of recurrent infections and treatment failure. Eradicating the biofilms necessitates the need for agents with promising anti-biofilm potentials. In the present study, the secondary metabolites of the fungal endophyte Cephalotheca foveolata (N11) isolated from the woody tissues of the medicinal plant Teucrium stocksianum were investigated for their antibiofilm potential against the test organisms. For evaluating the antibiofilm activities, in-vitro assays including biofilm inhibition and eradication assays were employed. The bioactive metabolites of the N11 strain exhibited the highest biofilm inhibition and eradication potential of 87.62% and 79.22% respectively against S. epidermidis. The results were further validated by light microscopy and confocal laser scanning microscope which revealed considerable distortion of the biofilm architecture by test agents. Besides, the effect of secondary metabolites on biofilms of test strain was also observed using Raman spectroscopy. The Raman spectra of treated biofilms exhibited a significant reduction in the intensities of the peaks indicating the denaturation and conformational changes in biomolecules. Furthermore, the partial purification of antibiofilm metabolites of N11 was carried out using solvent extraction following TLC and silica column with further characterization done using FTIR. These findings highlight the remarkable potential of bioactive secondary metabolites of endophytic fungi associated with Teucrium stocksianum in disrupting the biofilms thus suggesting that these metabolites can be exploited for manufacturing effective agents against biofilm-associated complications.

Good brain health plays a significant role in an individual’s well-being and profoundly impacts the collective economy and society. Brain development does not stop at birth and some aspects continue throughout childhood and adolescence, allowing the full development of cognitive functions. Different determinants related to physical health, healthy environments, safety and security, life-long learning, and social connection as well as access to quality services influence the way our brains develop, adapt, and respond to stress and adversity. Ongoing progress in neurobiology and cognitive neuroscience allow the design of better prevention and intervention strategies to help avoid brain deficits and/or limit their impact and maintain brain health. The European Brain Council (EBC) convened an expert meeting during the FENS Forum 2024 to address youth brain health challenges. In recent years, the importance of brain health has garnered significant attention across scientific, medical, and policy-making communities. While much focus has traditionally been on neurodegenerative conditions affecting the elderly, a paradigm shift towards prioritizing brain health in youth is both timely and necessary. This shift can profoundly impact individual lives and society, necessitating an interdisciplinary approach that brings neuroscience to the forefront of public health and informs evidence-based policy. The topic is of utmost importance as EBC launched this year a new campaign on No Health Without Brain Health rallying support with its member organisations and the wider brain community for the increased prioritization of brain health on EU health and research agendas.

A document by Daniel Estevez-Barcia. Click on the document to view its contents.

Edible orchids are increasingly threatened by unsustainable use in their natural habitats. Several studies highlight the need for propagation to counter this threat. However, a critical gap persists in understanding the environmental conditions that support these species in Malawi. This study aimed to identify potential habitats suitable for propagating edible orchids, focusing on Disa engleriana, to enhance ex-situ conservation efforts. Present and future environmental data were sourced from WorldClim. Species occurrence data was obtained during field surveys and existing dataset. Using MaxEnt, continuous habitat suitability for D. engleriana was modeled based on presence-only occurrence data, Bioclim variables, and elevation. The integration of ArcGIS allowed for a detailed analysis, reclassifying the continuous suitability map into suitable and unsuitable habitats. The results of the study show the most suitable habitats align with the boundaries of protected areas, emphasizing their critical importance in conservation planning. Majority of orchid harvesters live near these protected areas, therefore, engaging them in propagation trials becomes a strategic step toward conservation. The study found that suitable habitats for D. engleriana are typically at altitudes between 1500 and 1600 meters, with temperatures not exceeding 15°C during the wettest months. In addition, the results also revealed the negative impact of climate change on habitat suitability, projecting a decrease in suitable areas over the next 50 years. This study addresses a significant knowledge gap and provides valuable insights to guide conservation strategies for D. engleriana.

Understanding the mechanisms that constrain or promote the evolution of species’ geographic ranges has emerged as a fundamental question at the intersection of evolution, ecology, and conservation. A long-held, empirically understudied idea is that asymmetrical gene flow from a more densely populated range center may restrict species’ geographic ranges by preventing local adaptation and the expansion of populations at the range edge. In this study, we use ecophysiology, population genetics, and niche modeling to evaluate whether asymmetrical gene flow from the range center toward the range edge swamps out physiological differentiation in peripheral populations preventing local adaptation. Our focal species, the plethodontid salamander Plethodon ouachitae, is isolated among six mountaintops (sky islands) in the Interior Highlands of the United States that differ in climate across mountaintop isolates and along elevational gradients within mountains. Within mountaintop isolates we found no genetic structure, uniformly high rates of gene flow, and no evidence of physiological divergence along elevational gradients. Although population density peaked at mid- to high-elevations, inferred gene flow was not consistently biased from high- to low-density sites. We found significant genetic differentiation among mountains and evidence for divergence in the environmental niche across mountains separated by low-elevation barriers to dispersal. Despite variation in climate among mountains and the potential for adaptive divergence, we found no evidence for differentiation in ecophysiology among populations isolated on different mountains. Our findings do not support asymmetric gene flow as a force restricting local physiological adaptation and expansion at the range edge, although uniformly high estimated gene flow within mountains could play such a role. However, a lack of physiological differentiation among sky-island populations that differ in climate provides additional support for the idea that gene flow does not limit local adaptation in this species.

Freezing tolerance plays a pivotal role in shaping the distribution and diversification of organisms. We investigated the dynamics of adaptation to climate and potential trade-offs between stem freezing tolerance and growth rate in 48 Quercus species. Species from colder regions exhibited higher freezing tolerance, lower growth rates and higher winter-acclimation potential than species from warmer climates. Despite an evolutionary lag, freezing tolerance in oaks is closely aligned with its optimal state. Deciduous species showed marked variability in freezing tolerance across their broad climatic range while evergreen species, confined to warm climates, displayed low freezing tolerance. Annual growth rates were constrained in all deciduous species but those that evolved in warm latitudes lost freezing tolerance precluding a trade-off between freezing tolerance and growth. We provide evidence that capacity to adapt to a wide range of thermal environments was critical to adaptive radiation and current dominance of the North American oaks.

BACKGROUND AND AIMS: There is scarce information about pediatric lymphoblastic lymphoma (LLy) in low and middle-income countries. We describe the clinical characteristics, treatment and outcome of a cohort of children and adolescents with LLy in Latin America (LA). METHODS: Retrospective study analyzing pediatric patients with LLy in 10 institutions of the St. Jude Global Alliance from nine LA countries between 2007 and 2017. RESULTS: One-hundred and twenty-six patients were included. Sixty (47.6%) had T-LLy, 49 (38.9%) B-LLy and in 17 (13.5%) the immunophenotype was unknown. Ninety-seven (77%) presented with stage III/IV disease, and 42 (33.3%) in critical conditions. In 30 cases (23.8%), the results of pathology diagnosis exceeded 15 days from biopsy, and 23 patients (18%) required a review at another institution. The EFS and OS at 5 years were 73% (SE 0.047) and 78% (SE 0.0435), respectively. Five-year abandonment-sensitive EFS and OS were 65% (SE 0.0477) and 70% (SE 0.0459), respectively. Events included relapse/progression (n=22), refractory disease (n =1) abandonment (n=11), induction death (n=4), death in complete remission (n=4), and second malignancies (n=1). CONCLUSIONS: A balanced proportion of LLy-T and B phenotypes was observed. Diagnosis was a challenge. Most of the patients presented with high-risk disease, and many in critical conditions. Toxic deaths and abandonment represented nearly half of the events. Improvements in diagnosis, supportive measures and follow up are imperative to improve the outcomes of pediatric LLy in Latin America.

This study investigated the relationship between relational integration and semantic processing in numerical inductive reasoning using event-related potentials (ERPs). Participants were required to identify hidden rules in three-digit sequences and judged whether fourth probes were congruent with these rules. The experiment manipulated relational complexity: simple and hierarchical rules (e.g., ”12, 13, 14, 15” or ”12, 13, 15, 18”) shared identical first two numbers but differed in the third, in order to isolate the relational integration process. The type of cue was also manipulated: the no-cue condition presented only a fixation point, providing no rule information; the part-cue condition introduced operands (such as “+” or “–”) to ensure rules could be identified after presenting second numbers and confirmed after the onset of third numbers. Both the time domain and mass univariate ERP results locked to the third numbers revealed independent main effects of relational complexity and cue type on both the Late Negative Component (LNC) . The independent effects especially on the LNC implies that high-order numerical reasoning distinct from semantic processing.

Under the global Sustainable Development Goals initiative, the pursuit of well-being is gradually shifting from wealth to sustainable development. Re-examining the contribution of regional economic, ecological, and social development to the common creation of well-being, analyzing their deep connections, will help us understand the multidimensional concepts and processes of development, and provide ideas for further promoting the construction of a more equitable and sustainable world. China is moving from comprehensive prosperity to common prosperity, and the continuous improvement of sustainable well-being provides effective samples for our research. This study focuses on 46 counties in the Qinba Mountains region of China, and constructs a coupled performance indicator system for sustainable well-being in mountain villages. The Super SBM model is used to evaluate the matching performance of input and output factors, with Economic capital, Ecological capital, and Social capital as explanatory variables and Sustainable Happiness Index as the expected output. Research has found that: (1) There is a mismatch between the input and output factors of sustainable well-being in the Qinba Mountain area, and management techniques are a key factor hindering the improvement of the coupling performance level of sustainable well-being in the Qinba Mountain area; (2) The coupling performance level of sustainable happiness in the Qinba Mountain area is showing a downward trend, and only adjusting the input-output relationship by about 1.02% can achieve optimization and growth in performance level; (3) There is a significant shortage of input factors, with 87% of counties experiencing insufficient economic capital, about 76% experiencing insufficient arable land, and 41% experiencing insufficient social capital. To solve these problems, it is necessary to strengthen the sustainable management level of each county in terms of ecology, economy, and social integration, continue to promote capital investment in mountainous areas to improve economic level, strictly use arable land, optimize land use structure, strengthen social governance level, improve residents’ satisfaction level, and thus enhance sustainable happiness level. This will provide useful reference for achieving sustainable development goals in similar regions of the world.

Titli Bhattacharjee1, Raj Ahmad Rain2*, Prayushi Patel3, Mohit Badhai4, G. Anil K. Reddy5

Unmasking the Wolf in Sheep’s Clothing: Atypical Presentation of Pulmonary Embolism as Acute Abdomen - A Case Report1st and Corresponding Author: Dr. Lolwa Al-Khulaifi, Emergency Medicine Resident, Medical Education.Hamad Medical Cooperation.Email: [email protected] Author: Dr. Mohammed Elgassim, Emergency Medicine Resident, Medical Education.Hamad Medical Cooperation.Email: [email protected] Author: Dr. Waleed Salem, Emergency Medicine Senior Consultant, Hamad Medical Education.Email: [email protected]’s contributions: The authors confirm contribution to the paper as followsLiterature review: 1st Author.Draft Manuscript preparation: 1st and 2nd Authors.Draft manuscript revision: 1st, 2nd,and 3rd Authors.Project supervision: 3rd Author.The patient has consented in a written form for the following information to be published and released; written information is provided.Keywords:Pulmonary Embolism (PE), Epigastric pain, Right heart strain, Anticoagulation.Introduction:Pulmonary embolism (PE) is defined as the blockage of the pulmonary artery or its branches by material that was created elsewhere in the body, such as thrombus, tumor, fat, or air [1]. There are multiple risk factors that can provoke the development of PE. There are all combined in one triad called Virchow’s triad, which include venous stasis, endothelial injury, and hypercoagulable status [2,3]. PE is considered one the common diseases and a fatal one too. It is thought to be responsible for 50,000-200,000 deaths yearly [4].The variety of its presenting features can range from no symptoms at all, to sudden death. Current resources consider dyspnea as the most common presenting feature for PE. Other common presentation includes chest pain, hemoptysis, syncope, or symptoms of deep venous thrombosis [5]. However, the uncommon presentation of PE is not well illustrated. And this may lead to misdiagnosis of this fatal disease. Herein, we present this case of one the uncommon presentation of PE in clinical practice.History and physical examination:A 40-year-old previously healthy Sri-Lankan male was referred to the emergency department from a private clinic due to epigastric pain and abnormal ECG, mainly to rule out myocardial infarction. The patient had abdominal pain localized to the epigastric area, sharp in nature, started suddenly today at around 4 hours prior to presentation. The non-radiating, with no exacerbating/alleviating factors. There was no history of chest pain, shortness of breath palpitations, dizziness, or syncope. The patient also denied any additional gastrointestinal or genitourinary symptoms. He had an appendectomy done 10 years back, otherwise he does not suffer from any chronic medical illnesses. His family history was unremarkable. He is smoker and drinks alcohol occasionally with no use of illicit drugs. And lastly, he works as a laundry business and no recent travel history.The ECG that was done in the clinic that raise the suspicion of MI had no changes compared to the ECG done in the emergency department, showing normal sinus rhythm, heart rate of 100, with T- wave inversion in lead V1-V3. No other remarkable findings were found. During his emergency department stay, he was initially calm and not in respiratory distress, with normal vital sings. Then when he was re-examined, vital signs were Temperature: 36.9 °C, Heart Rate: 119 bpm, Respiratory Rate: 27 bpm, Blood Pressure: 147/107, SpO2: 97%. Upon physical examination, the remarkable findings were epigastric tenderness with no obvious peritoneal signs. Cardiovascular and respiratory examinations were normal. In addition, point of care ultrasound (POCUS) was done by a POCUS subspeciality expert and showed normal heart contractility and function, no right ventricular dilation, no pericardial fluid, with normally sized abdominal aorta.Methods:Laboratory and imaging investigation were done to rule out the possibility of MI or a perforated viscus. These included complete blood count, complete metabolic panne, cardiac enzymes (Troponin-T), venous blood gas, chest x-ray (figure 1) and repeat ECG (figure 2). The remarkable results were leukocytosis and Troponin T of 9, then second set of 11. The patient status has progressed further with tachypnea and sweating; however, the pain was less after analgesia. This has prompted the physician to proceed with CT Abdomen to look for a possible perforated viscus. The result of that imaging showed that the visualized lower chest section has features concerning of bilateral pulmonary embolism. The next step after this report was to have an CT pulmonary angiography (figure 3 and 4), that confirmed the presence of bilateral pulmonary artery thromboembolism with right ventricular strain.Conclusion:After the confirmed diagnosis the patient received the therapeutic dose of anticoagulation (enoxaparin) and disposition to medical intensive care unit has been made, where he received thrombolysis. Further workup and observation have been done. The patient’s stay was uneventful, he was stepped down to the medical ward, then discharged home.Discussion:This case presents a diagnostic challenge, initially raising suspicion of myocardial infarction due to epigastric pain and abnormal ECG findings. The patient’s journey underscores the importance of a comprehensive diagnostic approach. The timely utilization of imaging played a pivotal role in steering the diagnostic process. The CT Abdomen, though initially sought to investigate a potential perforated viscus, revealed features concerning bilateral pulmonary embolism. Subsequent confirmation through CT pulmonary angiography provided critical insights into the extent of pulmonary artery thromboembolism. In the management of this case, swift initiation of therapeutic anticoagulation (enoxaparin) and subsequent medical intensive care unit admission for thrombolysis showcased the impact of prompt decision-making on positive patient outcomes.A comprehensive literature review revealed similar cases, emphasizing a 6.7% incidence of pulmonary embolism presenting with abdominal pain [6]. It hypothesizes possible mechanisms that may explain abdominal pain in PE, such as hepatic congestion due to right heart strain, diaphragmatic irritation, and tension on the parietal pleura nerve endings [6-9]. This enhances our understanding of atypical presentations. It is crucial to acknowledge the mortality risk associated with missed or untreated pulmonary embolism, estimated at around 30% [10]. Also, around 70% of misdiagnosed PEs were discovered postmortem [4]. Unfortunately, traditional learning resources often overlook unusual presentations [9]. Therefore, presenting this case contributes to existing literature, urging physicians to consider pulmonary embolism in patients with abdominal pain.The strengths in our case management include effective triaging, considering the patient’s clinical status, and the initial use of POCUS. However, areas for improvement include advocating for a broader initial differential diagnosis and recognizing the potential benefits of serial POCUS examinations.Lastly, this case serves as a reminder of the diagnostic intricacies surrounding pulmonary embolism, particularly its atypical presentations. By incorporating such cases into educational materials, we hope to enhance physician awareness, prompt further research, and ultimately reduce misdiagnosis and mortality rates associated with pulmonary embolism.Key clinical message:This case highlights the importance of implementing a systematic approach and keeping a wide differential when encountering nonspecific symptoms. Along with the other similar cases, here we remind the physicians to have high index of suspicion of PE, especially with uncommon symptoms such as abdominal pain. This realization could lead to a lifesaving decision in clinical practice.References:Rali, P., Gandhi, V., & Malik, K. (2016). Pulmonary embolism. Critical Care Nursing Quarterly, 39(2), 131–138. doi:10.1097/cnq.0000000000000106.Bagot, C. N., & Arya, R. (2008). Virchow and his triad: A question of attribution. British Journal of Haematology, 143(2), 180–190. doi:10.1111/j.1365-2141.2008.07323.Coon, W. W., & Willis, P. W. (1959). Deep venous thrombosis and pulmonary embolism. The American Journal of Cardiology, 4(5), 611–621. doi:10.1016/0002-9149(59)90145-6.Derr, C., Gantner, J., & Keffeler, J. (2013). Pulmonary embolism: An abdominal pain masquerader. Journal of Emergencies, Trauma, and Shock, 6(4), 280. doi:10.4103/0974-2700.120376.Stein, P. D., Terrin, M. L., Hales, C. A., Palevsky, H. I., Saltzman, H. A., Thompson, B. T., & Weg, J. G. (1991). Clinical, laboratory, roentgenographic, and electrocardiographic findings in patients with acute pulmonary embolism and no pre-existing cardiac or pulmonary disease. Chest, 100(3), 598–603. doi:10.1378/chest.100.3.598.Israel, H. L., & Goldstein, F. (1957). The varied clinical manifestations of pulmonary embolism. Annals of internal medicine, 47(2), 202–226. doi:10.7326/0003-4819-47-2-202.Kounis N. G. (1979). Pulmonary embolism with neurological and abdominal manifestations. The Practitioner, 223(1333), 115–116.Gorham, L. W. (1961). A study of pulmonary embolism. Archives of Internal Medicine, 108(2), 189. doi:10.1001/archinte.1961.03620080021003.Han, Y., & Gong, Y. (2019). Pulmonary embolism with abdominal pain as the chief complaint. Medicine, 98(44). doi:10.1097/md.0000000000017791.Carson, J. L., Kelley, M. A., Duff, A., Weg, J. G., Fulkerson, W. J., Palevsky, H. I, Terrin, M. L. (1992). The clinical course of pulmonary embolism. New England Journal of Medicine, 326(19), 1240–1245. doi:10.1056/nejm199205073261902.Images:

Acinetobacter baumannii is an opportunistic pathogen causing several infections that are increasingly difficult to treat due to its ability to rapidly gain antibiotic resistances. These resistances can arise due to mutations during the DNA damage response (DDR), through the activity of error-prone DNA polymerases, such as DNA polymerase V (DNA Pol V). Currently, the DDR in A. baumannii is not well understood and the regulation of genes encoding multiple copies of DNA Pol V is not fully characterized. Through genome wide mutagenesis, we have identified a novel TetR-like family regulator of genes that encode DNA Pol V, which we have named E rror- p rone p olymerase r egulator, EppR. We have found that EppR represses the expression of the genes encoding DNA Pol V and itself through direct binding to a conserved EppR motif in their promoters. Lastly, we show that EppR also regulates UmuDAb, previously identified as a regulator of genes encoding DNA Pol V. These two gene products are functionally required to ensure regulation of expression of genes encoding DNA Pol Vs and umuDAb. With these results, we propose a co-repressor model for the regulation of genes encoding DNA Pol V and umuDAb.

Aim: This study aims to refine the anticholinergic burden (AB) scale developed in our previous research by incorporating additional drug properties, such as Lipophilicity and Molecular Weight, and implementing a new weighting approach to address the varying influence of each drug property on anticholinergic burden. The objective is to improve the scale’s predictive accuracy and compare its performance against established scales. Methods: The scale, which covers 87 drugs, was expanded to include seven drug properties, combining new properties, Lipophilicity and Molecular Weight, with previously utilised experimental and in silico ADME, physicochemical, and pharmacological properties. A weighting approach was introduced to the hierarchical clustering process to account for the differential impact of each drug property on AB. The performance of this revised scale was evaluated through 10-fold cross-validation against the clinical Anticholinergic Cognitive Burden (ACB) scale and the non-clinical Anticholinergic Toxicity Scores (ATS) scale. Results: The scale showed improved alignment with the ACB and ATS scales, agreeing with the rankings of 54 out of 87 drugs and 16 out of 25 drugs respectively. The Area Under the Receiver Operating Characteristic Curve (AUROC) indicated strong performance. The ML-ACB and ACB has an AUC of 0.99 and 0.81 respectively, whilst the ML-ACB and ATS had an AUC of 0.96 and 0.62. Conclusion: The ML-ACB scale offers improved alignment with the established ACB scale. This highlights the potential of the ML-ACB scale as a valuable tool for clinical and research applications, providing a data-driven alternative that closely correlates with existing validated scales.