bluuebunny/crossref_metadata_2025 huggingface dataset:
Acute heart failure in elderly patients admitted to the emergency department with acute dyspnea: a multimarker approach diagnostic study
Authors: Taheri Omide , Mauny Frédéric , Ray Patrick , Puyraveau Marc , Dubart Alain-Eric , Chenevier-Gobeaux Camille , Seronde Marie-France , Mebazaa Alexandre , Martin Bérenger , Pretalli Jean-Baptiste , Desmettre Thibaut ,   for the READ Study group
Published: August 2023

Background and importance

Diagnosing acute heart failure (AHF) is difficult in elderly patients presenting with acute dyspnea to the emergency department.

Objectives

To assess the diagnostic accuracy of NT-proBNP, high-sensitivity cardiac troponin-I (Hs-cTnI), soluble ST2 (ST2), galectin-3 and CD146 alone and in combination for diagnosing AHF in elderly patients presenting with acute dyspnea to the emergency department.

Design, settings and participants

This was a prospective, multicenter study performed between September 2016 and January 2020, including elderly patients presenting with acute dyspnea to the emergency department of 6 French hospitals.

Intervention

Measurement of NT-proBNP, hs-cTnI, ST2, galectin-3 and CD146.

Outcome measure and analysis

The reference standard, AHF, was adjudicated by two independent physicians based on ED and hospitalization clinical, biological (excluding biomarkers), radiological and echocardiography data (performed by a cardiologist in the cardiology department specifically for this study). Three exploratory methods (two using a cross-sectional approach with logistic regression and counting all biomarker combinations, and one using a sequential approach with gray zone optimizations) were applied to create comprehensive combinations of the 5 biomarkers for measuring diagnostic accuracy.

Main results

Two hundred thirty-eight patients (median age of 85 years, IQR = 8) were analyzed, and 110 (46%) were diagnosed with AHF. The accuracies of NT-proBNP, CD146, hs-cTnI, galectin-3, and ST2 were 0.72 [95% confidence interval (CI) 0.66–0.77], 0.63 (95% CI 0.57–0.69), 0.59 (95% CI 0.53–0.65), 0.55 (95% CI 0.49–0.61) and 0.51 (95% CI 0.45–0.57), respectively. Regardless of the approach used or how the 5 biomarkers were combined, the best accuracy for diagnosing AHF (0.73, 95% CI 0.67–0.78) did not differ from that of NT-proBNP alone.

Conclusion

In this study, NT-proBNP alone exhibited the best diagnostic accuracy for diagnosing AHF in elderly patients presenting with acute dyspnea to the emergency departments. None of the other biomarkers alone or combined improved the accuracy compared to NT-proBNP, which is the only biomarker to use in this setting.
Assessing study methodological quality and integrating this data into meta-analysis
Authors: Stone Jennifer C. , Habibi Nahal , Aromataris Edoardo
Published: August 2023

Purpose of review

Results of meta-analyses are frequently used to inform clinical practice guidelines and healthcare policy. However, healthcare recommendations derived from these meta-analyses may not be trustworthy if based on the results of biased studies. This literature review aims to provide an up-to-date summary of the state-of-the-art methods for integrating methodological quality data into meta-analyses, also known as bias adjustment, as well as the strengths and weaknesses of current methods. This is essential to ensure meta-analyses are conducted in a way that produces trustworthy and valid results.

Recent findings

This literature review outlines the various bias adjustment methods and some of the advantages and limitations of each. Quality effects modelling has emerged as a promising option, with few limitations and ease of application for meta-analysts.

This paper outlines what systematic reviewers can expect from different bias adjustment methods, which will be helpful in minimizing the impact of bias on study results and increasing the validity and reliability of findings from meta-analysis.
Factors associated with CD4 cell count recovery among males and females with advanced HIV disease
Authors: Kouamou Vinie , Gundidza Patricia , Ndhlovu Chiratidzo Ellen , Makadzange Azure Tariro
Published: August 2023

Objective:

HIV/AIDS mortality remains significantly high in Sub-Saharan Africa, mostly driven by opportunistic infections and advanced HIV disease (AHD). This study aimed to assess CD4 cell count recovery following ART initiation and factors associated with immune reconstitution.

Methods:

We conducted a prospective cohort study between 2015-2016. HIV-infected adults (≥18 years) with AHD (CD4 cell count ≤100 cells/mm3) receiving care at 20 outpatient HIV treatment facilities in Harare, Zimbabwe were enrolled. CD4 cell count recovery (CD4 cell count >200 cells/mm3) was assessed following 12-month ART initiation and factors associated with immune reconstitution were investigated using Logistic regression analysis. All statistical analyses were performed on SPSS v23.

Results:

1320 participants were enrolled and 56.4% were males. The median (IQR) age was 37 (32–43) years. Tuberculosis was seen in 16.0%. Of the 739 participants that had CD4 cell count at 12 months, CD4 cell count recovery above 200 cells/mm3 was observed in 163 (22.1%) participants. Median (IQR) CD4 cell count at 12-months increased to 127 (75–190) cells/mm3 from 31 (14 – 55) at baseline. Factors associated with CD4 cell count recovery were younger age at baseline (OR≥40/<40 = 0.58, 95%CI: 0.40–0.85, P = 0.005), sex (ORfemale/male = 2.07, 95%CI:1.44–2.99,P < 0.0001) and baseline CD4 cell count (OR≥50/<50 = 1.60, 95%CI:1.10–2.33,P = 0.013).

Conclusion:

A significant proportion (77.9%) of patients seeking care with AHD in a resource limited setting failed to recover a CD4 cell count >200 cells/mm3. Male sex, older age and low CD4 cell count at ART initiation were factors associated with poor immune reconstitution. Better differentiated care deliveries targeting this vulnerable population are critical for improving clinical outcomes and quality of life of the patients.
Introduction to the special issue: challenges and opportunities in the fight against neglected tropical diseases: a decade from the London Declaration on NTDs
Authors: Forbes Kathryn , Basáñez Maria-Gloria , Hollingsworth T. Déirdre , Anderson Roy M.
Published: August 2023

Twenty neglected tropical diseases (NTDs) are currently prioritised by the World Health Organization for eradication, elimination as a public health problem, elimination of transmission or control by 2030. This issue celebrates progress made since the 2012 London Declaration on NTDs and discusses challenges currently faced to achieve these goals. It comprises 14 contributions spanning NTDs tackled by intensified disease management to those addressed by preventive chemotherapy. Although COVID-19 negatively affected NTD programmes, it also served to spur new multisectoral approaches to strengthen school-based health systems. The issue highlights the needs to improve impact survey design, evaluate new diagnostics, understand the consequences of heterogeneous prevalence and human movement, the potential impact of alternative treatment strategies and the importance of zoonotic transmission.

This article is part of the theme issue ‘Challenges and opportunities in the fight against neglected tropical diseases: a decade from the London Declaration on NTDs’.
How important is the spatial movement of people in attempts to eliminate the transmission of human helminth infections by mass drug administration?
Authors: Collyer Benjamin S. , Truscott James E. , Mwandawiro Charles S. , Njenga Sammy M. , Anderson Roy M.
Published: August 2023

Human mobility contributes to the spatial dynamics of many infectious diseases, and understanding these dynamics helps us to determine the most effective ways to intervene and plan surveillance. In this paper, we describe a novel transmission model for the spatial dynamics of hookworm, a parasitic worm which is a common infection across sub-Saharan Africa, East Asia and the Pacific islands. We fit our model, with and without mobility, to data obtained from a sub-county in Kenya, and validate the model's predictions against the decline in prevalence observed over the course of a clustered randomized control trial evaluating methods of administering mass chemotherapy. We find that our model which incorporates human mobility is able to reproduce the observed patterns in decline of prevalence during the TUMIKIA trial, and additionally, that the widespread bounce-back of infection may be possible over many years, depending on the rates of people movement between villages. The results have important implications for the design of mass chemotherapy programmes for the elimination of human helminth transmission.

This article is part of the theme issue ‘Challenges and opportunities in the fight against neglected tropical diseases: a decade from the London Declaration on NTDs’.
Reaching the World Health Organization elimination targets for schistosomiasis: the importance of a One Health perspective
Authors: Díaz Adriana V. , Walker Martin , Webster Joanne P.
Published: August 2023

The past three years has seen the launch of a new World Health Organization (WHO) neglected tropical diseases (NTDs) roadmap, together with revised control and elimination guidelines. Across all, there is now a clear emphasis on the need to incorporate a One Health approach, recognizing the critical links between human and animal health and the environment. Schistosomiasis, caused by
Schistosoma
spp. trematodes, is a NTD of global medical and veterinary importance, with over 220 million people and untold millions of livestock currently infected. Its burden remains extremely high in certain regions, particularly within sub-Saharan Africa, despite over two decades of mass preventive chemotherapy (mass drug administration), predominantly to school-aged children. In Africa, in contrast to Asia, any zoonotic component of schistosomiasis transmission and its implications for disease control has, until recently, been largely ignored. Here, we review recent epidemiological, clinical, molecular, and modelling work across both Asia and Africa. We outline the evolutionary history and transmission dynamics of
Schistosoma
species, and emphasize the emerging risk raised by both wildlife reservoirs and viable hybridization between human and animal schistosomes. To achieve the 2030 WHO roadmap elimination targets, a truly multi-disciplinary One Health perspective must be implemented.

This article is part of the theme issue ‘Challenges and opportunities in the fight against neglected tropical diseases: a decade from the London Declaration on NTDs’.
Reproducibility matters: intra- and inter-sample variation of the point-of-care circulating cathodic antigen test in two
Schistosoma mansoni
endemic areas in Uganda
Authors: Kabbas-Piñango Elías , Arinaitwe Moses , van Dam Govert J. , Moses Adriko , Namukuta Annet , Nankasi Andrina Barungi , Mwima Nicholas Khayinja , Besigye Fred , Prada Joaquin M. , Lamberton Poppy H. L.
Published: August 2023

Over 240 million people are infected with schistosomiasis. Detecting
Schistosoma mansoni
eggs in stool using Kato–Katz thick smears (Kato-Katzs) is highly specific but lacks sensitivity. The urine-based point-of-care circulating cathodic antigen test (POC-CCA) has higher sensitivity, but issues include specificity, discrepancy between batches and interpretation of trace results. A semi-quantitative G-score and latent class analyses making no assumptions about trace readings have helped address some of these issues. However, intra-sample and inter-sample variation remains unknown for POC-CCAs. We collected 3 days of stool and urine from 349 and 621 participants, from high- and moderate-endemicity areas, respectively. We performed duplicate Kato-Katzs and one POC-CCA per sample. In the high-endemicity community, we also performed three POC-CCA technical replicates on one urine sample per participant. Latent class analysis was performed to estimate the relative contribution of intra- (test technical reproducibility) and inter-sample (day-to-day) variation on sensitivity and specificity. Within-sample variation for Kato-Katzs was higher than between-sample, with the opposite true for POC-CCAs. A POC-CCA G3 threshold most accurately assesses individual infections. However, to reach the WHO target product profile of the required 95% specificity for prevalence and monitoring and evaluation, a threshold of G4 is needed, but at the cost of reducing sensitivity.

This article is part of the theme issue ‘Challenges and opportunities in the fight against neglected tropical diseases: a decade from the London Declaration on NTDs’.
Modernizing the design and analysis of prevalence surveys for neglected tropical diseases
Authors: Diggle Peter J , Fronterre Claudio , Gass Katherine , Hundley Lee , Niles-Robin Reza , Sampson Annastacia , Morice Ana , Scholte Ronaldo Carvalho
Published: August 2023

Current WHO guidelines set prevalence thresholds below which a neglected tropical disease can be considered to have been eliminated as a public health problem, and specify how surveys to assess whether elimination has been achieved should be designed and analysed, based on classical survey sampling methods. In this paper, we describe an alternative approach based on geospatial statistical modelling. We first show the gains in efficiency that can be obtained by exploiting any spatial correlation in the underlying prevalence. We then suggest that the current guidelines' implicit use of a significance testing argument is not appropriate; instead, we argue for a predictive inferential framework, leading to design criteria based on controlling the rates at which areas whose true prevalence lies above and below the elimination threshold are incorrectly classified. We describe how this approach naturally accommodates context-specific information in the form of georeferenced covariates that have been shown to be predictive of disease prevalence. Finally, we give a progress report of an ongoing collaboration with the Guyana Ministry of Health Neglected Tropical Disease programme on the design of an IDA (ivermectin, diethylcarbamazine and albendazole) Impact Survey of lymphatic filariasis to be conducted in Guyana in early 2023.

This article is part of the theme issue ‘Challenges and opportunities in the fight against neglected tropical diseases: a decade from the London Declaration on NTDs’.
From serological surveys to disease burden: a modelling pipeline for Chagas disease
Authors: Ledien Julia , Cucunubá Zulma M. , Parra-Henao Gabriel , Rodríguez-Monguí Eliana , Dobson Andrew P. , Adamo Susana B. , Castellanos Luis Gerardo , Basáñez María-Gloria , Nouvellet Pierre
Published: August 2023

In 2012, the World Health Organization (WHO) set the elimination of Chagas disease intradomiciliary vectorial transmission as a goal by 2020. After a decade, some progress has been made, but the new 2021–2030 WHO roadmap has set even more ambitious targets. Innovative and robust modelling methods are required to monitor progress towards these goals. We present a modelling pipeline using local seroprevalence data to obtain national disease burden estimates by disease stage. Firstly, local seroprevalence information is used to estimate spatio-temporal trends in the Force-of-Infection (FoI). FoI estimates are then used to predict such trends across larger and fine-scale geographical areas. Finally, predicted FoI values are used to estimate disease burden based on a disease progression model. Using Colombia as a case study, we estimated that the number of infected people would reach 506 000 (95% credible interval (CrI) = 395 000–648 000) in 2020 with a 1.0% (95%CrI = 0.8–1.3%) prevalence in the general population and 2400 (95%CrI = 1900–3400) deaths (approx. 0.5% of those infected). The interplay between a decrease in infection exposure (FoI and relative proportion of acute cases) was overcompensated by a large increase in population size and gradual population ageing, leading to an increase in the absolute number of Chagas disease cases over time.

This article is part of the theme issue ‘Challenges and opportunities in the fight against neglected tropical diseases: a decade from the London Declaration on NTDs’.
Evaluation of Kato-Katz and multiplex quantitative polymerase chain reaction performance for clinical helminth infections in Thailand using a latent class analysis
Authors: Rotejanaprasert Chawarat , Chuaicharoen Pavadee , Prada Joaquin M. , Thantithaveewat Thanawadee , Adisakwattana Poom , Pan-ngum Wirichada
Published: August 2023

Using an appropriate diagnostic tool is essential to soil-transmitted helminth control and elimination efforts. Kato-Katz (KK) is the most commonly used diagnostic, but recently other tools, such as real-time quantitative polymerase chain reaction (multiplex qPCR), are starting to be employed more. Here, we evaluated the performance of these two diagnostic tools for five helminth species in Thailand. In the absence of a gold standard, diagnostic performance can be evaluated using latent class analysis. Our results suggest that in moderate to high prevalence settings above 2% multiplex qPCR could be more sensitive than KK, this was particularly apparent for
Opisthorchis viverrini
in the northeastern provinces. However, for low prevalence, both diagnostics suffered from low sensitivity. Specificity of both diagnostics was estimated to be high (above 70%) across all settings. For some specific helminth infection such as
O. viverrini
, multiplex qPCR is still a preferable choice of diagnostic test. KK performed equally well in detecting
Ascaris lumbricoides
and
Taeniasis
(
Taenia
spp.) when the prevalence is moderate to high (above 2%). Neither test performed well when the prevalence of infection is low (below 2%), and certainly in the case for hookworm and
Trichuris trichiura
. Combination of two or more diagnostic tests can improve the performance although the cost would be high. Development of new methods for helminth surveillance at the pre-elimination phase is therefore very important.

This article is part of the theme issue ‘Challenges and opportunities in the fight against neglected tropical diseases: a decade from the London Declaration on NTDs’.
A modelling analysis of a new multi-stage pathway for classifying achievement of public health milestones for leprosy
Authors: Davis Emma L. , Crump Ron E. , Medley Graham F. , Solomon Anthony W. , Pemmaraju Venkata Ranganadha Rao , Hollingsworth T. Déirdre
Published: August 2023

Several countries have come close to eliminating leprosy, but leprosy cases continue to be detected at low levels. Due to the long, highly variable delay from infection to detection, the relationship between observed cases and transmission is uncertain. The World Health Organization's new technical guidance provides a path for countries to reach elimination. We use a simple probabilistic model to simulate the stochastic dynamics of detected cases as transmission declines, and evaluate progress through the new public health milestones. In simulations where transmission is halted, 5 years of zero incidence in autochthonous children, combined with 3 years of zero incidence in all ages is a flawed indicator that transmission has halted (54% correctly classified). A further 10 years of only occasional sporadic cases is associated with a high probability of having interrupted transmission (99%). If, however, transmission continues at extremely low levels, it is possible that cases could be misidentified as historic cases from the tail of the incubation period distribution, although misleadingly achieving all three milestones is unlikely (less than 1% probability across a 15-year period of ongoing low-level transmission). These results demonstrate the feasibility and challenges of a phased progression of milestones towards interruption of transmission, allowing assessment of programme status.

This article is part of the theme issue ‘Challenges and opportunities in the fight against neglected tropical diseases: a decade from the London Declaration on NTDs’.
Knowledge, attitudes, practices and acceptability of a school preventive chemotherapy programme for schistosomiasis and soil-transmitted helminths control in Angola
Authors: Bartlett Adam W. , Mendes Elsa P. , Dahmash Latifeh , Peliganga Luis B. , Lufunda Luis M. M. , Direito Ana , Mwinzi Pauline N. , Eulogio Pablo , Lopes Sergio , Nery Susana Vaz
Published: August 2023

Schistosomiasis and soil-transmitted helminth (STH) control programs require target population engagement, assessed through knowledge, attitudes and practices (KAP) surveys. We report the results of a KAP survey of Angolan schoolchildren supported by a school preventive chemotherapy (PC) programme, without or with a school water, sanitation and hygiene (WASH) programme (PC+/WASH− and PC+/WASH+, respectively); and schoolchildren without a school PC or WASH program (PC−/WASH−). Schoolchildren from PC+/WASH− (
N
= 218), PC+/WASH+ (
N
= 250) and PC−/WASH− (
N
= 254) schools were interviewed. Descriptive statistics were used to report demographics and survey responses. Chi-square or Fisher's exact test was used to compare PC+/WASH− schoolchildren with (i) PC+/WASH+ and (ii) PC−/WASH− schoolchildren. A lower proportion of PC+/WASH− schoolchildren used latrines and a higher proportion practised open defecation at school compared with PC+/WASH+ schoolchildren. A lower proportion of PC+/WASH− schoolchildren always washed their hands after toileting and before meals at school compared with PC+/WASH+ schoolchildren. However, the PC+/WASH− schoolchildren reported better toileting and handwashing practices at school compared to PC−/WASH− schoolchildren. Over 90% of PC+ schoolchildren agreed with schistosomiasis and STH control and accepted schoolteacher PC delivery. Expanding the integration of both school PC and WASH programs will improve health behaviours relevant to reduce the risk of schistosomiasis and STHs in schoolchildren.

This article is part of the theme issue ‘Challenges and opportunities in the fight against neglected tropical diseases: a decade from the London Declaration on NTDs’.
A Computational Model of Hippocampus: A Unified Theory About Engram and Sharp-Ware Ripples
Authors: Zishuo ZHENG
Published: August 2023

The hippocampus is key to memory encoding, consolidation, and retrieval. Previous work shows that neurons in the hippocampus fire in sequence to encode spatial information. The same group of cells will replay in memory consolidation, coupled with ripples, spindle, and slow waves. As for episodic memory, engram cells have been proposed to explain the encoding and transformation of episodic memory. Another universe theory about memory is the cognitive map theory. Here I use cognitive map theory as the bridge to overcome the gap between spatial and episodic memory. I believe spatial memory is a highly compressed case of episodic memory. In addition, I propose the hypothesis that engram can trigger sharp-wave ripples. I use a spike neural network-based computational model to verify this hypothesis. In conclusion, I believe engram cells and sharp-wave ripples are two different phenomena under a unified memory system.
Local CpG-Stat3siRNA treatment improves antitumor effects of immune checkpoint inhibitors
Authors: Zhang Chunyan , Huang Rui , Ren Lyuzhi , Song JiEun , Kortylewski Marcin , Swiderski Piotr , Forman Stephen , Yu Hua
Published: August 2023

Immune checkpoint blockade (ICB) therapy has significantly benefited patients with several types of solid tumors and some lymphomas. However, many of the treated patients do not have durable clinical response. It has been demonstrated that rescuing exhausted CD8+T cells is required for ICB-mediated antitumor effects. We recently developed an immunostimulatory strategy based on silencing STAT3 while stimulating immune responses by CpG, ligand for Toll-like receptor 9 (TLR9). The CpG-small interfering RNA (siRNA) conjugates efficiently enter immune cells, silencing STAT3 and activating innate immunity to enhance T-cell mediated antitumor immune responses. In the present study, we demonstrate that blocking STAT3 through locally delivered CpG-Stat3siRNA enhances the efficacies of the systemic PD-1 and CTLA4 blockade against mouse A20 B cell lymphoma. In addition, locally delivered CpG-Stat3siRNA combined with systemic administration of PD-1 antibody significantly augmented both local and systemic antitumor effects against mouse B16 melanoma tumors, with enhanced tumor-associated T cell activation. Overall, our studies in both B cell lymphoma and melanoma mouse models demonstrate the potential of combinatory immunotherapy with CpG-Stat3siRNA and checkpoint inhibitors as a therapeutic strategy for B cell lymphoma and melanoma.
Neural signatures for temporal order memory in the macaque medial posterior parietal cortex
Authors: Zuo Shuzhen , Wang Chenyu , Wang Lei , Jin Zhiyong , Zhou Xufeng , Su Ning , Liu Jianhua , McHugh Thomas J. , Kusunoki Makoto , Kwok Sze Chai
Published: August 2023

Episodic memory involves encoding and remembering the order of events experienced over time. Previous work examining the mechanisms of temporal-order memories has focused on the hippocampus and prefrontal cortices but has largely ignored the memory ensembles in the medial posterior parietal cortex (mPPC). Combiningin vivomulti-unit electrophysiology and a temporal-order judgment task with cinematic material in the macaque, we find that mPPC neuronal activity reflects temporal context both during encoding and recall. During learning, mPPC neuronal ensembles encode the temporal information as well as contextual information embedded in the videos, whereas at retrieval these neurons fire in synchrony prior to memory-guided decisions. Moreover, the similarity between encoding and retrieval correlates with the animal’s performance. A control experiment further ruled out eye saccades, fixation, and scan path for their confounding roles in the neural results. Together, these data suggest that neurons in mPPC track the passage of time and contextual changes, thereby orchestrating for successful temporal-order memories at retrieval.

SIGNIFICANCE

Remembering the temporal order of events is a vital function of the brain. This study provides the first evidence for the retrieval of temporal order of episodes at both single neuron and ensemble levels in the primate parietal cortex. The study’s key breakthrough is the revelation that ensembles of time perceptive neurons, acting as “temporal context cells”, can encode a spectrum of time constants and contexts for the experienced past and subsequently utilize this temporal record to discriminate the chronological order of past experiences. These results enhance theoretical frameworks for how encoded temporal past is maintained and reconstructed during memory retrieval.
Targeting CD19-positive lymphomas with the antibody-drug conjugate (ADC) loncastuximab tesirine: preclinical evidence as single agent and as combinatorial approach
Authors: Tarantelli Chiara , Wald David , Munz Nicolas , Spriano Filippo , Bruscaggin Alessio , Cannas Eleonora , Cascione Luciano , Gaudio Eugenio , Arribas Alberto J. , Manjappa Shivaprasad , Golino Gaetanina , Scalise Lorenzo , Zucca Emanuele , Stathis Anastasios , van Berkel Patrick H. , Rossi Davide , Caimi Paolo F. , Zammarchi Francesca , Bertoni Francesco
Published: August 2023

Purpose

Antibody-drug conjugates (ADCs) represent one of the most successful therapeutic approaches introduced in clinical practice in the last years. Loncastuximab tesirine (ADCT-402) is a CD19 targeting ADC, in which the antibody is conjugated through a protease cleavable dipeptide linker to a pyrrolobenzodiazepine (PBD) dimer warhead (SG3199). Based on the results of a phase 2 study, loncastuximab tesirine was recently approved for adult patients with relapsed/refractory large B-cell lymphoma.

Experimental Design

We assessed the activity of loncastuximab tesirine inin vitroandin vivomodels of lymphomas, correlated its activity with CD19 expression levels and identified combination partners providing synergy with loncastuximab tesirine.

Results

Loncastuximab tesirine was tested across 60 lymphoma cell lines. Loncastuximab tesirine has strong cytotoxic activity in B-cell lymphoma cell lines and thein vitroactivity is correlated with CD19 expression level and with intrinsic sensitivity of cell lines to the ADC’s warhead.

Loncastuximab tesirine was more potent than other anti-CD19 ADCs (coltuximab ravtansine, huB4-DGN462), albeit the pattern of activity across cell lines was correlated. Loncastuximab tesirine activity also largely correlated with cell line sensitivity to R-CHOP.

Combinatorial in vitro and in vivo experiments identified the benefit of adding loncastuximab tesirine to other agents, especially BCL2 and PI3K inhibitors.

Conclusions

Our data support the further development of loncastuximab tesirine as single agent and in combination for patients affected by mature B-cell neoplasms. The results also highlight the importance of CD19 expression, and the existence of lymphoma populations characterized by resistance to multiple therapies.
Predicting forest damage using relative abundance of multiple deer species and national forest inventory data
Authors: Brock Colin , Morera-Pujol Virginia , Murphy Kilian J. , Nieuwenhuis Maarten , Ciuti Simone
Published: August 2023

Human modification of landscape and natural resources have facilitated deer population irruptions across the world resulting in widespread human-wildlife conflicts. These conflicts occur across the field of natural resource management and negatively affect both the public and vested stakeholders when their livelihoods are placed at risk, for instance, the forestry sector. Deer, both native and non-native, at high densities can damage forest ecosystems impacting biodiversity and ecological functioning at multiple levels and can inflict large ecological and economic costs. The ecological drivers of forest damage and the roles of single and multiple co-occurring deer species is not well understood due to a lack of coordinated high resolution deer distribution, deer abundance and forest damage data. Here, we aim to disentangle the relationship between forest damage, forest characteristics and the roles deer play in damaging forest ecosystems. To achieve this, we adopt a novel approach integrating recent high resolution deer distribution data for multiple deer species (native and non-native) and combining them with forest inventory data collected in 1,681 sampling stations across Ireland to provide risk scenario predictions for practitioners to use on a national scale. Forest characteristics played a key role in the severity and type of damage risk that deer posed. We found all damage types were more prevalent in forests with greater tree densities where deer are more likely to find refuge from human disturbance. Bark stripping damage was more prevalent in mature forests with high tree diversity and ground level flora (e.g., bryophytes, herbs, and shrubs). Similarly, browsing damage was more prevalent in forests with greater tree richness but with understorey vegetation dominated by grass and ferns. Fraying damage was more common in mixed woodlands with understory dominated by bryophytes and grass. Crucially, we found that type and severity of forest damage were shaped by the interaction of multiple deer species occurring simultaneously, particularly at high densities, suggesting subtle inter-species competition and exclusion/partition dynamics that require further investigation to understand the ecological mechanism. Finally, we produce risk scenarios of forest damage by co-occurring deer species and precisely predict where damage is likely to occur on a national scale. We predict high levels of damage in sika and/or red deer hotspots, matching areas of highly concentrated deer distributions. This study highlights the ecological drivers and the role that co-occurring native and non-native deer species have on forest damage within a large spatial scale. By combining reliable species distribution models with the national forest inventory data, we can now provide a useful tool for practitioners to help alleviate and mitigate forest damage and human wildlife conflicts.
Hemopexin Reverses Activation of Lung eIF2a and Decreases Mitochondrial Injury in Chlorine Exposed Mice
Authors: Matalon Sadis , Yu Zhihong , Dubey Shubham , Ahmad Israr , Stephens Emily M. , Alishlash Ammar Saadoon , Meyers Ashley , Cossar Douglas , Stewart Donald , Acosta Edward P. , Kojima Kyoko , Jilling Tamas , Mobley James A.
Published: August 2023

We assessed the mechanisms by which non-encapsulated heme, released in the plasma of mice post exposure to chlorine (Cl2) gas, resulted in the initiation and propagation of acute lung injury. We exposed adult C57BL/6 male and female to Cl2(500 ppm for 30 min) in environmental chambers and returned them to room air and injected them intramuscularly with a single dose of human hemopexin (hHPX; 5 µg/ g BW), the most efficient scavenger of heme, 30-60 min post exposure. Concentrations of hHPX in plasma of air and Cl2exposed mice were 9081±900 vs. 1879± 293 at 6 h and 2966±463 vs. 1555±250 at 50 h post injection (ng/ml; X±1 SEM=3; p<0.01). Cl2exposed mice developed progressive acute lung injury post exposure characterized by increased concentrations of plasma heme, marked inflammatory response, respiratory acidosis and increased concentrations of plasma proteins in the alveolar space. Injection of hHPX decreased the onset of acute lung injury at 24 h post exposure; mean survival, for the saline and hHPX groups were 40 vs. 80% (P<0.001) at 15 d post exposure. Non-supervised global proteomics analysis of mouse lungs at 24 h post exposure, revealed the upregulation of 92 and downregulation of 145 lung proteins. Injection of hHPX at one h post exposure moderated the Cl2induced changes in eighty-three of these 237 lung proteins. System biology analysis of the global proteomics data showed that hHPX reversed changes in mitochondrial dysfunction and elF2 and integrin signaling. Western blot analysis of lung tissue showed significant increase of phosphorylated elF2 at 24 h post exposure in vehicle treated mice but normal levels in those injected with hHPX. Similarly, RT-PCR analysis of lung tissue showed that hHPX reversed the onset of mtDNA lesions. A form of recombinant human hemopexin generated in tobacco plants was equally effective in reversing acute lung and mtDNA injury. The results of this study offer new insights as to the mechanisms by which exposure to Cl2results in acute lung injury and to the therapeutic effects of hemopexin.
Endothelial TMEM16F lipid scramblase regulates angiogenesis
Authors: Shan Ke Zoe , Le Trieu , Liang Pengfei , Dong Ping , Yang Huanghe
Published: August 2023

Dynamic loss of lipid asymmetry through the activation of TMEM16 Ca2+-activated lipid scramblases (CaPLSases) has been increasingly recognized as an essential membrane event in a wide range of physiological and pathological processes, including blood coagulation, microparticle release, bone development, pain sensation, cell-cell fusion, and viral infection. Despite the recent implications of TMEM16F CaPLSase in vascular development and endothelial cell-mediated coagulation, its signaling role in endothelial biology remains to be established. Here, we show that endothelial TMEM16F regulatesin vitroandin vivoangiogenesis through intracellular signaling. Developmental retinal angiogenesis is significantly impaired in TMEM16F deficient mice, as evidenced by fewer vascular loops and larger loop areas. Consistent with ourin vivoobservation, TMEM16F siRNA knockdown in human umbilical vein endothelial cells compromises angiogenesisin vitro. We further discovered that TMEM16F knockdown enhances VE-cadherin phosphorylation and reduces its expression. Moreover, TMEM16F knockdown also promotes Src kinase phosphorylation at tyrosine 416, which may be responsible for downregulating VE-cadherin expression. Our study thus uncovers a new biological function of TMEM16F in angiogenesis and provides a potential mechanism for how the CaPLSase regulates angiogenesis through intracellular signaling.
Air Pollution Aggravates Renal Ischemia-Reperfusion-Induced Acute Kidney Injury
Authors: Sanches Talita Rojas , Parra Antonio Carlos , Sun Peiqi , Graner Mariana , Itto Lucas Yuji Umesaki , Butter Loes M. , Claessen Nike , Roelofs Joris J.T.H. , Florquin Sandrine , Veras Mariana Matera , Andrade Maria de Fátima , Saldiva Paulo Hilário Nascimento , Kers Jesper , Andrade Lucia , Tammaro Alessandra
Published: August 2023

Chronic kidney disease (CKD) has emerged as a significant global public health concern. Recent epidemiological studies have highlighted the link between exposure to fine particulate matter (PM2.5) and declined renal function. PM2.5 exerts its harmful effects on various organs through oxidative stress and inflammation. Acute kidney injury (AKI) resulting from ischemia reperfusion injury (IRI) involves similar biological processes involved in PM2.5 toxicity and is a known risk factor for CKD. The objective of this study was to investigate the impact of PM2.5 exposure on IRI-induced AKI. Mice were exposed to PM2.5 or filtered air for 12 weeks before IRI, and were euthanized 48h after IRI. Animals exposed to PM2.5 and IRI exhibited reduced glomerular filtration and impaired urine concentration ability. Moreover, they showed elevated tubular damage markers NGAL and KIM-1, along with significant tubular necrosis. PM2.5 exposure exacerbated local innate immune activation, leading to an increased infiltration of Ly6G+ granulocytes and F480+ macrophages in the kidney. This, in turn, contributed to heightened renal senescence markers and myofibroblast infiltration. Collectively, our findings suggest that AKI-induced hampered tubular function is worsened by PM2.5, leading to reduced resilience to stress, activation of aging mechanisms and early hallmarks of fibrosis. Decreasing PM2.5 and implementing preventive strategies can improve AKI patients outcome and prevent AKI progression.
Autophagy counters inflammation-driven glycolytic impairment in aging hematopoietic stem cells
Authors: Dellorusso Paul V. , Proven Melissa A. , Calero-Nieto Fernando J. , Wang Xiaonan , Mitchell Carl A. , Hartmann Felix , Amouzgar Meelad , Favaro Patricia , DeVilbiss Andrew , Swann James W. , Ho Theodore T. , Zhao Zhiyu , Bendall Sean C. , Morrison Sean , Göttgens Berthold , Passegué Emmanuelle
Published: August 2023

Aging of the hematopoietic system promotes various blood, immune and systemic disorders and is largely driven by hematopoietic stem cell (HSC) dysfunction (1). Autophagy is central for the benefits associated with activation of longevity signaling programs (2), and for HSC function and response to nutrient stress (3,4). With age, a subset of HSCs increases autophagy flux and preserves some regenerative capacity, while the rest fail to engage autophagy and become metabolically overactivated and dysfunctional (4). However, the signals that promote autophagy in old HSCs and the mechanisms responsible for the increased regenerative potential of autophagy-activated old HSCs remain unknown. Here, we demonstrate that autophagy activation is an adaptive survival response to chronic inflammation in the aging bone marrow (BM) niche (5). We find that inflammation impairs glucose metabolism and suppresses glycolysis in aged HSCs through Socs3-mediated impairment of AKT/FoxO-dependent signaling. In this context, we show that inflammation-mediated autophagy engagement preserves functional quiescence by enabling metabolic adaptation to glycolytic impairment. Moreover, we demonstrate that transient autophagy induction via a short-term fasting/refeeding paradigm normalizes glucose uptake and glycolytic flux and significantly improves old HSC regenerative potential. Our results identify inflammation-driven glucose hypometabolism as a key driver of HSC dysfunction with age and establish autophagy as a targetable node to reset old HSC glycolytic and regenerative capacity.

One-Sentence Summary

Autophagy compensates for chronic inflammation-induced metabolic deregulation in old HSCs, and its transient modulation can reset old HSC glycolytic and regenerative capacity.
Evaluation of the RNA-dependence of PRC2 binding to chromatin in human pluripotent stem cells
Authors: Long Yicheng , Hwang Taeyoung , Gooding Anne R. , Goodrich Karen J. , Hanson Skylar D. , Vallery Tenaya K. , Rinn John L. , Cech Thomas R.
Published: August 2023

Polycomb Repressive Complex 2 (PRC2), an important histone modifier and epigenetic repressor, has been known to interact with RNA for almost two decades. In our previous publication (Long, Hwang et al. 2020), we presented data supporting the functional importance of RNA interaction in maintaining PRC2 occupancy on chromatin, using comprehensive approaches including an RNA-binding mutant of PRC2 and an rChIP-seq assay. Recently, concerns have been expressed regarding whether the RNA-binding mutant has impaired histone methyltransferase activity and whether the rChIP-seq assay can potentially generate artifacts. Here we provide new data that support a number of our original findings. First, we found the RNA-binding mutant to be fully capable of maintaining H3K27me3 levels in human induced pluripotent stem cells. The mutant had reduced methyltransferase activity in vitro, but only on some substrates at early time points. Second, we found that our rChIP-seq method gave consistent data across antibodies and cell lines. Third, we further optimized rChIP-seq by using lower concentrations of RNase A and incorporating a catalytically inactive mutant RNase A as a control, as well as using an alternative RNase (RNase T1). The EZH2 rChIP-seq results using the optimized protocols supported our original finding that RNA interaction contributes to the chromatin occupancy of PRC2.
Synthetic Homoserine Lactone Sensors for Gram-PositiveBacillus subtilisusing LuxR-type Regulators
Authors: Zeng Min , Sarker Biprodev , Howitz Nathaniel , Shah Ishita , Andrews Lauren B.
Published: August 2023

A universal biochemical signal for bacterial cell-cell communication could facilitate programming dynamic responses in diverse bacterial consortia. However, the classical quorum sensing paradigm is that gram-negative and gram-positive bacteria generally communicate via homoserine lactones (HSL) or oligopeptide molecular signals, respectively, to elicit population responses. Here, we create synthetic HSL sensors for gram-positiveBacillus subtilis168 using allosteric LuxR-type regulators (RpaR, LuxR, RhlR, and CinR) and synthetic promoters. Promoters were combinatorially designed from different sequence elements (–35, –16, –10, and transcriptional start regions). We quantified the effects of these combinatorial promoters on sensor activity and determined how regulator expression affects its activation, achieving up to 293-fold activation. Using statistical design of experiments, we identified significant effects of promoter regions and pairwise interactions on sensor activity, which helped to understand the sequence-function relationships for synthetic promoter design. We present the first known set of functional HSL sensors (≥ 20-fold dynamic range) inB. subtilisfor four different HSL chemical signals:p-coumaroyl-HSL, 3-oxohexanoyl-HSL,n-butyryl-HSL, andn-(3-hydroxytetradecanoyl)-HSL. This set of synthetic HSL sensors for a gram-positive bacterium can pave the way for designable interspecies communication within microbial consortia.
How reliable are estimates of key parameters in viral dynamic models?
Authors: Zitzmann Carolin , Ke Ruian , Ribeiro Ruy M. , Perelson Alan S.
Published: August 2023

Mathematical models of viral infection have been developed and fit to data to gain insight into disease pathogenesis for a number of agents including HIV, hepatitis C and B virus. However, for acute infections such as influenza and SARS-CoV-2, as well as for infections such as hepatitis C and B that can be acute or progress to being chronic, viral load data are often collected after symptoms develop, usually around or after the peak viral load. Consequently, we frequently lack data in the exponential phase of viral growth, i.e., when most transmission events occur. Missing data may make estimation of the time of infection, the infectious period, and parameters in viral dynamic models, such as the cell infection rate, difficult. Here, we evaluated the reliability of estimates of key model parameters when viral load data prior to the viral load peak is missing. We estimated the time from infection to peak viral load by fitting non-linear mixed models to a dataset with frequent viral RNA measurements, including pre-peak. We quantified the reliability of estimated infection times, key model parameters, and the time to peak viral load. Although estimates of the time of infection are sensitive to the quality and amount of available data, other parameters important in understanding disease pathogenesis, such as the loss rate of infected cells, are less sensitive. We find a lack of data in the exponential growth phase underestimates the time to peak viral load by several days leading to a shorter predicted exponential growth phase. On the other hand, having an idea of the time of infection and fixing it, results in relatively good estimates of dynamical parameters even in the absence of early data.
Acto3D: user- and budget-friendly software for multichannel high-resolution three-dimensional imaging
Authors: Takeshita Naoki , Sakaki Shinichiro , Saba Rie , Inoue Satoshi , Nishikawa Kosuke , Ueyama Atsuko , Matsuo Kazuhiko , Shigeta Masaki , Nakajima Yoshiro , Kobayashi Daisuke , Yamazaki Hideya , Yamada Kei , Iehara Tomoko , Yashiro Kenta
Published: August 2023

Advances in fluorescence microscopy and tissue-clearing technology have revolutionized three-dimensional (3D) imaging of fluorescently labeled tissues, organs, and embryos. However, the complexity and high cost of existing software and computer solutions for such imaging limit its widespread adoption by researchers with limited resources. We here introduce Acto3D as a user- and budget-friendly, open-source computer software application designed to streamline the generation and observation of high-resolution 3D images of targets labeled with multiple fluorescent probes. Acto3D features an intuitive interface that simplifies the importation, visualization, and analysis of data sets, has an associated tool for annotation of vascular lumens, and incorporates multiple fluorescence channels for comprehensive imaging. Underpinned by an integrated graphics processing unit, Acto3D allows accurate image reconstruction and efficient data processing without the need for expensive high-performance computers. We validated the software by imaging mouse embryonic structures. Acto3D thus constitutes a cost-effective and efficient platform to support biological research.