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The cart-ruts are one of the most elusive enigmas of Maltese archaeology. Like the prehistoric megalithic temples and the corpulent statues found in them, they defy a comprehensive and satisfying explanation. They are a fascinating subject for discussion not only for archaeologists but also for the ordinary citizens, whether resident or visiting. In fact they have been treated both in archaeological and in other kinds of literature, as well as in television documentaries.

Immune cell engagers are engineered antibodies with at least one arm binding a tumor-associated antigen and at least another one directed against an activating receptor in immune effector cells: CD3 for recruitment of T cells and CD16a for NK cells. The first T cell engager (the anti-CD19 blinatumomab) was approved by the FDA in 2014, but no other one hit the market until 2022. Now the field is gaining momentum, with three approvals in 2022 and 2023 (as of May): the anti-CD20 × anti-CD3 mosunetuzumab and epcoritamab and the anti-B cell maturation antigen (BCMA) × anti-CD3 teclistamab, and another three molecules in regulatory review. T cell engagers will likely revolutionize the treatment of hematological malignancies in the short term, as they are considerably more potent than conventional monoclonal antibodies recognizing the same tumor antigens. The field is thriving, with a plethora of different formats and targets, and around 100 bispecific T cell engagers more are already in clinical trials. Bispecific NK cell engagers are also in early-stage clinical studies and may offer similar efficacy with milder side effects. Trispecific antibodies (engaging either T cell or NK cell receptors) raise the game even further with a third binding moiety, which allows either the targeting of an additional tumor-associated antigen to increase specificity and avoid immune escape or the targeting of additional costimulatory receptors on the immune cell to improve its effector functions. Altogether, these engineered molecules may change the paradigm of treatment for relapsed or refractory hematological malignancies.

Chemotherapy is still the cornerstone for malaria control. Developing drugs against Plasmodium parasites and monitoring their efficacy requires methods to accurately determine the parasite killing rate in response to treatment. Commonly used techniques essentially measure metabolic activity as a proxy for parasite viability. However, these approaches are susceptible to artefacts, as viability and metabolism are two parameters that are coupled during the parasite life cycle but can be differentially affected in response to drug actions. Moreover, traditional techniques do not allow to measure the speed-of-action of compounds on parasite viability, which is an essential efficacy determinant. We present here a comprehensive methodology to measure in vitro the direct effect of antimalarial compounds over the parasite viability, which is based on limiting serial dilution of treated parasites and re-growth monitoring. This methodology allows to precisely determine the killing rate of antimalarial compounds, which can be quantified by the parasite reduction ratio and parasite clearance time, which are key mode-of-action parameters. Importantly, we demonstrate that this technique readily permits to determine compound killing activities that might be otherwise missed by traditional, metabolism-based techniques. The analysis of a large set of antimalarial drugs reveals that this viability-based assay allows to discriminate compounds based on their antimalarial mode-of-action. This approach has been adapted to perform medium throughput screening, facilitating the identification of fast-acting antimalarial compounds, which are crucially needed for the control and possibly the eradication of malaria.

Malaria is a devastating infection caused by protozoa of the genus Plasmodium . Drug resistance is widespread, no new chemical class of antimalarials has been introduced into clinical practice since 1996 and there is a recent rise of parasite strains with reduced sensitivity to the newest drugs. We screened nearly 2 million compounds in GlaxoSmithKline’s chemical library for inhibitors of P. falciparum , of which 13,533 were confirmed to inhibit parasite growth by at least 80% at 2 µM concentration. More than 8,000 also showed potent activity against the multidrug resistant strain Dd2. Most (82%) compounds originate from internal company projects and are new to the malaria community. Analyses using historic assay data suggest several novel mechanisms of antimalarial action, such as inhibition of protein kinases and host–pathogen interaction related targets. Chemical structures and associated data are hereby made public to encourage additional drug lead identification efforts and further research into this disease. Antimalarial arsenal There are still nearly 250 million malaria cases reported annually, over 800,000 fatal, with most deaths being children under 5. The malaria parasite Plasmodium falciparum is notoriously adept at developing drug resistance, and new drugs are urgently needed. Two reports raise hopes that alternatives to artemisinins might be found, by identifying thousands of compounds inhibiting the growth of P. falciparum asexual-stage parasites in red blood cells, many distinct in structure and mechanism from current drugs. Guiguemde et al . present a chemical genomics screen of over 300,000 compounds: the 1,300 'hits' include 561 with good potency and broad therapeutic windows. Gamo et al . screened nearly 2 million compounds from GlaxoSmithKline's chemicals library, finding over 13,500 hits, many active against multidrug-resistant isolates. These studies provide a rich source of potential leads, freely available to academic and industry labs looking for new antimalarials. Here, nearly 2 million compounds from GlaxoSmithKline's chemical library were screened for inhibitors of the malaria parasite Plasmodium falciparum , grown in red blood cells. Of these compounds, some 13,500 inhibited parasite growth, and more than 8,000 also showed potent activity against a multidrug resistant strain. The targets of these compounds were inferred through bioinformatic analysis, revealing several new mechanisms of antimalarial action.

Pericytes (PC) are mural cells that surround endothelial cells in small blood vessels. PC have traditionally been credited with structural functions, being essential for vessel maturation and stabilization. However, an accumulating body of evidence suggests that PC also display immune properties. They can respond to a series of pro-inflammatory stimuli and are able to sense different types of danger due to their expression of functional pattern-recognition receptors, contributing to the onset of innate immune responses. In this context, PC not only secrete a variety of chemokines but also overexpress adhesion molecules such as ICAM-1 and VCAM-1 involved in the control of immune cell trafficking across vessel walls. In addition to their role in innate immunity, PC are involved in adaptive immunity. It has been reported that interaction with PC anergizes T cells, which is attributed, at least in part, to the expression of PD-L1. As components of the tumor microenvironment, PC can also modulate the antitumor immune response. However, their role is complex, and further studies will be required to better understand the crosstalk of PC with immune cells in order to consider them as potential therapeutic targets. In any case, PC will be looked at with new eyes by immunologists from now on.

According to Steuart, falsetto was understood in the eighteenth century as an integral component of most voices and a unique approach used in order to attain extreme ranges, something that could appear in parodic contexts but could also be associated with the illusory and unbelievable. Nardini's discussion of prosulas highlighted research from her recent book Chants, Hypertext, and Prosulas: Re-texting the Proper of the Mass in Beneventan Manuscripts (New York: Oxford University Press, 2021), and coincidentally provided valuable context for ensuing presentations concerning ornamentation and improvisation processes in later periods (recurring topics at this year's conference). The day ended with a masterclass by Guido Olivieri and Marc Vanscheeuwijck, featuring early-music students from the University of Oregon School of Music and Dance. The final event of the conference was the concert ‘Sacred Music in Baroque Naples’, given by guest artist Kraig Scott, Marc Vanscheeuwijck, and staff and students of the University Oregon's early-music programme.

Benzoxaboroles are effective against bacterial, fungal and protozoan pathogens. We report potent activity of the benzoxaborole AN3661 against Plasmodium falciparum laboratory-adapted strains (mean IC 50 32 nM), Ugandan field isolates (mean ex vivo IC 50 64 nM), and murine P. berghei and P. falciparum infections (day 4 ED 90 0.34 and 0.57 mg kg −1 , respectively). Multiple P. falciparum lines selected in vitro for resistance to AN3661 harboured point mutations in pfcpsf3 , which encodes a homologue of mammalian cleavage and polyadenylation specificity factor subunit 3 (CPSF-73 or CPSF3). CRISPR-Cas9-mediated introduction of pfcpsf3 mutations into parental lines recapitulated AN3661 resistance. PfCPSF3 homology models placed these mutations in the active site, where AN3661 is predicted to bind. Transcripts for three trophozoite-expressed genes were lost in AN3661-treated trophozoites, which was not observed in parasites selected or engineered for AN3661 resistance. Our results identify the pre-mRNA processing factor PfCPSF3 as a promising antimalarial drug target. Benzoxaboroles have been shown to be active against different pathogens. Here, the authors show that the benzoxaborole AN3661 inhibits Plasmodium falciparum in vitro and in mouse models, and identify a homologue of a mammalian cleavage and polyadenylation specificity factor as a drug target.

The early stages of the COVID-19 pandemic presented the characteristics of a traumatic event that could trigger post-traumatic stress disorder. Emergency Medical Services workers are already a high-risk group due to their professional development. The research project aimed to analyse the impact of the COVID-19 pandemic on EMS professionals in terms of their mental health. For this purpose, we present a descriptive crosssectional study with survey methodology. A total of 317 EMS workers (doctors, nurses, and emergency medical technicians) were recruited voluntarily. Psychological distress, post-traumatic stress disorder, and insomnia were assessed. The instruments were the General Health Questionnaire-12 (GHQ-12), the Davidson Trauma Scale (DTS-8), and the Athens Insomnia Scale (AIS-8). We found that 36% of respondents had psychological distress, 30.9% potentially had PTSD, and 60.9% experienced insomnia. Years of work experience were found to be positively correlated, albeit with low effect, with the PTSD score (r = 0.133). Finally, it can be stated that the COVID-19 pandemic has been a traumatic event for EMS workers. The number of professionals presenting psychological distress, possible PTSD, or insomnia increased dramatically during the early phases of the pandemic. This study highlights the need for mental health disorder prevention programmes for EMS workers in the face of a pandemic.

Marine shells incorporate oxygen isotope signatures during growth, creating valuable records of seawater temperature and marine oxygen isotopic compositions. Secondary ion mass spectrometry (SIMS) measures these compositions in situ at finer length‐scales than traditional stable isotope analyses. However, determining oxygen isotope ratios in aragonite, the most common shell mineral, is hampered by a lack of ideal reference materials, limiting the accuracy of SIMS‐based seawater temperature reconstructions. Here, we tested the capability of SIMS to produce seawater temperature reconstructions despite the matrix calibration challenges associated with aragonite. We cultured Anadara trapezia bivalves at four controlled seawater temperatures (13–28°C) and used strontium labeling to mark the start of the temperature‐controlled shell increment, allowing for more spatially precise SIMS analysis. An improved matrix calibration was developed to ensure more accurate bio‐aragonite analyses that addressed matrix differences between the pure abiotic reference materials and the bio‐aragonite samples with intricate mineral‐organic architectures and distinct minor and trace element compositions. We regressed SIMS‐IRMS biases of abiotic and biogenic aragonites that account for their systematic differences in major, minor, and trace elements, allowing for more accurate SIMS analyses of the temperature‐controlled shell increment. The thorough matrix calibration allowed us to provide a SIMS‐based seawater‐corrected oxygen isotope thermometer of T(°C) = 23.05 ± 0.36 − 4.48 · (δ18Oaragonite [‰ VPDB] − δ18Oseawater [‰ VSMOW] ± 0.25) and 103lnαaragonite‐seawater = (17.78 ± 0.88) · 103/T (K) − (29.44 ± 2.40) that agrees with existing aragonitic IRMS‐based thermometer relationships and improves the applicability of SIMS‐based paleo‐environmental reconstructions of marine bio‐aragonites. Plain Language Summary In this study, we grew marine bivalves under tightly constrained aquaculture conditions at four different seawater temperatures and marked the start of the growth period in the shell structure using strontium labeling. The newly grown shell material between the strontium‐labeled increment and the shell edge was analyzed for its oxygen isotopic composition. The compositions were measured in situ using a high resolution ion microprobe and a newly developed analytical post‐processing strategy specifically designed for biomineral samples with mineral‐organic architectures. The strategy involved two reference materials and the major, minor, and trace element content in the shell and the reference materials. The new approach resulted in an accurate and robust model for determining past seawater temperatures from fossil or historic shells based on their oxygen isotope composition at over an order of magnitude finer length scales than traditional oxygen isotope analyses. Key Points Bivalve mollusks were cultured at different temperatures under tightly constrained seawater composition and environmental conditions SIMS δ18O accuracy was improved with a new paired proxy‐like matrix bias correction using major, minor, and trace element abundances The first high‐resolution SIMS‐based stable oxygen isotope calibration for determining modern and ancient seawater temperatures is derived

There is an urgent need for new drugs to treat malaria, with broad therapeutic potential and novel modes of action, to widen the scope of treatment and to overcome emerging drug resistance. Here we describe the discovery of DDD107498, a compound with a potent and novel spectrum of antimalarial activity against multiple life-cycle stages of the Plasmodium parasite, with good pharmacokinetic properties and an acceptable safety profile. DDD107498 demonstrates potential to address a variety of clinical needs, including single-dose treatment, transmission blocking and chemoprotection. DDD107498 was developed from a screening programme against blood-stage malaria parasites; its molecular target has been identified as translation elongation factor 2 (eEF2), which is responsible for the GTP-dependent translocation of the ribosome along messenger RNA, and is essential for protein synthesis. This discovery of eEF2 as a viable antimalarial drug target opens up new possibilities for drug discovery. The description of a compound (DDD107498) with antimalarial activity against multiple life-cycle stages of Plasmodium falciparum and good pharmacokinetic and safety properties, with potential for single-dose treatment, chemoprotection and prevention of transmission. A new antimalarial agent With artemisinin resistance spreading, there is an urgent need to develop new therapeutics to target Plasmodium falciparum , the causative agent of malaria. Here Ian Gilbert and colleagues report the discovery of a compound (DDD107498) with antimalarial activity against multiple life-cycle stages of the parasite and good pharmacokinetic and safety properties. It is non-mutagenic and has potential for both single-dose treatment and once-weekly chemoprotection. DDD107498 acts through inhibition of cytosolic protein synthesis, with translation elongation factor eEF2 as its target.