Correction: Correia et al. Beyond Penicillin: The Potential of Filamentous Fungi for Drug Discovery in the Age of Antibiotic Resistance. 2023, 12, 1250.

Manuel Simões was included as a corresponding author in the original publication [...].

99mTc(I)-Labeled His-Tagged Proteins: Impact in the Development of Novel Imaging Probes and in Drug Discovery.

Technetium-99 m (99mTc) remains the cornerstone of nuclear medicine for single photon emission computed tomography (SPECT) due to its widespread availability and chemical and physical features. Its multiple oxidation states allow for the design and production of radiopharmaceuticals with versatile properties, namely in terms of pharmacokinetic profile. 99mTc(V) is the most common oxidation state, but 99mTc(I) gained traction after the pioneering work of Alberto and colleagues, which resulted in the introduction of the organometallic core fac-[99mTc(CO)3(H2O)3]+. This core is readily available from [99mTcO4]- and displays three labile water molecules that can be easily swapped for ligands with different denticity and/or donor atoms in aqueous environment. This makes it possible to radiolabel small molecules as well as high molecular weight molecules, such as antibodies or other proteins, while assuring biological activity. Direct radiolabelling of those proteins with fac-[99mTc(CO)3]+ under mild conditions is accomplished through incorporation of a polyhistidine tag (His-tag), a commonly used tag for purification of recombinant proteins. This review aims to address the direct radiolabelling of His-tagged macromolecules with fac-[99mTc(CO)3]+ for development of molecular imaging agents and the impact of this technology in the discovery and development of imaging and/or therapeutic agents towards clinical application.

Entomological indicators and food sources of triatomines in the Brazilian semi-arid region.

BACKGROUND: Triatomines are biological vectors of Trypanosoma cruzi, the etiological agent of Chagas Disease (CD) and have various mammalian hosts. This study evaluated the entomological indicators and food sources of triatomines in Petrolina in the semi-arid region of Brazil, where CD is endemic. METHODS: Triatomines were captured indoors and outdoors through an active search and entomological indices (household and natural infections) were calculated. Parasitological analyses were performed through microscopic visualization using Giemsa-stained insect feces, and DNA sequencing was employed to identify food sources from the gut contents of 82 insects (9.05%) that were better preserved. RESULTS: We captured triatomines (906) in peridomicile (807) and intradomicile (99): Triatoma brasiliensis (84.7%, 767 specimens), Triatoma spp. (8.2%, 74 specimens), T. pseudomaculata (6.5%, 59 specimens), Rhodnius spp. (0.4%, four specimens), R. nasutus (0.1%, one specimen), and T. sordida (0.1%, one specimen). The household infestation index is 11.8%. Thirty-five triatomines were infected (33 T. brasiliensis and two T. pseudomaculata), corresponding to a natural infection index of 3.8%. The identified food sources were human T. pseudomaculata and T. brasiliensis, dogs for T. brasiliensis and rodents (Mus musculus) for T. brasiliensis. CONCLUSIONS: The results reinforce the need to intensify CD diagnosis, surveillance, and control actions, as an increase in entomological indices was recorded. Blood from humans and domestic and synanthropic animals was detected in the infected triatomines, suggesting a risk of CD vector transmission in Petrolina. As CD is a zoonosis, multidisciplinary and intersectoral CD surveillance must be conducted in the context of the One Health.

Optical coherence tomography angiography based prognostic factors and visual outcomes in primary rhegmatogenous retinal detachment after pars plana vitrectomy.

PURPOSE: To evaluate the visual outcomes and changes in the retinal microcirculation in patients with primary rhegmatogenous retinal detachment (RRD) following successful pars plana vitrectomy (PPV). METHODS: Nine macula-on RRD and 23 macula-off RRD eyes were retrospectively evaluated. Clinical data was collected at admission and 3 months after PPV. Optical coherence tomography angiography (OCTA) was performed 3 months after PPV. Superficial vascular plexus data obtained with OCTA was compared between affected and fellow eyes and according to macular involvement. Quantitative measurements of the superficial retinal capillary associated with the preoperative and intraoperative factors were analyzed. RESULTS: Overall RRD inner vessel densities (IVD), full vessel densities (FVD), inner perfusion densities (IPD) and full perfusion densities (FPD) were significantly and positively correlated with best corrected visual acuity (BCVA)(p = 0.002, p = 0.006, p = 0.009, p = 0.023, respectively). In the macula-off RRD, IVD and FVD were significantly decreased compared with macula-on RRD (p = 0.014 and p = 0.034, respectively) and significantly correlated with a longer duration and larger extension of detachment. Higher differences of IVD and FVD between the fellow and affected eyes were significantly correlated with worse BCVA in the macula-off subgroup. CONCLUSION: Macula-off RRD presented worse OCTA superficial vascular parameters compared with the macula-on group and fellow eyes, which were correlated with a poorer visual outcome and exacerbated by a longer duration and larger extension of the detachment. Macula-off RRD causes not only retinal structural damage but also a reduction in retinal perfusion despite successful anatomical repair.

A New Class of Gold(I) NHC Complexes with Proapoptotic and Resensitizing Properties towards Multidrug Resistant Leukemia Cells Overexpressing BCL-2.

From previous studies, it is evident that metal-organic gold(I) complexes have antiproliferative activities. The aim of this study is not only to find new anticancer agents but also to overcome existing cytostatic resistance in cancer cells. The synthesis and medicinal evaluation of two cationic 1,3-disubstituted gold(I) bis-tetrazolylidene complexes 1 and 2 are reported. To determine apoptosis-inducing properties of the complexes, DNA fragmentation was measured using propidium iodide staining followed by flow cytometry. Gold(I) complex 1 targets explicitly malignant cells, effectively inhibiting their growth and selectively inducing apoptosis without signs of necrosis. Even in cells resistant to common treatments such as doxorubicin, it overcomes multidrug resistance and sensitizes existing drug-resistant cells to common cytostatic drugs. It is assumed that gold(I) complex 1 involves the mitochondrial pathway in apoptosis and targets members of the BCL-2 family, enhancing its potential as a therapeutic agent in cancer treatment.

Cooperative housing under a grant-of-use in Catalonia and health: pre-post analysis.

BACKGROUND: Housing is considered a social determinant of health. In Catalonia and Spain, ensuring affordable housing is challenging and cooperative housing under a grant-of-use emerges as an alternative, challenging traditional housing models. This study aims to quantify its impact on health before and after moving to the cooperative house. METHODS: A longitudinal study of individuals in cooperative housing projects in Catalonia (July 2018-April 2023) was conducted. Data, including sociodemographic, housing information, and health-related details, were collected through baseline and follow-up surveys. RESULTS: Seventy participants (42 women, 28 men) showed positive changes in housing conditions during follow-up. Improved perceptions of health, mental health, and social support were observed. Despite limitations in sample size and short follow-up, initial findings suggest improvements in health. CONCLUSIONS: Cooperative housing under a grant-of-use in Catalonia appears promising for improving health and living conditions. Further research is warranted to explore its full potential as an alternative amid housing challenges in the region.

Computer-aided design and implementation of efficient biosynthetic pathways to produce high added-value products derived from tyrosine in Escherichia coli.

Developing efficient bioprocesses requires selecting the best biosynthetic pathways, which can be challenging and time-consuming due to the vast amount of data available in databases and literature. The extension of the shikimate pathway for the biosynthesis of commercially attractive molecules often involves promiscuous enzymes or lacks well-established routes. To address these challenges, we developed a computational workflow integrating enumeration/retrosynthesis algorithms, a toolbox for pathway analysis, enzyme selection tools, and a gene discovery pipeline, supported by manual curation and literature review. Our focus has been on implementing biosynthetic pathways for tyrosine-derived compounds, specifically L-3,4-dihydroxyphenylalanine (L-DOPA) and dopamine, with significant applications in health and nutrition. We selected one pathway to produce L-DOPA and two different pathways for dopamine-one already described in the literature and a novel pathway. Our goal was either to identify the most suitable gene candidates for expression in Escherichia coli for the known pathways or to discover innovative pathways. Although not all implemented pathways resulted in the accumulation of target compounds, in our shake-flask experiments we achieved a maximum L-DOPA titer of 0.71 g/L and dopamine titers of 0.29 and 0.21 g/L for known and novel pathways, respectively. In the case of L-DOPA, we utilized, for the first time, a mutant version of tyrosinase from Ralstonia solanacearum. Production of dopamine via the known biosynthesis route was accomplished by coupling the L-DOPA pathway with the expression of DOPA decarboxylase from Pseudomonas putida, resulting in a unique biosynthetic pathway never reported in literature before. In the context of the novel pathway, dopamine was produced using tyramine as the intermediate compound. To achieve this, tyrosine was initially converted into tyramine by expressing TDC from Levilactobacillus brevis, which, in turn, was converted into dopamine through the action of the enzyme encoded by ppoMP from Mucuna pruriens. This marks the first time that an alternative biosynthetic pathway for dopamine has been validated in microbes. These findings underscore the effectiveness of our computational workflow in facilitating pathway enumeration and selection, offering the potential to uncover novel biosynthetic routes, thus paving the way for other target compounds of biotechnological interest.

FELASA Working Group report: Capture and transport of live cephalopods - recommendations for scientific purposes.

On 1 January 2013, research using cephalopod molluscs, from hatchlings to adults, became regulated within Directive 2010/63/EU. There are significant difficulties in captive breeding in the great majority of currently utilised species. Thus, scientific research relies upon the use of wild-caught animals. Furthermore, live cephalopods are shared and transported between different stakeholders and laboratories across Europe and other continents. Despite existing European and national legislation, codes, guidelines and reports from independent organisations, a set of recommendations specifically addressing the requirements for the capture and transport of animals belonging to this taxon are missing. In addition, although training and development of competence for all people involved in the supply chain are essential and aim to ensure that animals do not suffer from pain, distress or lasting harm, the requirements for those capturing and transporting wild cephalopods have not been considered. This Working Group reviewed the current literature to recognise scientific evidence and the best practice, and compiled a set of recommendations to provide guidance on the 'techniques' to be used for the capture and transport of live cephalopods for their use in scientific procedures. In addition, we propose to (a) develop standardised approaches able to assess recommended methods and objectively quantify the impact of these processes on animals' health, welfare and stress response, and (b) design a training programme for people attaining the necessary competence for capture and transportation of live cephalopods, as required by Directive 2010/63/EU.

Palinacousis in amyloidosis: exploring the hallucinatory phenomenon in brain pathology-a case report.

BACKGROUND: Hereditary transthyretin amyloidosis, caused by transthyretin gene mutations, progresses with systemic impact and often presents peripheral neuropathy. Recent research reveals central nervous system involvement, marked by leptomeningeal amyloid accumulation and transient focal neurological episodes displaying cortical dysfunction. CASE PRESENTATION: A 47-year-old Caucasian man with hereditary transthyretin amyloidosis presented with motor aphasia, right hemiparesis, fever, and an altered state of consciousness. Tests ruled out stroke or infection. While improving, the patient reported an ongoing auditory repetition phenomenon for 48 hours despite efforts to shift focus or introduce new stimuli. CONCLUSION: This represents the first known case report documenting palinacousis in hereditary transthyretin amyloidosis attributed to central nervous system involvement. This case highlights the complexities in assessment and management of patients when neurological and psychiatric symptoms overlap.

Creatine Kinase and Respiratory Decline in Amyotrophic Lateral Sclerosis.

Respiratory dysfunction is an important hallmark of amyotrophic lateral sclerosis (ALS). Elevation of creatine kinase (CK) has been reported in 23-75% of ALS patients, but the underlying mechanisms remain unknown. This work aims to enlighten the role of CK as a prognostic factor of respiratory dysfunction in ALS. A retrospective analysis of demographic and clinical variables, CK, functional decline per month (ΔFS), forced vital capacity (%FVC), and mean amplitude of the phrenic nerve compound motor action potential (pCMAP) in 319 ALS patients was conducted. These measurements were evaluated at study entry, and patients were followed from the moment of first observation until death or last follow-up visit. High CK values were defined as above the 90th percentile (CK ≥ P90) adjusted to sex. We analyzed survival and time to non-invasive ventilation (NIV) as proxies for respiratory impairment. Linear regression analysis revealed that high CK was associated with male sex (p < 0.001), spinal onset (p = 0.018), and FVC ≥ 80% (p = 0.038). CK was 23.4% higher in spinal-onset ALS patients (p < 0.001). High CK levels were not linked with an increased risk of death (p = 0.334) in Cox multivariate regression analysis. CK ≥ P90 (HR = 1.001, p = 0.038), shorter disease duration (HR = 0.937, p < 0.001), lower pCMAP (HR = 0.082, p < 0.001), and higher ΔFS (HR = 1.968, p < 0.001) were risk factors for respiratory failure. The association between high CK levels and poorer respiratory outcomes could derive from cellular metabolic stress or a specific phenotype associated with faster respiratory decline. Our study suggests that CK measurement at diagnosis should be more extensively investigated as a possible marker of poor respiratory outcome in future studies, including a larger population of patients.

Ensemble learning for fetal ultrasound and maternal-fetal data to predict mode of delivery after labor induction.

Providing adequate counseling on mode of delivery after induction of labor (IOL) is of utmost importance. Various AI algorithms have been developed for this purpose, but rely on maternal-fetal data, not including ultrasound (US) imaging. We used retrospectively collected clinical data from 808 subjects submitted to IOL, totaling 2024 US images, to train AI models to predict vaginal delivery (VD) and cesarean section (CS) outcomes after IOL. The best overall model used only clinical data (F1-score: 0.736; positive predictive value (PPV): 0.734). The imaging models employed fetal head, abdomen and femur US images, showing limited discriminative results. The best model used femur images (F1-score: 0.594; PPV: 0.580). Consequently, we constructed ensemble models to test whether US imaging could enhance the clinical data model. The best ensemble model included clinical data and US femur images (F1-score: 0.689; PPV: 0.693), presenting a false positive and false negative interesting trade-off. The model accurately predicted CS on 4 additional cases, despite misclassifying 20 additional VD, resulting in a 6.0% decrease in average accuracy compared to the clinical data model. Hence, integrating US imaging into the latter model can be a new development in assisting mode of delivery counseling.

Preparation Regimens to Improve Capsule Endoscopy Visualization and Diagnostic Yield (PrepRICE): a multicenter randomized trial.

BACKGROUND AND AIMS: Current guidelines recommend bowel preparation before small-bowel capsule endoscopy (SBCE). However, the optimal protocol is yet to be defined. To determine the best timing for preparation in SBCE, we compared small-bowel visualization quality (SBVQ), diagnostic yield (DY), and patient-reported outcomes across 4 purgative regimens. METHODS: In this prospective, randomized (1:1:1:1), multicenter study, patients with suspected small-bowel bleeding were randomized into 4 arms: G1 (1 L of polyethylene glycol + ascorbic acid [Moviprep, Norgine, Amsterdam, Netherlands] the night before SBCE), G2 (1 L in the morning up to 2 hours before SBCE), G3 (0.5 L up to 2 hours before SBCE + 0.5 L after the capsule reached the duodenum), and G4 (1 L after the capsule reached the duodenum). To assess DY, lesions were categorized as having high (P2) or low (P0 or P1) bleeding potential. SBVQ was assessed using the Brotz score. Transit times were measured, and patient tolerability was scored from 0 to 5, with higher scores indicating better tolerability. RESULTS: A total of 387 patients were included, 59% female and with a median age of 73 years (interquartile range, 23). The examination completion rate was lower in G1 (90%, P < .001). Small-bowel transit time was shorter for patients receiving purgative during SBCE (G3 and G4, P = .001). SBVQ was better in patients receiving purgative after reaching the small bowel (P < .001): a median of 7 for G1, 8 for G2, and 9 for G3 and G4. The overall DY of patients receiving intraprocedure purgatives (G3 + G4) was superior (42.7 vs 31.3%, P = .02); significant differences were found in the second and third terciles. Likewise, G3 and G4 had higher angioectasia detection (P = .04). Patients' satisfaction was significantly superior for G4 (median, 4 points; interquartile range, 1). CONCLUSIONS: The group that received the bowel preparation the night before SBCE had poorer outcomes. Intraprocedure purgative regimens reduced SBTT, enhanced visualization, improved DY, and increased angioectasia detection. G4 was the best-tolerated regimen.

Tailored Viral-like Particles as Drivers of Medical Breakthroughs.

Despite the recognized potential of nanoparticles, only a few formulations have progressed to clinical trials, and an even smaller number have been approved by the regulatory authorities and marketed. Virus-like particles (VLPs) have emerged as promising alternatives to conventional nanoparticles due to their safety, biocompatibility, immunogenicity, structural stability, scalability, and versatility. Furthermore, VLPs can be surface-functionalized with small molecules to improve circulation half-life and target specificity. Through the functionalization and coating of VLPs, it is possible to optimize the response properties to a given stimulus, such as heat, pH, an alternating magnetic field, or even enzymes. Surface functionalization can also modulate other properties, such as biocompatibility, stability, and specificity, deeming VLPs as potential vaccine candidates or delivery systems. This review aims to address the different types of surface functionalization of VLPs, highlighting the more recent cutting-edge technologies that have been explored for the design of tailored VLPs, their importance, and their consequent applicability in the medical field.

Cariprazine in the acute treatment of unipolar and bipolar depression: A systematic review and meta-analysis.

BACKGROUND: Cariprazine has emerged as a promising augmenting treatment agent for unipolar depression and as a monotherapy option for bipolar depression. We evaluated cariprazine's efficacy in treating acute major depressive episodes in individuals with major depressive disorder (MDD) or bipolar disorder. METHODS: A systematic review was conducted on MEDLINE, Embase, PsycINFO, Scopus and Web of Science, ClinicalTrials.gov and ScanMedicine. Study quality was assessed using the RoB 2 tool. Pairwise and dose-response meta-analyses were conducted with RStudio. Evidence quality was assessed with GRADE. RESULTS: Nine RCTs meeting inclusion criteria encompassed 4889 participants. Cariprazine, compared to placebo, significantly reduced the MADRS score (MD = -1.49, 95 % CI: -2.22 to -0.76) and demonstrated significantly higher response (RR = 1.21, 95 % CI: 1.12 to 1.30) and remission (RR = 1.19, 95 % CI: 1.06 to 1.34) rates. Subgroup analysis unveiled statistically significant reductions in MADRS score in MDD (MD = -1.15, 95 % CI: -2.04 to -0.26) and bipolar I disorder (BDI) (MD = -2.53, 95 % CI: -3.61 to -1.45), higher response rates for both MDD (RR = 1.19, 95 % CI: 1.08 to 1.31) and BDI (RR = 1.27, 95 % CI: 1.10 to 1.46), and higher remission rates only for BDI (RR = 1.41, 95 % CI: 1.24 to 1.60). A higher rate of treatment discontinuation due to adverse events was observed. LIMITATIONS: Reliance solely on RCTs limits generalisability; strict criteria might not reflect real-world diversity. CONCLUSIONS: Cariprazine demonstrates efficacy in treating major depressive episodes, although variations exist between MDD and BDI and tolerability may be an issue.

Small Bowel Villous Atrophy in a Young Patient: A Challenging Diagnosis.

Common variable immunodeficiency enteropathy is a sprue-like disease, which may manifest as a severe malabsorption syndrome with nutritional deficits and cachexia. The authors report a case of a 33-year-old Afghan man, who presented to the emergency department due to chronic watery diarrhea and severe malnourishment. He had been previously misdiagnosed with celiac disease in his early adulthood; however, this was based on inconclusive findings. After a thorough diagnostic workup, the final diagnosis of common variable immunodeficiency enteropathy with symptomatic norovirus infection of the gut was obtained during his prolonged hospitalization. A slow but progressive improvement was observed with immunoglobulin replacement therapy, corticotherapy, and ribavirin treatment. This is a noteworthy case of a rare malabsorption disorder, and it reviews important aspects concerning the differential diagnosis of small bowel villous atrophy of unknown etiology, as well as gastrointestinal manifestations of common variable immunodeficiency disorder.

A Enteropatia associada à Imunodeficiência Comum Variável é uma entidade com características clínicas e endoscópicas semelhantes à doença celíaca. Por vezes apresenta-se como um síndrome de malabsorção, levando a défices nutricionais e caquexia severa. Os autores relatam o caso de um homem de 33 anos de idade de naturalidade afegã, que recorreu ao serviço de urgência por um quadro de diarreia aquosa crónica e desnutrição severa. O doente teria sido diagnosticado erroneamente com doença celíaca no início da vida adulta, com bases em dados clínicos inconclusivos. Após um estudo exaustivo durante um internamento prolongado, o doente foi diagnosticado com uma Enteropatia associada à Imunodeficiência Comum Variável com sobreinfeção por Norovirus. Foi observada uma melhoria lenta e progressiva com instituição de terapêutica substitutiva com imunoglobulina, corticoterapia e ribavirina. Este caso retrata uma causa rara de malabsorção, abordando pontos essenciais no diagnóstico diferencial da atrofia vilositária do intestinal delgado, bem como das manifestações gastrointestinais da Imunodeficiência Comum Variável.

Molecular determinants for brain targeting by peptides: a meta-analysis approach with experimental validation.

Blood-brain barrier (BBB) peptide-shuttles (BBBpS) are able to translocate the BBB and reach the brain. Despite the importance of brain targeting in pharmacology, BBBpS are poorly characterized. Currently, their development relies on the empiric assumption that cell-penetrating peptides (CPPs), with proven ability to traverse lipid membranes, will likewise behave as a BBBpS. The relationship between CPPs/BBBpS remains elusive and, to the best of our knowledge, has not hitherto been subject to thorough experimental scrutiny. In this work, we have identified/quantified the main physicochemical properties of BBBpS and then searched for CPPs with these properties, hence potential BBBpS. The specific features found for BBBpS are: (i) small size, (ii) none or few aromatic residues, (iii) hydrophobic, and (iv) slight cationic nature. Then, we selected the 10 scoring best in an ordinary least squares analysis, and tested them in vitro and in vivo. Overall, we identified the molecular determinants for brain targeting by peptides, devised a methodology that can be used to assist in the design of peptides with potential brain penetration from amino acid residue sequences, and found four new BBBpS within the CPP library.

AsIII Selectively Induces a Disorder-to-Order Transition in the Metalloid Binding Region of the AfArsR Protein.

Arsenic is highly toxic and a significant threat to human health, but certain bacteria have developed defense mechanisms initiated by AsIII binding to AsIII-sensing proteins of the ArsR family. The transcriptional regulator AfArsR responds to AsIII and SbIII by coordinating the metalloids with three cysteines, located in a short sequence of the same monomer chain. Here, we characterize the binding of AsIII and HgII to a model peptide encompassing this fragment of the protein via solution equilibrium and spectroscopic/spectrometric techniques (pH potentiometry, UV, CD, NMR, PAC, EXAFS, and ESI-MS) combined with DFT calculations and MD simulations. Coordination of AsIII changes the peptide structure from a random-coil to a well-defined structure of the complex. A trigonal pyramidal AsS3 binding site is formed with almost exactly the same structure as observed in the crystal structure of the native protein, implying that the peptide possesses all of the features required to mimic the AsIII recognition and response selectivity of AfArsR. Contrary to this, binding of HgII to the peptide does not lead to a well-defined structure of the peptide, and the atoms near the metal binding site are displaced and reoriented in the HgII model. Our model study suggests that structural organization of the metal site by the inducer ion is a key element in the mechanism of the metalloid-selective recognition of this protein.