Selective Enhancement of REM Sleep in Male Rats through Activation of MT1 Receptors Located in the Locus Coeruleus Norepinephrine neurons.

Sleep disorders affect millions of people around the world and have a high comorbidity with psychiatric disorders. While current hypnotics mostly increase non-rapid eye movement sleep (NREMS), drugs acting selectively on enhancing rapid eye movement sleep (REMS) are lacking. This polysomnographic study in male rats showed that the first-in-class selective melatonin MT1 receptor partial agonist UCM871 increases the duration of REMs without affecting that of NREMS. The REMS-promoting effects of UCM871 occurred by inhibiting, in a dose-response manner, the firing activity of the locus coeruleus (LC) norepinephrine (NE) neurons, which express MT1 receptors. The increase of REMS duration and the inhibition of LC-NE neuronal activity by UCM871 were abolished by MT1 pharmacological antagonism and by an adeno-associated viral (AAV) vector which selectively knocked down MT1 receptors in the LC-NE neurons. In conclusion, MT1 receptor agonism inhibits LC-NE neurons and triggers REMS, thus representing a novel mechanism and target for REMS disorders and/or psychiatric disorders associated with REMS impairments.Significance Statement Rapid eye movement sleep (REMS) is involved in the processes of memory consolidation and emotional regulation, but drugs selectively enhancing REMS are scant. Herein, we show that the first-in-class selective melatonin MT1 receptor agonist UCM871, by inhibiting the activity of norepinephrine neurons in the locus coeruleus, an important nucleus regulating the sleep/wake cycle, selectively increases the duration of REMS. These findings enhance our current understanding of the neurobiology and pharmacology of REMS and provide a possible novel mechanism and target for disorders associated with REMS dysfunctions.

Anterior Cruciate Ligament Repair Using a Re-tensionable All-Suture Construct.

Anterior cruciate ligament (ACL) tears are among the most common injuries to the knee. With recent improvements in imaging that allow for more precise identification of ACL tear patterns, improved techniques for repair, and advancements in biological augmentation, there has been a re-emerging interest in primary ACL repair, especially for acute proximal ACL tears. This article aims to describe a surgical technique for primary ACL repair using a re-tensionable all-suture-based construct.

Changes in landscape and climate in Mexico and Texas reveal small effects on migratory habitat of monarch butterflies (Danaus plexippus).

The decline of the iconic monarch butterfly (Danaus plexippus) in North America has motivated research on the impacts of land use and land cover (LULC) change and climate variability on monarch habitat and population dynamics. We investigated spring and fall trends in LULC, milkweed and nectar resources over a 20-year period, and ~ 30 years of climate variables in Mexico and Texas, U.S. This region supports spring breeding, and spring and fall migration during the annual life cycle of the monarch. We estimated a - 2.9% decline in milkweed in Texas, but little to no change in Mexico. Fall and spring nectar resources declined < 1% in both study extents. Vegetation greenness increased in the fall and spring in Mexico while the other climate variables did not change in both Mexico and Texas. Monarch habitat in Mexico and Texas appears relatively more intact than in the midwestern, agricultural landscapes of the U.S. Given the relatively modest observed changes in nectar and milkweed, the relatively stable climate conditions, and increased vegetation greenness in Mexico, it seems unlikely that habitat loss (quantity or quality) in Mexico and Texas has caused large declines in population size or survival during migration.

Does Telotristat Have a Role in Preventing Carcinoid Heart Disease?

Carcinoid heart disease (CHD) is a frequent and life-threatening complication in patients with carcinoid tumors. Its clinical management is challenging is some cases since serotonin-induced valve fibrosis leads to heart failure. Telotristat is an inhibitor of tryptophan-hydroxylase (TPH), a key enzyme in serotonin production. Telotristat use in patients with carcinoid syndrome and uncontrollable diarrhea under somatostatin analogs is approved, but its specific role in patients with CHD is still not clear. IN this context, we aimed to explore the effect of telotristat in heart fibrosis using a mouse model of serotonin-secreting metastasized neuroendocrine neoplasm (NEN). To this aim, four treatment groups (n = 10/group) were evaluated: control, monthly octreotide, telotristat alone, and telotristat combined with octreotide. Plasma serotonin and NT-proBNP levels were determined. Heart fibrosis was histologically evaluated after 6 weeks of treatment or when an individual mouse's condition was close to being terminal. Heart fibrosis was observed in all groups. Non-significant reductions in primary tumor growth were observed in all of the treated groups. Feces volume was increased in all groups. A non-significant decrease in feces volume was observed in the octreotide or telotristat-treated groups, while it was significantly reduced with the combined treatment at the end of the study compared with octreotide (52 g reduction; p < 0.01) and the control (44.5 g reduction; p = 0.05). Additionally, plasma NT-proBNP decreased in a non-significant, but clinically relevant, manner in the octreotide (28.2% reduction), telotristat (45.9% reduction), and the octreotide + telotristat (54.1% reduction) treatment groups. No significant changes were observed in plasma serotonin levels. A similar non-significant decrease in heart valve fibrosis was observed in the three treated groups. In conclusion, Telotristat alone and especially in combination with octreotide decreases NT-proBNP levels in a mouse model of serotonin-secreting metastasized NEN, when compared with the control and octreotide, but its effect on heart valve fibrosis (alone and in combination) was not superior to octreotide in monotherapy.

Metagenomic analysis of carbohydrate-active enzymes and their contribution to marine sediment biodiversity.

Marine sediments constitute the world's most substantial long-term carbon repository. The microorganisms dwelling in these sediments mediate the transformation of fixed oceanic carbon, but their contribution to the carbon cycle is not fully understood. Previous culture-independent investigations into sedimentary microorganisms have underscored the significance of carbohydrates in the carbon cycle. In this study, we employ a metagenomic methodology to investigate the distribution and abundance of carbohydrate-active enzymes (CAZymes) in 37 marine sediments sites. These sediments exhibit varying oxygen availability and were isolated in diverse regions worldwide. Our comparative analysis is based on the metabolic potential for oxygen utilisation, derived from genes present in both oxic and anoxic environments. We found that extracellular CAZyme modules targeting the degradation of plant and algal detritus, necromass, and host glycans were abundant across all metagenomic samples. The analysis of these results indicates that the oxic/anoxic conditions not only influence the taxonomic composition of the microbial communities, but also affect the occurrence of CAZyme modules involved in the transformation of necromass, algae and plant detritus. To gain insight into the sediment microbial taxa, we reconstructed metagenome assembled genomes (MAG) and examined the presence of primary extracellular carbohydrate active enzyme (CAZyme) modules. Our findings reveal that the primary CAZyme modules and the CAZyme gene clusters discovered in our metagenomes were prevalent in the Bacteroidia, Gammaproteobacteria, and Alphaproteobacteria classes. We compared those MAGs to organisms from the same taxonomic classes found in soil, and we found that they were similar in its CAZyme repertoire, but the soil MAG contained a more abundant and diverse CAZyme content. Furthermore, the data indicate that abundant classes in our metagenomic samples, namely Alphaproteobacteria, Bacteroidia and Gammaproteobacteria, play a pivotal role in carbohydrate transformation within the initial few metres of the sediments.

Dysregulation of RNA-Exosome machinery is directly linked to major cancer hallmarks in prostate cancer: Oncogenic role of PABPN1.

Novel biomarkers and therapeutic strategies for prostate-cancer (PCa) are required to overcome its lethal progression. The dysregulation/implication of the RNA-Exosome-complex (REC; cellular machinery controlling the 3'-5'processing/degradation of most RNAs) in different cancer-types, including PCa, is poorly known. Herein, different cellular/molecular/preclinical approaches with human PCa-samples (tissues and/or plasma of 7 independent cohorts), and in-vitro/in-vivo PCa-models were used to comprehensively characterize the REC-profile and explore its role in PCa. Moreover, isoginkgetin (REC-inhibitor) effects were evaluated on PCa-cells. We demonstrated a specific dysregulation of the REC-components in PCa-tissues, identifying the Poly(A)-Binding-Protein-Nuclear 1 (PABPN1) factor as a critical regulator of major cancer hallmarks. PABPN1 is consistently overexpressed in different human PCa-cohorts and associated with poor-progression, invasion and metastasis. PABPN1 silencing decreased relevant cancer hallmarks in multiple PCa-models (proliferation/migration/tumourspheres/colonies, etc.) through the modulation of key cancer-related lncRNAs (PCA3/FALEC/DLEU2) and mRNAs (CDK2/CDK6/CDKN1A). Plasma PABPN1 levels were altered in patients with metastatic and tumour-relapse. Finally, pharmacological inhibition of REC-activity drastically inhibited PCa-cell aggressiveness. Altogether, the REC is drastically dysregulated in PCa, wherein this novel molecular event/mechanism, especially PABPN1 alteration, may be potentially exploited as a novel prognostic and therapeutic tool for PCa.

The interaction of the ribotoxin α-sarcin with complex model lipid vesicles.

Fungal ribotoxins are extracellular RNases that inactivate ribosomes by cleaving a single phosphodiester bond at the universally conserved sarcin-ricin loop of the large rRNA. However, to reach the ribosomes, they need to cross the plasma membrane. It is there where these toxins show their cellular specificity, being especially active against tumoral or virus-infected cells. Previous studies have shown that fungal ribotoxins interact with negatively charged membranes, typically containing phosphatidylserine or phosphatidylglycerol. This ability is rooted on their long, non-structured, positively charged loops, and its N-terminal ß-hairpin. However, its effect on complex lipid mixtures, including sphingophospholipids or cholesterol, remains poorly studied. Here, wild-type α-sarcin was used to evaluate its interaction with a variety of membranes not assayed before, which resemble much more closely mammalian cell membranes. The results confirm that α-sarcin is particularly sensitive to charge density on the vesicle surface. Its ability to induce vesicle aggregation is strongly influenced by both the lipid headgroup and the degree of saturation of the fatty acid chains. Acyl chain length is indeed particularly important for lipid mixing. Finally, cholesterol plays an important role in diluting the concentration of available negative charges and modulates the ability of α-sarcin to cross the membrane.

Low peripheral blood chemokine (C-C motif) ligand 5 and tumor necrosis factor α gene expression is associated with unfavorable progression of respiratory syncytial virus bronchiolitis in infants.

OBJECTIVES: We aimed to analyze whether the expression of inflammatory and antiviral genes in respiratory syncytial virus (RSV)-infected infants' peripheral blood is associated with bronchiolitis progression. METHODS: We conducted a prospective study on 117 infants between 2015 and 2023. The expression levels of nine genes were quantified by quantitative polymerase chain reaction. Infants were classified according to their clinical evolution during hospital admission: (i) non-progression (n = 74), when the RSV bronchiolitis severity remained stable or improved; (ii) unfavorable progression (n = 43), when the RSV bronchiolitis severity increased. The association analysis was performed by logistic regression, adjusted by age, gender, prematurity, and RSV bronchiolitis severity in the emergency room. RESULTS: Infants were 57.3% male, and the median age of the study population was 61 days. Thirty-five infants (30.7%) were admitted to the intensive care unit after hospital admission. Univariate logistic models showed that tumor necrosis factor (TNFα) and chemokine (C-C motif) ligand (CCL5) gene expression at baseline were inversely associated with unfavorable progression, which was confirmed by multivariate analyses: TNFα (adjusted odds ratio = 0.8 [95% confidence interval = 0.64-0.99], P-value = 0.038) and CCL5 (adjusted odds ratio = 0.76 [95% confidence interval = 0.62-0.93], P-value = 0.007). CONCLUSIONS: An inadequate immune response to RSV, characterized by reduced gene expression levels of CCL5 and TNFα in peripheral blood, was associated with an unfavorable progression of RSV bronchiolitis.

Bolometric detection of Josephson inductance in a highly resistive environment.

The Josephson junction is a building block of quantum circuits. Its behavior, well understood when treated as an isolated entity, is strongly affected by coupling to an electromagnetic environment. In 1983, Schmid predicted that a Josephson junction shunted by a resistance exceeding the resistance quantum RQ = h/4e2 ≈ 6.45 kΩ for Cooper pairs would become insulating since the phase fluctuations would destroy the coherent Josephson coupling. However, recent microwave measurements have questioned this interpretation. Here, we insert a small Josephson junction in a Johnson-Nyquist-type setup where it is driven by weak current noise arising from thermal fluctuations. Our heat probe minimally perturbs the junction's equilibrium, shedding light on features not visible in charge transport. We find that the Josephson critical current completely vanishes in DC charge transport measurement, and the junction demonstrates Coulomb blockade in agreement with the theory. Surprisingly, thermal transport measurements show that the Josephson junction acts as an inductor at high frequencies, unambiguously demonstrating that a supercurrent survives despite the Coulomb blockade observed in DC measurements.

Cadaveric Adipose-Derived Stem Cells for Regenerative Medicine and Research.

Advances in regenerative medicine have enabled the search for new solutions to current health problems in so far unexplored fields. Thus, we focused on cadaveric subcutaneous fat as a promising source of adipose-derived stem cells (ADSCs) that have potential to differentiate into different cell lines. With this aim, we isolated and characterized ADSCs from cadaveric samples with a postmortem interval ranging from 30 to 55 h and evaluated their ability to differentiate into chondrocytes or osteocytes. A commercial ADSC line was used as reference. Morphological and protein expression analyses were used to confirm the final stage of differentiation. Eight out of fourteen samples from patients were suitable to complete the whole protocol. Cadaveric ADSCs exhibited features of stem cells based upon several markers: CD29 (84.49 ± 14.07%), CD105 (94.38 ± 2.09%), and CD44 (99.77 ± 0.32%). The multiparametric assessment of differentiation confirmed the generation of stable lines of chondrocytes and osteocytes. In conclusion, we provide evidence supporting the feasibility of obtaining viable postmortem human subcutaneous fat ADSCs with potential application in tissue engineering and research fields.

Multiple ammonia-induced episodes of hepatic encephalopathy provoke neuronal cell loss in bile-duct ligated rats.

Background & Aims: Hepatic encephalopathy (HE) is defined as a reversible syndrome and therefore should resolve following liver transplantation (LT). However, neurological complications have been reported in up to 47% of LT recipients, which have been documented to be associated with a history of overt HE pre-LT. We hypothesise that multiple episodes of HE lead to permanent cell injury and exacerbate neurological dysfunction. Our goal was to evaluate the impact of cumulative HE episodes on neurological status and brain integrity in rats with chronic liver disease. Methods: Episodes of overt HE (loss of righting reflex) were induced following injection of ammonium acetate in bile duct ligation (BDL) rats (BDL-Ammonia) every 4 days starting at week 3 post-BDL. Neurobehaviour was evaluated after the last episode. Upon sacrifice, plasma ammonia, systemic oxidative stress, and inflammation markers were assessed. Neuronal markers including neuron-specific nuclear antigen and SMI311 (anti-neurofilament marker) and apoptotic markers (cleaved caspase-3, Bax, and Bcl2) were measured. Total antioxidant capacity, oxidative stress marker (4-hydroxynonenal), and proinflammatory cytokines (tumour necrosis factor-alpha and interleukin-1ß) were measured in brain (hippocampus, frontal cortex, and cerebellum). Proteomic analysis was conducted in the hippocampus. Results: In hippocampus of BDL-Ammonia rats, cleaved caspase-3 and Bax/Bcl2 ratio were significantly increased, whereas NeuN and SMI311 were significantly decreased compared with BDL-Vehicle rats. Higher levels of oxidative stress-induced post-translational modified proteins were found in hippocampus of BDL-Ammonia group which were associated with a lower total antioxidant capacity. Conclusions: Ammonia-induced episodes of overt HE caused neuronal cell injury/death in BDL rats. These results suggest that multiple bouts of HE can be detrimental on the integrity of the brain, translating to irreversibility and hence neurological complications post-LT. Impact and implications: Hepatic encephalopathy (HE) is defined as a reversible neuropsychiatric syndrome resolving following liver transplantation (LT); however, ∼47% of patients demonstrate neurological impairments after LT, which are associated with a previous history of overt HE pre-LT. Our study indicates that multiple episodes of overt HE can cause permanent neuronal damage which may lead to neurological complications after LT. Nevertheless, preventing the occurrence of overt HE episodes is critical for reducing the risk of irreversible neuronal injury in patients with cirrhosis.

Mass animal sacrifice at casas del Turuñuelo (Guareña, Spain): A unique Tartessian (Iron Age) site in the southwest of the Iberian Peninsula.

Zooarchaeological analyses of the skeletal remains of 52 animals unearthed in the courtyard of an Iron Age Tartessian building known as Casas del Turuñuelo (Badajoz, Spain) shed light on a massive sacrifice forming part of a series of rituals linked to the site's last period of activity and final abandonment. The rites took place towards the end of the 5th century BCE when both the building (intentionally destroyed) and the sacrificed animals were intentionally buried under a tumulus 90 m in diameter and 6 m high. The main objective of the zooarchaeological and microstratigraphic analyses was to determine the phasing of the sacrificial depositions. Evidence gathered from taphonomic assessments and a series of radiocarbon datings indicate that the sacrifices fall into three consecutive phases spanning several years. The findings of the zooarchaeological analyses clearly point to a selection of equid and cattle males. Adult equids predominate (MNI = 41) followed by adult and sub-adult cattle (MNI = 6). Pigs, in turn, are only represented by a few adults and sub-adult females (MNI = 4). Among the animals is a single dog of undetermined sex between 3 and 4 years of age. The fact that the animals are mostly adults discards the likelihood that they died from natural causes or an epidemic. In addition, the scenographic deposition of certain equids in pairs, as well as evidence of the burning of plant offerings, suggest an intentional ritualistic sacrifice. Nine of the initial depositions of Phase 1 in the SE quadrant were scattered and certain of their bones bear marks characteristic of both prolonged open air exposure and scavengers. Another 31 animals from Phases 1 and 2 are represented by almost complete, articulated skeletons, indicating they were promptly covered. Phase 3, by contrast, reveals both almost complete and partial animals bearing clear signs of processing for human consumption. This study thus sheds light on both the sequence of the animal sacrifices and the protocols linked to rites accompanied by the celebration of banquets. Certain features associated with the sealing of this building under a tumulus offer evidence of the decline of the Tartessian Culture. This study thus advances notions serving to contextualize ritual animal sacrifices in the framework of practice observed at other Iron Age sites in the Iberian Peninsula and elsewhere throughout Europe.

The Future of Patient Education: AI-Driven Guide for Type 2 Diabetes.

Introduction and aim The surging incidence of type 2 diabetes has become a growing concern for the healthcare sector. This chronic ailment, characterized by its complex blend of genetic and lifestyle determinants, has witnessed a notable increase in recent times, exerting substantial pressure on healthcare resources. As more individuals turn to online platforms for health guidance and embrace the utilization of Chat Generative Pre-trained Transformer (ChatGPT; San Francisco, CA: OpenAI), a text-generating AI (TGAI), to get insights into their well-being, evaluating its effectiveness and reliability becomes crucial. This research primarily aimed to evaluate the correctness of TGAI responses to type 2 diabetes (T2DM) inquiries via ChatGPT. Furthermore, this study aimed to examine the consistency of TGAI in addressing common queries on T2DM complications for patient education. Material and methods Questions on T2DM were formulated by experienced physicians and screened by research personnel before querying ChatGPT. Each question was posed thrice, and the collected answers were summarized. Responses were then sorted into three distinct categories as follows: (a) appropriate, (b) inappropriate, and (c) unreliable by two seasoned physicians. In instances of differing opinions, a third physician was consulted to achieve consensus. Results From the initial set of 110 T2DM questions, 40 were dismissed by experts for relevance, resulting in a final count of 70. An overwhelming 98.5% of the AI's answers were judged as appropriate, thus underscoring its reliability over traditional online search engines. Nonetheless, a 1.5% rate of inappropriate responses underlines the importance of ongoing AI improvements and strict adherence to medical protocols. Conclusion TGAI provides medical information of high quality and reliability. This study underscores TGAI's impressive effectiveness in delivering reliable information about T2DM, with 98.5% of responses aligning with the standard of care. These results hold promise for integrating AI platforms as supplementary tools to enhance patient education and outcomes.

As above, so below: Deposition, modification, and reutilization of human remains at Marmoles cave (Cueva de los Marmoles: Southern Spain, 4000-1000 cal. BCE).

The deposition and manipulation of human remains in natural caves are well known for the Neolithic of Southern Iberia. The cultural meaning of these practices is however still largely unclear. Cueva de los Marmoles (CM, Priego-Córdoba) is one of the most important cave contexts from Southern Spain, which returned a large number of commingled skeletal remains suggesting its funerary use from the Neolithic to the Late Bronze Age. Here we discuss CM from a chronological and cultural perspective based on new radiocarbon, anthropological, and taphonomic analyses. These include the estimation of the minimum number of individuals, the exploration of fragmentation patterns characterizing different skeletal regions, and the macroscopic and microscopic analysis of modifications to the remains of possible anthropic origin. Radiocarbon data point to a funerary use of CM between the 5th -2nd millennium cal. BCE. MNI estimates reveal the presence of at least 12 individuals (seven adults and five nonadults). The low representation of elements from hands and feet suggests that individuals were placed in the cave while partially decomposed. Anthropic traces on the remains (e.g. fresh fractures, marrow canal modifications, and scraping marks) hint at their intentional fragmentation, cleaning from residual soft tissues, and in some cases reutilization. These practices are well-exemplified by the recovery of one "skull cup" and of two long bones used as tools. These data align with those from other cave contexts from the same geographic region, suggesting the presence, especially during the Neolithic period, of shared ideologies centered on the human body.

The earliest basketry in southern Europe: Hunter-gatherer and farmer plant-based technology in Cueva de los Murciélagos (Albuñol).

Plant material culture can offer unique insights into the ways of life of prehistoric societies; however, its perishable nature has prevented a thorough understanding of its diverse and complex uses. Sites with exceptional preservation of organic materials provide a unique opportunity for further research. The burial site of Cueva de los Murciélagos in southern Iberia, uncovered during 19th-century mining activities, contained the best-preserved hunter-gatherer basketry in southern Europe, together with other unique organic artifacts associated with the first farming communities, such as sandals and a wooden hammer. We present 14 14C dates for the perishable artifacts (N = 76), situating the assemblage between the Early and Middle Holocene (c. 7500 to 4200 cal BCE). Our integrated analysis includes raw material determination and technological and chrono-cultural contextualization of this unique and important set of materials.

Epidemiology of Fabry disease in patients in hemodialysis in the Madrid community / Epidemiología de la enfermedad de Fabry en pacientes en hemodiálisis de la Comunidad de Madrid

This study screened for Fabry disease (FD) in patients in hemodialysis (HD) in the region of Madrid (CAM) with a cross-sectional design to evaluate HD-prevalent patients, followed by a three-year period prospective design to analyze HD-incident patients. Inclusion criteria: patients older than 18 years on HD in the CAM, excluding patients diagnosed with any other hereditary disease with renal involvement different from FD, that sign the Informed Consent (IC). Exclusion criteria: underaged patients or not agreeing or not being capable of signing the IC. Results: 3470 patients were included, 63% males and with an average age of 67.9±9.7 years. 2357 were HD-prevalent patients and 1113 HD-incident patients. For HD-prevalent patients, average time in HD was 45.2 months (SD 51.3), in HD-incident patients proteinuria was present in 28.4%. There were no statistical differences in plasmatic alpha-galactosidase A (α-GAL-A) activity or Lyso-GL-3 values when comparing HD-prevalent and HD-incident populations and neither between males and females. A genetic study was performed in 87 patients (2.5% of patients): 60 male patients with decreased enzymatic activity and 27 female patients either with a decreased GLA activity, increased Lyso-Gl3 levels or both. The genetic variants identified were: p.Asp313Tyr (4 patients), p.Arg220Gln (3 patients) and M290I (1 patient). None of the identified variants is pathogenic. Conclusions: 76% of HD Centers of the CAM participated in the study. This is the first publication to describe the prevalence of FD in the HD-population of a region of Spain as well as its average α-GAL-A-activity and plasmatic Lyso-Gl3 levels. It is also the first study that combines a cross-sectional design with a prospective follow-up design. This study has not identified any FD patient. (AU)

El objetivo del estudio ha sido realizar un mapa descriptivo de la enfermedad de Fabry (EF) en la Comunidad de Madrid, así como realizar un despistaje de la EF a todo paciente incidente durante un período de 3 años. Criterios de inclusión: Pacientes mayores de 18 años, excluyendo aquellos diagnosticados de cualquier otra enfermedad hereditaria con afectación renal diferente de la EF, que firmaran el consentimiento informado. Criterios de exclusión: pacientes menores de edad, no estar de acuerdo o no ser capaces de firmar el consentimiento informado. Resultados: Se incluyeron 3.470 pacientes (63% hombres), con una edad media de 67,9±9,7 años, de los cuales 2.357 eran pacientes prevalentes y 1.113 incidentes. En el caso de los pacientes prevalentes, el tiempo medio en hemodiálisis (HD) fue de 45,2 (DE 51,3) meses. En pacientes incidentes, la proteinuria estuvo presente en el 28,4%. No hubo diferencias estadísticamente significativas en la actividad plasmática de alfa-galactosidasa A o valores de Lyso-Gl3 al comparar las poblaciones de incidentes y de prevalentes, y tampoco entre hombres y mujeres. Se realizó estudio genético en 87 pacientes (2,5% de los pacientes): 60 varones con disminución de la actividad enzimática y 27 mujeres con una disminución de la actividad enzimática, aumento de los niveles de Lyso-Gl3 o ambos. Las variantes genéticas identificadas fueron: p.Asp313Tyr (4 pacientes), p.Arg220Gln (3 pacientes) y M290I (un paciente). Ninguna de las variantes identificadas fue patógena. Conclusiones: El 76% de los centros de HD de la Comunidad de Madrid participaron en el estudio. Este es el primer estudio epidemiológico prospectivo de EF en la población de HD de una región de España. También es la primera vez que se describen niveles de alfa-galactosidasa A y Lyso-Gl3 en HD, sin embargo, en este estudio no se han identificado pacientes con EF. (AU)

Post-mortem findings in Spanish patients with COVID-19; a special focus on superinfections.

Introduction: Whole-body autopsies may be crucial to understand coronavirus disease 2019 (COVID-19) pathophysiology. We aimed to analyze pathological findings in a large series of full-body autopsies, with a special focus on superinfections. Methods: This was a prospective multicenter study that included 70 COVID-19 autopsies performed between April 2020 and February 2021. Epidemiological, clinical and pathological information was collected using a standardized case report form. Results: Median (IQR) age was 70 (range 63.75-74.25) years and 76% of cases were males. Most patients (90%,) had at least one comorbidity prior to COVID-19 diagnosis, with vascular risk factors being the most frequent. Infectious complications were developed by 65.71% of the patients during their follow-up. Mechanical ventilation was required in most patients (75.71%) and was mainly invasive. In multivariate analyses, length of hospital stay and invasive mechanical ventilation were significantly associated with infections (p = 0.036 and p = 0.013, respectively). Necropsy findings revealed diffuse alveolar damage in the lungs, left ventricular hypertrophy in the heart, liver steatosis and pre-infection arteriosclerosis in the heart and kidneys. Conclusion: Our study confirms the main necropsy histopathological findings attributed to COVID-19 in a large patient series, while underlining the importance of both comorbid conditions and superinfections in the pathology.

Evolutionary origin, population diversity, and diagnostics for a cryptic hybrid pathogen.

Cryptic fungal pathogens pose significant identification and disease management challenges due to their morphological resemblance to known pathogenic species while harboring genetic and (often) infectionrelevant trait differences. The cryptic fungal pathogen Aspergillus latus, an allodiploid hybrid originating from Aspergillus spinulosporus and an unknown close relative of Aspergillus quadrilineatus within section Nidulantes, remains poorly understood. The absence of accurate diagnostics for A. latus has led to misidentifications, hindering epidemiological studies and the design of effective treatment plans. We conducted an in-depth investigation of the genomes and phenotypes of 44 globally distributed isolates (41 clinical isolates and three type strains) from Aspergillus section Nidulantes. We found that 21 clinical isolates were A. latus; notably, standard methods of pathogen identification misidentified all A. latus isolates. The remaining isolates were identified as A. spinulosporus (8), A. quadrilineatus (1), or A. nidulans (11). Phylogenomic analyses shed light on the origin of A. latus, indicating one or two hybridization events gave rise to the species during the Miocene, approximately 15.4 to 8.8 million years ago. Characterizing the A. latus pangenome uncovered substantial genetic diversity within gene families and biosynthetic gene clusters. Transcriptomic analysis revealed that both parental genomes are actively expressed in nearly equal proportions and respond to environmental stimuli. Further investigation into infection-relevant chemical and physiological traits, including drug resistance profiles, growth under oxidative stress conditions, and secondary metabolite biosynthesis, highlight distinct phenotypic profiles of the hybrid A. latus compared to its parental and closely related species. Leveraging our comprehensive genomic and phenotypic analyses, we propose five genomic and phenotypic markers as diagnostics for A. latus species identification. These findings provide valuable insights into the evolutionary origin, genomic outcome, and phenotypic implications of hybridization in a cryptic fungal pathogen, thus enhancing our understanding of the underlying processes contributing to fungal pathogenesis. Furthermore, our study underscores the effectiveness of extensive genomic and phenotypic analyses as a promising approach for developing diagnostics applicable to future investigations of cryptic and emerging pathogens.

Hippocampal subfield abnormalities and biomarkers of pathologic brain changes: from SARS-CoV-2 acute infection to post-COVID syndrome.

BACKGROUND: Cognitive deficits are among the main disabling symptoms in COVID-19 patients and post-COVID syndrome (PCS). Within brain regions, the hippocampus, a key region for cognition, has shown vulnerability to SARS-CoV-2 infection. Therefore, in vivo detailed evaluation of hippocampal changes in PCS patients, validated on post-mortem samples of COVID-19 patients at the acute phase, would shed light into the relationship between COVID-19 and cognition. METHODS: Hippocampal subfields volume, microstructure, and perfusion were evaluated in 84 PCS patients and compared to 33 controls. Associations with blood biomarkers, including glial fibrillary acidic protein (GFAP), myelin oligodendrocyte glycoprotein (MOG), eotaxin-1 (CCL11) and neurofilament light chain (NfL) were evaluated. Besides, biomarker immunodetection in seven hippocampal necropsies of patients at the acute phase were contrasted against eight controls. FINDINGS: In vivo analyses revealed that hippocampal grey matter atrophy is accompanied by altered microstructural integrity, hypoperfusion, and functional connectivity changes in PCS patients. Hippocampal structural and functional alterations were related to cognitive dysfunction, particularly attention and memory. GFAP, MOG, CCL11 and NfL biomarkers revealed alterations in PCS, and showed associations with hippocampal volume changes, in selective hippocampal subfields. Moreover, post mortem histology showed the presence of increased GFAP and CCL11 and reduced MOG concentrations in the hippocampus in post-mortem samples at the acute phase. INTERPRETATION: The current results evidenced that PCS patients with cognitive sequalae present brain alterations related to cognitive dysfunction, accompanied by a cascade of pathological alterations in blood biomarkers, indicating axonal damage, astrocyte alterations, neuronal injury, and myelin changes that are already present from the acute phase. FUNDING: Nominative Grant FIBHCSC 2020 COVID-19. Department of Health, Community of Madrid. Instituto de Salud Carlos III through the project INT20/00079, co-funded by European Regional Development Fund "A way to make Europe" (JAMG). Instituto de Salud Carlos III (ISCIII) through Sara Borrell postdoctoral fellowship Grant No. CD22/00043) and co-funded by the European Union (MDC). Instituto de Salud Carlos III through a predoctoral contract (FI20/000145) (co-funded by European Regional Development Fund "A way to make Europe") (MVS). Fundación para el Conocimiento Madri+d through the project G63-HEALTHSTARPLUS-HSP4 (JAMG, SOM).