BMAL1 and CLOCK proteins exhibit differential association with mitochondrial dynamics, protein synthesis pathways and muscle strength in human muscle.

Murine models lacking CLOCK/BMAL1 proteins in skeletal muscle (SkM) present muscle deterioration and mitochondria abnormalities. It is unclear whether humans with lower levels of these proteins in the SkM have similar alterations. Here we evaluated the association between BMAL1 and CLOCK protein mass with mitochondrial dynamics parameters and molecular and functional SkM quality markers in males. SkM biopsies were taken from the vastus lateralis of 16 male (non-athletes, non-obese and non-diabetic) subjects (8-9 a.m.). The morphology of mitochondria and their interaction with the sarcoplasmic reticulum (mitochondria-SR) were determined using transmission electron microscopy images. Additionally, protein abundance of the OXPHOS complex, mitochondria fusion/fission regulators, mitophagy and signalling proteins related to muscle protein synthesis were measured. To evaluate the quality of SkM, the cross-sectional area and maximal SkM strength were also measured. The results showed that BMAL1 protein mass was positively associated with mitochondria-SR distance, mitochondria size, mitochondria cristae density and mTOR protein mass. On the other hand, CLOCK protein mass was negatively associated with mitochondria-SR interaction, but positively associated with mitochondria complex III, OPA1 and DRP1 protein mass. Furthermore, CLOCK protein mass was positively associated with the protein synthesis signalling pathway (total mTOR, AKT and P70S6K protein mass) and SkM strength. These findings suggest that the BMAL1 and CLOCK proteins play different roles in regulating mitochondrial dynamics and SkM function in males, and that modulation of these proteins could be a potential therapeutic target for treating muscle diseases. KEY POINTS: In murine models, reductions in BMAL1 and CLOCK proteins lead to changes in mitochondria biology and a decline in muscle function. However, this association has not been explored in humans. We found that in human skeletal muscle, a decrease in BMAL1 protein mass is linked to smaller intermyofibrillar mitochondria, lower mitochondria cristae density, higher interaction between mitochondria and sarcoplasmic reticulum, and reduced mTOR protein mass. Additionally, we found that a decrease in CLOCK protein mass is associated with a higher interaction between mitochondria and sarcoplasmic reticulum, lower protein mass of OPA1 and DRP1, which regulates mitochondria fusion and fission, lower protein synthesis signalling pathway (mTOR, AKT and P70S6K protein mass), and decreased skeletal muscle strength. According to our findings in humans, which are supported by previous studies in animals, the mitochondrial dynamics and skeletal muscle function could be regulated differently by BMAL1 and CLOCK proteins. As a result, targeting the modulation of these proteins could be a potential therapeutic approach for treating muscle diseases and metabolic disorders related to muscle.

An Acute Promyelocytic Leukemia Resistant to All-Trans Retinoic Acid: A Case Report of the ZBTB16::RARa Variant and Review of the Literature.

Introduction: Acute promyelocytic leukemia (APL) is characterized by the PML::RARa gene fusion and treatment consists of all-trans retinoic acid (ATRA). Rarely, genetic APL variants have been described which are insensitive to ATRA treatment and are therefore associated with a worse prognosis. Rapid identification of the APL variant is essential to start the correct treatment. Case Presentation: Here, we present a case of a 66-year-old male patient with weight loss and arthralgia. Laboratory results showed an anemia and mild leukocytosis with predominantly monocytes. Bone marrow investigation unexpectedly revealed a t(11;17)(q23;q21). This raised suspicion of an ATRA-resistant APL. By demonstrating the ZBTB16::RARa gene fusion, the diagnosis was confirmed. Conclusion: This case study emphasizes the importance of integrated diagnostics and provides guidance to recognize the ZBTB16::RARa APL, which is the most prevalent ATRA-resistant APL. Furthermore, an overview of other genetic APL variants is presented and how to treat these uncommon diseases in clinical practice.

Reduced frequencies and functional impairment of dendritic cell subsets and non-classical monocytes in myelodysplastic syndromes.

In myelodysplastic syndromes (MDS) the immune system is involved in pathogenesis as well as in disease progression. Dendritic cells (DC) are key players of the immune system by serving as regulators of immune responses. Their function has been scarcely studied in MDS and most of the reported studies didn't investigate naturally occurring DC subsets. Therefore, we here examined the frequency and function of DC subsets and slan+ non-classical monocytes in various MDS risk groups. Frequencies of DC as well as of slan+ monocytes were decreased in MDS bone marrow compared to normal bone marrow samples. Transcriptional profiling revealed down-regulation of transcripts related to pro-inflammatory pathways in MDS-derived cells as compared to normal bone marrow. Additionally, their capacity to induce T-cell proliferation was impaired. Multidimensional mass cytometry showed that whereas healthy donor-derived slan+ monocytes supported Th1/Th17/Treg differentiation/expansion their MDS-derived counterparts also mediated substantial Th2 expansion. Our findings point to a role for an impaired ability of DC subsets to adequately respond to cellular stress and DNA damage in the immune escape and progression of MDS. As such, it paves the way toward potential novel immunotherapeutic interventions.

Assessing the Biodegradation of Vulcanised Rubber Particles by Fungi Using Genetic, Molecular and Surface Analysis.

Millions of tonnes of tyre waste are discarded annually and are considered one of the most difficult solid wastes to recycle. A sustainable alternative for the treatment of vulcanised rubber is the use of microorganisms that can biotransform polymers and aromatic compounds and then assimilate and mineralise some of the degradation products. However, vulcanised rubber materials present great resistance to biodegradation due to the presence of highly hydrophobic cross-linked structures that are provided by the additives they contain and the vulcanisation process itself. In this work, the biodegradation capabilities of 10 fungal strains cultivated in PDA and EM solid medium were studied over a period of 4 weeks. The growth of the strains, the mass loss of the vulcanised rubber particles and the surface structure were analysed after the incubation period. With the white rot fungi Trametes versicolor and Pleurotus ostreatus, biodegradation percentages of 7.5 and 6.1%, respectively, were achieved. The FTIR and SEM-EDS analyses confirmed a modification of the abundance of functional groups and elements arranged on the rubber surface, such as C, O, S, Si, and Zn, due to the biological treatment employed. The availability of genomic sequences of P. ostreatus and T. versicolor in public repositories allowed the analysis of the genetic content, genomic characteristics and specific components of both fungal species, determining some similarities between both species and their relationship with rubber biodegradation. Both fungi presented a higher number of sequences for laccases and manganese peroxidases, two extracellular enzymes responsible for many of the oxidative reactions reported in the literature. This was confirmed by measuring the laccase and peroxidase activity in cultures of T. versicolor and P. ostreatus with rubber particles, reaching between 2.8 and 3.3-times higher enzyme activity than in the absence of rubber. The integrative analysis of the results, supported by genetic and bioinformatics tools, allowed a deeper analysis of the biodegradation processes of vulcanised rubber. It is expected that this type of analysis can be used to find more efficient biotechnological solutions in the future.

Comorbidity and prognostic factors on admission in a COVID-19 cohort of a general hospital.

ANTECEDENTS AND OBJECTIVE: To describe clinical features, comorbidity, and prognostic factors associated with in-hospital mortality in a cohort of COVID-19 admitted to a general hospital. MATERIAL AND METHODS: Retrospective cohort study of patients with COVID-19 admitted from 26th February 2020, who had been discharged or died up to 29th April 2020. A descriptive study and an analysis of factors associated with intrahospital mortality were performed. RESULTS: Out of the 101 patients, 96 were analysed. Of these, 79 (82%) recovered and were discharged, and 17 (18%) died in the hospital. Diagnosis of COVID-19 was confirmed by polymerase chain reaction to SARS-CoV2 in 92 (92.5%). The mean age was 63 years, and 66% were male. The most frequent comorbidities were hypertension (40%), diabetes mellitus (16%) y cardiopathy (14%). Patients who died were older (mean 77 vs 60 years), had higher prevalence of hypertension (71% vs 33%), and cardiopathy (47% vs 6%), and higher levels of lactate dehydrogenase (LDH) and reactive C protein (mean 662 vs 335 UI/L, and 193 vs 121mg/L respectively) on admission. In a multivariant analysis the variables significantly associated to mortality were the presence of cardiopathy (CI 95% OR 2,58-67,07), levels of LDH≥345 IU/L (CI 95% OR 1,52-46,00), and age≥65 years (CI 95% OR 1,23-44,62). CONCLUSIONS: The presence of cardiopathy, levels of LDH≥345 IU/L and age≥65 years, are associated with a higher risk of death during hospital stay for COVID-19. This model should be validated in prospective cohorts.

Comorbilidad y factores pronósticos al ingreso en una cohorte COVID-19 de un hospital general / Comorbidity and prognostic factors on admission in a COVID-19 cohort of a general hospital

Antecedentes y objetivo Describir el perfil clínico, la comorbilidad y los factores pronósticos de mortalidad intrahospitalaria en una cohorte COVID-19 de un hospital general. Material y métodos Estudio de cohortes retrospectivo de pacientes con COVID-19 ingresados desde el 26 de febrero, y dados de alta o fallecidos hasta el 29 de abril de 2020; estudio descriptivo y análisis de factores asociados a la mortalidad intrahospitalaria. Resultados De los pacientes ingresados (N=101), se analizaron 96: 79 (82%) dados de alta por curación y 17 (18%) fallecidos. En 92 casos (92,5%) se confirmó COVID-19 por reacción en cadena de la polimerasa a SARS-CoV-2. La edad media fue de 63 años, y el 66% eran varones. La comorbilidad previa más frecuente fue hipertensión arterial (40%), diabetes mellitus (16%) y cardiopatía (14%). Los pacientes que fallecieron tenían significativamente más edad (media 77 vs. 60 años), hipertensión arterial (71% vs. 33%), cardiopatía previa (47% vs. 6%), y niveles más elevados de lactato deshidrogenasa (LDH) (662 vs. 335UI/L) y proteína C reactiva (PCR) (193 vs. 121mg/L) al ingreso. En el análisis multivariante, se asociaron significativamente a mayor riesgo de muerte la presencia de cardiopatía (IC 95% OR 2,58-67,07), los niveles de LDH≥345UI/L (IC 95% OR 1,52-46,00), y la edad≥65 años (IC 95% OR 1,23-44,62). Conclusiones El antecedente de cardiopatía, los niveles de LDH≥345UI/L al ingreso y una edad≥65 años se asocian a una mayor mortalidad durante el ingreso por COVID-19. Hay que validar este modelo pronóstico en cohortes prospectivas (AU)

Antecedents and objective To describe clinical features, comorbidity, and prognostic factors associated with in-hospital mortality in a cohort of COVID-19 admitted to a general hospital. Material and methods Retrospective cohort study of patients with COVID-19 admitted from 26th February, who had been discharged or died, up to 29th April, 2020. A descriptive study and an analysis of factors associated with intrahospital mortality were performed. Results Out of the 101 patients, 96 were analysed. Of these, 79 (82%) recovered and were discharged, and 17 (18%) died in the hospital. Diagnosis of COVID-19 was confirmed by polymerase chain reaction to SARS-CoV-2 in 92 (92.5%). The mean age was 63 years, and 66% were male. The most frequent comorbidities were hypertension (40%), diabetes mellitus (16%) and cardiopathy (14%). Patients who died were older (mean 77 vs 60 years), had higher prevalence of hypertension (71% vs 33%), and cardiopathy (47% vs 6%), and higher levels of lactate dehydrogenase (LDH) and reactive C protein (mean 662 vs 335UI/L, and 193 vs 121mg/L respectively) on admission. In a multivariant analysis the variables significantly associated to mortality were the presence of cardiopathy (CI 95% OR 2,58-67,07), levels of LDH≥345IU/L (CI 95% OR 1,52-46,00), and age≥65 years (CI 95% OR 1,23-44,62). Conclusions The presence of cardiopathy, levels of LDH≥345IU/L and age ≥65 years are associated with a higher risk of death during hospital stay for COVID-19. This model should be validated in prospective cohorts (AU)

The seeds of invasion: enhanced germination in invasive European populations of black locust (Robinia pseudoacacia L.) compared to native American populations.

Local adaptation and the evolution of phenotypic plasticity may facilitate biological invasions. Both processes can enhance germination and seedling recruitment, which are crucial life-history traits for plants. The rate, timing and speed of germination have recently been documented as playing a major role during the invasion process. Black locust (Robinia pseudoacacia L.) is a North American tree, which has spread widely throughout Europe. A recent study demonstrated that a few populations are the source of European black locust. Thus, invasive populations can be compared to native ones in order to identify genetic-based phenotypic differentiation and the role of phenotypic plasticity can thereby be assessed. A quantitative genetics experiment was performed to evaluate 13 juvenile traits of both native and invasive black locust populations (3000 seeds, 20 populations) subjected to three different thermal treatments (18 °C, 22 °C and 31 °C). The results revealed European populations to have a higher germination rate than the native American populations (88% versus 60%), and even when genetic distance between populations was considered. Moreover, this trait showed lower plasticity to temperature in the invasive range than in the native one. Conversely, other studied traits showed high plasticity to temperature, but they responded in a similar way to temperature increase: the warmer the temperature, the higher the growth rate or germination traits values. The demonstrated genetic differentiation between native and invasive populations testifies to a shift between ranges for the maximum germination percentage. This pattern could be due to human-mediated introduction of black locust.

Engineering large-scale chromosomal deletions by CRISPR-Cas9.

Large-scale chromosomal deletions are a prevalent and defining feature of cancer. A high degree of tumor-type and subtype specific recurrencies suggest a selective oncogenic advantage. However, due to their large size it has been difficult to pinpoint the oncogenic drivers that confer this advantage. Suitable functional genomics approaches to study the oncogenic driving capacity of large-scale deletions are limited. Here, we present an effective technique to engineer large-scale deletions by CRISPR-Cas9 and create isogenic cell line models. We simultaneously induce double-strand breaks (DSBs) at two ends of a chromosomal arm and select the cells that have lost the intermittent region. Using this technique, we induced large-scale deletions on chromosome 11q (65 Mb) and chromosome 6q (53 Mb) in neuroblastoma cell lines. A high frequency of successful deletions (up to 30% of selected clones) and increased colony forming capacity in the 11q deleted lines suggest an oncogenic advantage of these deletions. Such isogenic models enable further research on the role of large-scale deletions in tumor development and growth, and their possible therapeutic potential.

Demonstration of the trapped-ion quantum CCD computer architecture.

The trapped-ion quantum charge-coupled device (QCCD) proposal1,2 lays out a blueprint for a universal quantum computer that uses mobile ions as qubits. Analogous to a charge-coupled device (CCD) camera, which stores and processes imaging information as movable electrical charges in coupled pixels, a QCCD computer stores quantum information in the internal state of electrically charged ions that are transported between different processing zones using dynamic electric fields. The promise of the QCCD architecture is to maintain the low error rates demonstrated in small trapped-ion experiments3-5 by limiting the quantum interactions to multiple small ion crystals, then physically splitting and rearranging the constituent ions of these crystals into new crystals, where further interactions occur. This approach leverages transport timescales that are fast relative to the coherence times of the qubits, the insensitivity of the qubit states of the ion to the electric fields used for transport, and the low crosstalk afforded by spatially separated crystals. However, engineering a machine capable of executing these operations across multiple interaction zones with low error introduces many difficulties, which have slowed progress in scaling this architecture to larger qubit numbers. Here we use a cryogenic surface trap to integrate all necessary elements of the QCCD architecture-a scalable trap design, parallel interaction zones and fast ion transport-into a programmable trapped-ion quantum computer that has a system performance consistent with the low error rates achieved in the individual ion crystals. We apply this approach to realize a teleported CNOT gate using mid-circuit measurement6, negligible crosstalk error and a quantum volume7 of 26 = 64. These results demonstrate that the QCCD architecture provides a viable path towards high-performance quantum computers.

Loss of FLCN-FNIP1/2 induces a non-canonical interferon response in human renal tubular epithelial cells.

Germline mutations in the Folliculin (FLCN) tumor suppressor gene cause Birt-Hogg-Dubé (BHD) syndrome, a rare autosomal dominant disorder predisposing carriers to kidney tumors. FLCN is a conserved, essential gene linked to diverse cellular processes but the mechanism by which FLCN prevents kidney cancer remains unknown. Here, we show that disrupting FLCN in human renal tubular epithelial cells (RPTEC/TERT1) activates TFE3, upregulating expression of its E-box targets, including RRAGD and GPNMB, without modifying mTORC1 activity. Surprisingly, the absence of FLCN or its binding partners FNIP1/FNIP2 induces interferon response genes independently of interferon. Mechanistically, FLCN loss promotes STAT2 recruitment to chromatin and slows cellular proliferation. Our integrated analysis identifies STAT1/2 signaling as a novel target of FLCN in renal cells and BHD tumors. STAT1/2 activation appears to counterbalance TFE3-directed hyper-proliferation and may influence immune responses. These findings shed light on unique roles of FLCN in human renal tumorigenesis and pinpoint candidate prognostic biomarkers.

Dopamine transporter function fluctuates across sleep/wake state: potential impact for addiction.

The dopamine transporter (DAT) has been implicated in a variety of arousal-related processes including the regulation of motor activity, learning, motivated behavior, psychostimulant abuse, and, more recently, sleep/wake state. We previously demonstrated that DAT uptake regulates fluctuations in extracellular dopamine (DA) in the striatum across the light/dark cycle with DA levels at their highest during the dark phase and lowest during the light phase. Despite this evidence, whether fluctuations in DA uptake across the light/dark cycle are associated with changes in sleep/wake has not been tested. To address this, we employed a combination of sleep/wake recordings, fast scan cyclic voltammetry, and western blotting to examine whether sleep/wake state and/or light/dark phase impact DA terminal neurotransmission in male rats. Further, we assessed whether variations in plasma membrane DAT levels and/or phosphorylation of the threonine 53 site on the DAT accounts for fluctuations in DA neurotransmission. Given the extensive evidence indicating that psychostimulants increase DA through interactions with the DAT, we also examined to what degree the effects of cocaine at inhibiting the DAT vary across sleep/wake state. Results demonstrated a significant association between individual sleep/wake states and DA terminal neurotransmission, with higher DA uptake rate, increased phosphorylation of the DAT, and enhanced cocaine potency observed after periods of sleep. These findings suggest that sleep/wake state influences DA neurotransmission in a manner that is likely to impact a host of DA-dependent processes including a variety of neuropsychiatric disorders.

Comorbidity and prognostic factors on admission in a COVID-19 cohort of a general hospital. / Comorbilidad y factores pronósticos al ingreso en una cohorte COVID-19 de un hospital general.

ANTECEDENTS AND OBJECTIVE: To describe clinical features, comorbidity, and prognostic factors associated with in-hospital mortality in a cohort of COVID-19 admitted to a general hospital. MATERIAL AND METHODS: Retrospective cohort study of patients with COVID-19 admitted from 26th February, who had been discharged or died, up to 29th April, 2020. A descriptive study and an analysis of factors associated with intrahospital mortality were performed. RESULTS: Out of the 101 patients, 96 were analysed. Of these, 79 (82%) recovered and were discharged, and 17 (18%) died in the hospital. Diagnosis of COVID-19 was confirmed by polymerase chain reaction to SARS-CoV-2 in 92 (92.5%). The mean age was 63 years, and 66% were male. The most frequent comorbidities were hypertension (40%), diabetes mellitus (16%) and cardiopathy (14%). Patients who died were older (mean 77 vs 60 years), had higher prevalence of hypertension (71% vs 33%), and cardiopathy (47% vs 6%), and higher levels of lactate dehydrogenase (LDH) and reactive C protein (mean 662 vs 335UI/L, and 193 vs 121mg/L respectively) on admission. In a multivariant analysis the variables significantly associated to mortality were the presence of cardiopathy (CI 95% OR 2,58-67,07), levels of LDH≥345IU/L (CI 95% OR 1,52-46,00), and age≥65 years (CI 95% OR 1,23-44,62). CONCLUSIONS: The presence of cardiopathy, levels of LDH≥345IU/L and age ≥65 years are associated with a higher risk of death during hospital stay for COVID-19. This model should be validated in prospective cohorts.

Thrombomodulin-expressing monocytes are associated with low-risk features in myelodysplastic syndromes and dampen excessive immune activation.

The bone marrow of patients with low-risk myelodysplastic syndromes (MDS) is often an inflammatory environment and associated with an active cellular immune response. An active immune response generally contributes to antitumor responses and may prevent disease progression. However, chronic immune stimulation can also induce cell stress, DNA damage and contribute to the pathogenesis of MDS. The protective mechanisms against excessive immune activation are therefore an important aspect of the pathophysiology of MDS and characterizing them may help us to better understand the fine balance between protective and destabilizing inflammation in lower-risk disease. In this study we investigated the role of thrombomodulin (CD141/BDCA-3) expression, a molecule with anti-inflammatory properties, on monocytes in the bone marrow and peripheral blood of MDS patients in different risk groups. Patient-derived classical monocytes showed high expression levels of thrombomodulin, whereas monocytes from healthy donors hardly expressed any thrombomodulin. The presence of thrombomodulin on monocytes from MDS patients correlated with lower-risk disease groups and better overall and leukemia-free survival. Using multidimensional mass cytometry, in an in-vitro setting, we showed that thrombomodulin-positive monocytes could polarize naïve T cells toward cell clusters which are closer to T helper type 2 and T regulatory cell phenotypes and less likely to contribute to effective immune surveillance. In conclusion, the expression of thrombomodulin on classical monocytes is a favorable and early prognostic marker in patients with low-risk MDS and may represent a new mechanism in the protection against disproportionate immune activation.

Comorbilidad y factores pronósticos al ingreso en una cohorte COVID-19 de un hospital general / Comorbidity and prognostic factors on admission in a COVID-19 cohort of a general hospital

ANTECEDENTES Y OBJETIVO: Describir el perfil clínico, la comorbilidad y los factores pronósticos de mortalidad intrahospitalaria en una cohorte COVID-19 de un hospital general. MATERIAL Y MÉTODOS: Estudio de cohortes retrospectivo de pacientes con COVID-19 ingresados desde el 26 de febrero, y dados de alta o fallecidos hasta el 29 de abril de 2020; estudio descriptivo y análisis de factores asociados a la mortalidad intrahospitalaria. RESULTADOS: De los pacientes ingresados (N=101), se analizaron 96: 79 (82%) dados de alta por curación y 17 (18%) fallecidos. En 92 casos (92,5%) se confirmó COVID-19 por reacción en cadena de la polimerasa a SARS-CoV-2. La edad media fue de 63 años, y el 66% eran varones. La comorbilidad previa más frecuente fue hipertensión arterial (40%), diabetes mellitus (16%) y cardiopatía (14%). Los pacientes que fallecieron tenían significativamente más edad (media 77 vs. 60 años), hipertensión arterial (71% vs. 33%), cardiopatía previa (47% vs. 6%), y niveles más elevados de lactato deshidrogenasa (LDH) (662 vs. 335UI/L) y proteína C reactiva (PCR) (193 vs. 121mg/L) al ingreso. En el análisis multivariante, se asociaron significativamente a mayor riesgo de muerte la presencia de cardiopatía (IC 95% OR 2,58-67,07), los niveles de LDH≥345UI/L (IC 95% OR 1,52-46,00), y la edad≥65 años (IC 95% OR 1,23-44,62). CONCLUSIONES: El antecedente de cardiopatía, los niveles de LDH≥345UI/L al ingreso y una edad≥65 años se asocian a una mayor mortalidad durante el ingreso por COVID-19. Hay que validar este modelo pronóstico en cohortes prospectivas

ANTECEDENTS AND OBJECTIVE: To describe clinical features, comorbidity, and prognostic factors associated with in-hospital mortality in a cohort of COVID-19 admitted to a general hospital. MATERIAL AND METHODS: Retrospective cohort study of patients with COVID-19 admitted from 26th February, who had been discharged or died, up to 29th April, 2020. A descriptive study and an analysis of factors associated with intrahospital mortality were performed. RESULTS: Out of the 101 patients, 96 were analysed. Of these, 79 (82%) recovered and were discharged, and 17 (18%) died in the hospital. Diagnosis of COVID-19 was confirmed by polymerase chain reaction to SARS-CoV-2 in 92 (92.5%). The mean age was 63 years, and 66% were male. The most frequent comorbidities were hypertension (40%), diabetes mellitus (16%) and cardiopathy (14%). Patients who died were older (mean 77 vs 60 years), had higher prevalence of hypertension (71% vs 33%), and cardiopathy (47% vs 6%), and higher levels of lactate dehydrogenase (LDH) and reactive C protein (mean 662 vs 335UI/L, and 193 vs 121mg/L respectively) on admission. In a multivariant analysis the variables significantly associated to mortality were the presence of cardiopathy (CI 95% OR 2,58-67,07), levels of LDH≥345IU/L (CI 95% OR 1,52-46,00), and age≥65 years (CI 95% OR 1,23-44,62). CONCLUSIONS: The presence of cardiopathy, levels of LDH≥345IU/L and age ≥65 years are associated with a higher risk of death during hospital stay for COVID-19. This model should be validated in prospective cohorts

G protein ßγ subunits play a critical role in the actions of amphetamine.

Abnormal levels of dopamine (DA) are thought to contribute to several neurological and psychiatric disorders including drug addiction. Extracellular DA levels are regulated primarily via reuptake by the DA transporter (DAT). Amphetamine, a potent psychostimulant, increases extracellular DA by inducing efflux through DAT. Recently, we discovered that G protein ßγ subunits (Gßγ) interact with DAT, and that in vitro activation of Gßγ promotes DAT-mediated efflux. Here, we investigated the role of Gßγ in the actions of amphetamine in DA neurons in culture, ex vivo nucleus accumbens (NAc), and freely moving rats. Activation of Gßγ with the peptide myr-Ser-Ile-Arg-Lys-Ala-Leu-Asn-Ile-Leu-Gly-Tyr-Pro-Asp-Tyr-Asp (mSIRK) in the NAc potentiated amphetamine-induced hyperlocomotion, but not cocaine-induced hyperlocomotion, and systemic or intra-accumbal administration of the Gßγ inhibitor gallein attenuated amphetamine-induced, but not cocaine-induced hyperlocomotion. Infusion into the NAc of a TAT-fused peptide that targets the Gßγ-binding site on DAT (TAT-DATct1) also attenuated amphetamine-induced but not cocaine-induced hyperlocomotion. In DA neurons in culture, inhibition of Gßγ with gallein or blockade of the Gßγ-DAT interaction with the TAT-DATct1 peptide decreased amphetamine-induced DA efflux. Furthermore, activation of Gßγ with mSIRK potentiated and inhibition of Gßγ with gallein reduced amphetamine-induced increases of extracellular DA in the NAc in vitro and in freely moving rats. Finally, systemic or intra-accumbal inhibition of Gßγ with gallein blocked the development of amphetamine-induced, but not cocaine-induced place preference. Collectively, these results suggest that interaction between Gßγ and DAT plays a critical role in the actions of amphetamine and presents a novel target for modulating the actions of amphetamine in vivo.

Experimental Evidence of a Variant Neutron Spectrum from the T(t,2n)α Reaction at Center-of-Mass Energies in the Range of 16-50 keV.

Full calculations of six-nucleon reactions with a three-body final state have been elusive and a long-standing issue. We present neutron spectra from the T(t,2n)α (TT) reaction measured in inertial confinement fusion experiments at the OMEGA laser facility at ion temperatures from 4 to 18 keV, corresponding to center-of-mass energies (E_{c.m.}) from 16 to 50 keV. A clear difference in the shape of the TT-neutron spectrum is observed between the two E_{c.m.}, with the ^{5}He ground state resonant peak at 8.6 MeV being significantly stronger at the higher than at the lower energy. The data provide the first conclusive evidence of a variant TT-neutron spectrum in this E_{c.m.} range. In contrast to earlier available data, this indicates a reaction mechanism that must involve resonances and/or higher angular momenta than L=0. This finding provides an important experimental constraint on theoretical efforts that explore this and complementary six-nucleon systems, such as the solar ^{3}He(^{3}He,2p)α reaction.

Effect of chlorhexidine baths on central-line-associated bloodstream infections in a neonatal intensive care unit in a developing country.

Healthcare-associated infections, particularly central-line-associated bloodstream infections (CLABSIs), are worrisome in neonates. This study describes the impact of chlorhexidine baths on CLABSI rates in a neonatal intensive care unit in a developing country, through a quasi-experimental study undertaken over 62 months (January 2012 to February 2017) divided into two periods: before and after the implementation of a protocol for chlorhexidine baths in July 2014. The rate of CLABSIs per 1000 central-line-days decreased from 8.64 to 4.28 after implementation of the protocol. The use of chlorhexidine baths appears to reduce the number of CLABSIs in neonates.

Soil enzyme dynamics in chlorpyrifos-treated soils under the influence of earthworms.

Earthworms contribute, directly and indirectly, to contaminant biodegradation. However, most of bioremediation studies using these annelids focus on pollutant dissipation, thus disregarding the health status of the organism implied in bioremediation as well as the recovery of indicators of soil quality. A microcosm study was performed using Lumbricus terrestris to determine whether earthworm density (2 or 4individuals/kg wet soil) and the time of exposure (1, 2, 6, 12, and 18wk) could affect chlorpyrifos persistence in soil initially treated with 20mg active ingredientkg-1 wet soil. Additionally, selected earthworm biomarkers and soil enzyme activities were measured as indicators of earthworm health and soil quality, respectively. After an 18-wk incubation period, no earthworm was killed by the pesticide, but clear signs of severe intoxication were detected, i.e., 90% inhibition in muscle acetylcholinesterase and carboxylesterase (CbE) activities. Unexpectedly, the earthworm density had no significant impact on chlorpyrifos dissipation rate, for which the measured half-life ranged between 30.3d (control soils) and 44.5d (low earthworm density) or 36.7d (high earthworm density). The dynamic response of several soil enzymes to chlorpyrifos exposure was examined calculating the geometric mean and the treated-soil quality index, which are common enzyme-based indexes of microbial functional diversity. Both indexes showed a significant and linear increase of the global enzyme response after 6wk of chlorpyrifos treatment in the presence of earthworms. Examination of individual enzymes revealed that soil CbE activity could decrease chlorpyrifos-oxon impact upon the rest of enzyme activities. Although L. terrestris was found not to accelerate chlorpyrifos dissipation, a significant increase in the activity of soil enzyme activities was achieved compared with earthworm-free, chlorpyrifos-treated soils. Therefore, the inoculation of organophosphorus-contaminated soils with L. terrestris arises as a complementary bioremediation strategy in terms of recovery of soil biochemical performance and quality.