Unlocking SARS-CoV-2 detection in low- and middle-income countries

Low- and middle-income countries (LMICs) are significantly affected by SARS-CoV-2, partially due to their limited capacity for local production and implementation of molecular testing. Here, we provide detailed methods and validation of a molecular toolkit that can be readily produced and deployed using laboratory equipment available in LMICs. Our results show that lab-scale production of enzymes and nucleic acids can supply over 50,000 tests per production batch. The optimized one-step RT-PCR coupled to CRISPR-Cas12a-mediated detection showed a limit of detection of 102 ge/μL in a turnaround time of 2 h. The clinical validation indicated an overall sensitivity of 80%–88%, while for middle and high viral load samples (Cq ≤ 31) the sensitivity was 92%–100%. The specificity was 96%–100% regardless of viral load. Furthermore, we show that the toolkit can be used with the mobile laboratory Bento Lab, potentially enabling LMICs to implement detection services in unattended remote regions.Fondo Nacional de Desarrollo Científico, Tecnológico y de Innovación TecnológicaRevisión por pare

A genetic variant in telomerase reverse transcriptase (TERT) modifies cancer risk in Lynch syndrome patients harbouring pathogenic MSH2 variants

Individuals with Lynch syndrome (LS), have an increased risk of developing cancer. Common genetic variants of telomerase reverse transcriptase (TERT) have been associated with a wide range of cancers, including colorectal cancer (CRC) in LS. We combined genotype data from 1881 LS patients, carrying pathogenic variants in MLH1, MSH2 or MSH6, for rs2075786 (G>A, intronic variant), 1207 LS patients for rs2736108 (C>T, upstream variant) and 1201 LS patients for rs7705526 (C>A, intronic variant). The risk of cancer was estimated by heterozygous/homozygous odds ratio (OR) with mixed-effects logistic regression to adjust for gene/gender/country of sample origin considering family identity. The AA genotype of SNP rs2075786 is associated with 85% higher odds at developing cancer compared to GG genotype in MSH2 pathogenic variant carriers (p = 0.0160). Kaplan-Meier analysis also shows an association for rs2075786; the AA allele for MSH2 variant carriers confers risk for earlier diagnosis of LS cancer (log-rank p = 0.0011). We report a polymorphism in TERT to be a possible modifier of disease risk in MSH2 pathogenic variant carriers. The rs2075786 SNP in TERT is associated with a differential risk of developing cancer for MSH2 pathogenic variant carriers. Use of this information has the potential to personalise screening protocols for LS patients

Magnetovolume and magnetocaloric effects in Er2Fe17

Combining different experimental techniques, investigations in hexagonal P63/mmc Er2Fe17 show remarkable magnetovolume anomalies below the Curie temperature, TC. The spontaneous magnetostriction reaches 1.6×10−2 at 5 K and falls to zero well above TC, owing to short-range magnetic correlations. Moreover, Er2Fe17 exhibits direct and inverse magnetocaloric effects (MCE) with moderate isothermal magnetic entropy ΔSM, and diabatic temperature ΔTad changes [ΔSM∼−4.7 J(kgK)−1 and ΔTad∼2.5 K near the TC, and ΔSM∼1.3 J(kgK)−1 and ΔTad∼−0.6 K at 40 K for ΔH=80 kOe, respectively, determined from magnetization measurements]. The existence of an inverse MCE seems to be related to a crystalline electric field-level crossover in the Er sublattice and the ferrimagnetic arrangement between the magnetic moments of the Er and Fe sublattice. The main trends found experimentally for the temperature dependence of ΔSM and ΔTad as well as for the atomic magnetic moments are qualitatively well described considering a mean-field Hamiltonian that incorporates both crystalline electric field and exchange interactions. ΔSM(T) and ΔTad(T) curves are essentially zero at ∼150 K, the temperature where the transition from direct to inverse MCE occurs. A possible interplay between the MCE and the magnetovolume anomalies is also discussed.Financial support from Spanish MICINN (MAT2011-27573-C04-02) and from the Basque Government (IT-347- 07) is acknowledged. J.L.S.Ll. acknowledges the support received from CONACYT, Mexico, under the project CB2010-01-156932, and Laboratorio Nacional de Investigaciones en Nanociencias y Nanotecnología (LINAN, IPICyT). J.A.R.V. acknowledges the support from the research project MAT2007-61621. We thank ILL and CRG-D1B for allocating neutron beamtime, and ESRF for synchrotron beamtime. The SCTs at the University of Oviedo and the technical support received from M.Sc. G. J. Labrada-Delgado and B. A. Rivera-Escoto (DMA, IPICyT) are also acknowledged

Understanding the first Neolithic occupation of Cova d’En Pardo (Planes, Alicante): preliminary results of the multidisciplinary analysis of levels VIII and VIIIb

Se presentan los resultados de las excavaciones llevadas a cabo en la Cova d’En Pardo (Planes, Alicante), concretamente los niveles VIII y VIIIb. El desarrollo de un proyecto multidisciplinar ha permitido caracterizar la ocupación de una pequeña cavidad por parte de las primeras comunidades campesinas asociadas al inicio del proceso de neolitización del levante de la península Ibérica.We present the results of excavations carried out in the Cova d’En Pardo (Planes, Alicante), specifically the levels VIII and VIIIb. The development of a multidisciplinary project has allowed characterize the occupation of a small cavity by the first farming communities associated with the Neolithization process of the Levant of Iberian Peninsula.Este trabajo se ha realizado en el marco del proyecto Origins and Spread of Agriculture in the western Mediterranean región (ERC-2008-AdG 230561)

Adaptation of targeted nanocarriers to changing requirements in antimalarial drug delivery

The adaptation of existing antimalarial nanocarriers to new Plasmodium stages, drugs, targeting molecules, or encapsulating structures is a strategy that can provide new nanotechnology-based, cost-efficient therapies against malaria. We have explored the modification of different liposome prototypes that had been developed in our group for the targeted delivery of antimalarial drugs to Plasmodium-infected red blood cells (pRBCs). These new models include: (i) immunoliposome-mediated release of new lipid-based antimalarials; (ii) liposomes targeted to pRBCs with covalently linked heparin to reduce anticoagulation risks; (iii) adaptation of heparin to pRBC targeting of chitosan nanoparticles; (iv) use of heparin for the targeting of Plasmodium stages in the mosquito vector; and (v) use of the non-anticoagulant glycosaminoglycan chondroitin 4-sulfate as a heparin surrogate for pRBC targeting. The results presented indicate that the tuning of existing nanovessels to new malaria-related targets is a valid low-cost alternative to the de novo development of targeted nanosystems

Bio-Based Fire Retardant for Coco Lumber using Aloe barbadensis miller (Aloe Vera), Mangifera indica (Mango), or Persea americana (Avocado) and Boron Additives

Accidental fires are prevalent in low-income communities and one of the solutions to decrease fire risk is to apply fire retardants on combustible materials. While extensive research was available in creating fire retardants with inorganic chemicals, further studies are needed for bio-based fire retardants. The development of bio-based fire retardants involves testing organic matter for the presence of fire-retardant compounds such as nitrogen, phosphorus, and polyphenols. This study sought to determine the effectiveness of the peels of Aloe barbadensis miller (aloe vera), Mangifera indica (mangoes), and Persea americana (avocados) in creating bio-based fire retardants for coco lumber. Maceration was used to get the fruit and plant extracts. Boric acid and borax were also added as additives to boost fire retarding properties. The burning behavior of the lumber was observed in a modified horizontal flammability test and a modified flame spread test and measured in terms of mass loss, smoke density, char yield, and charring rate. The results revealed that among the fruits, the mango-based fire-retardant inhibited mass loss the most (M = 0.006, SD = 0.003), while the avocado-based fire-retardant inhibited smoke the most (M = 0.036, SD = 0.016). No significant difference was found among the groups as determined by One-way ANOVA and MANOVA (p \u3e 0.05). An indirect relationship was found between smoke density and char yield, which may be examined to improve the smoke suppressing ability of commercial fire retardants. Future studies may also refine the plant extracts and use standard flammability tests

Aspectos Relevantes de Recomendações Para Prevenção Clínica em Idoso - 2013

The American Academy of Family Physicians (AAFP) updated, in 2012, the “Recommendations for Clinical Preventive Services.”, based on the homonymous publication by the United States Preventive Services Task Force (USPSTF). These recommendations are provided as an aid for physicians in clinical decision making regarding the care of their patients. They reflect the best clinical evidence available at the time of publication. It should be used with the clear understanding that development of new knowledge may consequently result in updates and modifications at the recommended statements. Some recommendations of the USPSTF are important in clinical practice with the elderly, being presented in conjunction with other scientific societies.A American Academy of Family Physicians (AAFP) atualizou, em 2012, as “Recommendations for Clinical Preventive Services”, com base na publicação homônima editada pela United States Preventive Services Task Force (USPSTF). Estas recomendações são fornecidas como um auxílio para os médicos na tomada de decisões clínicas quanto aos cuidados de seus pacientes. Refletem as melhores evidências clínicas existentes no momento da publicação. Devem ser usadas com o claro entendimento de que o desenvolvimento de novos conhecimentos pode resultar na necessidade de atualizações e modificações nas condutas recomendadas. Dentre essas recomendações algumas são importantes na prática clínica com o paciente idoso, sendo apresentadas em conjunto com de outras sociedades científicas

Case Series and DARS2 Variant Analysis in Early Severe Forms With Unexpected Presentations

Objective: Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is regarded a relatively mild leukodystrophy, diagnosed by characteristic long tract abnormalities on MRI and biallelic variants in DARS2, encoding mitochondrial aspartyl-tRNA synthetase (mtAspRS). DARS2 variants in LBSL are almost invariably compound heterozygous; in 95% of cases, 1 is a leaky splice site variant in intron 2. A few severely affected patients, still fulfilling the MRI criteria, have been described. We noticed highly unusual MRI presentations in 15 cases diagnosed by WES. We examined these cases to determine whether they represent consistent novel LBSL phenotypes. Methods: We reviewed clinical features, MRI abnormalities, and gene variants and investigated the variants' impact on mtAspRS structure and mitochondrial function. Results: We found 2 MRI phenotypes: early severe cerebral hypoplasia/atrophy (9 patients, group 1) and white matter abnormalities without long tract involvement (6 patients, group 2). With antenatal onset, microcephaly, and arrested development, group 1 patients were most severely affected. DARS2 variants were severer than for classic LBSL and severer for group 1 than group 2. All missense variants hit mtAspRS regions involved in tRNAAsp binding, aspartyl-adenosine-5'-monophosphate binding, and/or homodimerization. Missense variants expressed in the yeast DARS2 ortholog showed severely affected mitochondrial function. Conclusions: DARS2 variants are associated with highly heterogeneous phenotypes. New MRI presentations are profound cerebral hypoplasia/atrophy and white matter abnormalities without long tract involvement. Our findings have implications for diagnosis and understanding disease mechanisms, pointing at dominant neuronal/axonal involvement in severe cases. In line with this conclusion, activation of biallelic DARS2 null alleles in conditional transgenic mice leads to massive neuronal apoptosis

Pathogenic variants in the human m(6)A reader YTHDC2 are associated with primary ovarian insufficiency

Primary ovarian insufficiency (POI) affects 1% of women and carries significant medical and psychosocial sequelae. Approximately 10% of POI has a defined genetic cause, with most implicated genes relating to biological processes involved in early fetal ovary development and function. Recently, Ythdc2, an RNA helicase and N6-methyladenosine reader, has emerged as a regulator of meiosis in mice. Here, we describe homozygous pathogenic variants in YTHDC2 in 3 women with early-onset POI from 2 families: C. 2567C>G, p.P856R in the helicase-associated (HA2) domain and c.1129G>T, p.E377*. We demonstrated that YTHDC2 is expressed in the developing human fetal ovary and is upregulated in meiotic germ cells, together with related meiosisassociated factors. The p.P856R variant resulted in a less flexible protein that likely disrupted downstream conformational kinetics of the HA2 domain, whereas the p.E377*variant truncated the helicase core. Taken together, our results reveal that YTHDC2 is a key regulator of meiosis in humans and pathogenic variants within this gene are associated with POI

Rarity of monodominance in hyperdiverse Amazonian forests.

Tropical forests are known for their high diversity. Yet, forest patches do occur in the tropics where a single tree species is dominant. Such "monodominant" forests are known from all of the main tropical regions. For Amazonia, we sampled the occurrence of monodominance in a massive, basin-wide database of forest-inventory plots from the Amazon Tree Diversity Network (ATDN). Utilizing a simple defining metric of at least half of the trees ≥ 10 cm diameter belonging to one species, we found only a few occurrences of monodominance in Amazonia, and the phenomenon was not significantly linked to previously hypothesized life history traits such wood density, seed mass, ectomycorrhizal associations, or Rhizobium nodulation. In our analysis, coppicing (the formation of sprouts at the base of the tree or on roots) was the only trait significantly linked to monodominance. While at specific locales coppicing or ectomycorrhizal associations may confer a considerable advantage to a tree species and lead to its monodominance, very few species have these traits. Mining of the ATDN dataset suggests that monodominance is quite rare in Amazonia, and may be linked primarily to edaphic factors