RNAi-mediated silencing of SOD1 profoundly extends survival and functional outcomes in ALS mice.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition, with 20% of familial and 2-3% of sporadic cases linked to mutations in the cytosolic superoxide dismutase (SOD1) gene. Mutant SOD1 protein is toxic to motor neurons, making SOD1 gene lowering a promising approach, supported by preclinical data and the 2023 FDA approval of the GapmeR ASO targeting SOD1, tofersen. Despite the approval of an ASO and the optimism it brings to the field, the pharmacodynamics and pharmacokinetics of therapeutic SOD1 modulation can be improved. Here, we developed a chemically stabilized divalent siRNA scaffold (di-siRNA) that effectively suppresses SOD1 expression in vitro and in vivo. With optimized chemical modification, it achieves remarkable CNS tissue permeation and SOD1 silencing in vivo. Administered intraventricularly, di-siRNASOD1 extended survival in SOD1-G93A ALS mice, surpassing survival previously seen in these mice by ASO modalities, slowed disease progression, and prevented ALS neuropathology. These properties offer an improved therapeutic strategy for SOD1-mediated ALS and may extend to other dominantly inherited neurological disorders.

Effect of drug therapies on self-reported chemosensory outcomes after COVID-19.

Objective: The aim of this study was to assess the relative efficacy of medications used following severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection on self-reported alterations in taste and/or smell function. Methods: Seven hundred and fourteen persons with self-reported postcoronavirus disease 2019 (post-COVID-19) chemosensory disorders were personally interviewed regarding specific medications they were administered following the acute phase of the disease. The dependent measure-self-reported total recovery of chemosensory symptoms-was subjected to stepwise logistic regression. Independent predictors included demographic and clinical variables, in addition to specific medications used to mitigate disease symptoms (i.e., systemic corticosteroids, oseltamivir, vitamin C, ibuprofen, hydroxychloroquine, azithromycin, ivermectin, nitazoxanide, anticoagulants, and zinc). Results: The median time between COVID-19 symptom onset and the interviews was 81 days (interquartile range: 60-104). Of the 714 subjects, 249 (34.9%) reported total recovery of their chemosensory function; 437 (61.2%) had at least one treatment since the beginning of the disease. Women and those with more comorbidities had undergone more treatments. The recovery rates of the treated and nontreated groups did not differ significantly. Nonetheless, respondents who had used nitazoxanide tended to have a higher rate of self-reported taste or smell recovery. Those who took oral zinc were less likely to improve. Conclusions: No medication employed during the first months after SARS-CoV-2 infection had a clear positive effect on returning self-reported smell or taste function to normal, although nitrazoxide trended in a positive direction. Oral zinc had a negative effect on the reported recovery of these senses.

Phaco-Chop versus Divide-and-Conquer in Patients Who Underwent Cataract Surgery: A Systematic Review and Meta-Analysis.

Background: Cataract surgery is one of the most frequently performed eye surgeries worldwide, and among several techniques, phacoemulsification has become the standard of care due to its safety and efficiency. We evaluated the advantages and disadvantages of two phacoemulsification techniques: phaco-chop and divide-and-conquer. Methods: PubMed, Cochrane, Embase, and Web of Science databases were queried for randomized controlled trial (RCT), prospective and retrospective studies that compared the phaco-chop technique over the divide-and-conquer technique and reported the outcomes of (1) Endothelial cell count change (ECC); (2) Ultrasound time (UST); (3) Cumulated dissipated energy (CDE); (4) Surgery time; and (5) Phacoemulsification time (PT). Heterogeneity was examined with I2 statistics. A random-effects model was used for outcomes with high heterogeneity. Results: Nine final studies, (6 prospective RCTs and 3 observational), comprising 837 patients undergoing phacoemulsification. 435 (51.9%) underwent the phaco-chop technique, and 405 (48.1%) underwent divide-and-conquer. Overall, the phaco-chop technique was associated with several advantages: a significant difference in ECC change postoperatively (Mean Difference [MD] -221.67 Cell/mm2; 95% Confidence Interval [CI] -401.68 to -41.66; p < 0.02; I2=73%); a shorter UST (MD -51.16 sec; 95% CI -99.4 to -2.79; p = 0.04; I2=98%); reduced CDE (MD -8.68 units; 95% CI -12.76 to -4.60; p < 0.01; I2=84%); a lower PT (MD -55.09 sec; 95% CI -99.29 to -12.90; p = 0.01; I2=100). There were no significant differences in surgery time (MD -3.86 min; 95% CI -9.55 to 1.83; p = 0.18; I2=99%). Conclusion: The phaco-chop technique proved to cause fewer hazards to the corneal endothelium, with less delivered intraocular ultrasound energy when compared to the divide-and-conquer technique.

Recent progress on nickel phthalocyanine-based electrocatalysts for CO2 reduction.

The electrocatalytic reduction of CO2 to high-value fuels by renewable electricity is a sustainable strategy, which can substitute for fossil fuels and circumvent climate changes induced by elevated CO2 emission levels, making the rational design of versatile electrocatalysts highly desirable. Among all the electrocatalytic materials used in the CO2 reduction reaction, nickel phthalocyanine (NiPc)-based electrocatalysts have attracted considerable attention recently because of their high CO selectivity and catalytic activity. Herein, we review the latest advances in CO2 electroreduction to CO catalyzed by immobilized NiPc and its derivatives on diverse surfaces. Specific strategies, the structure-performance relationship and the CO2-to-CO reaction mechanism of these NiPc-based electrocatalysts are analyzed. Future opportunities and challenges for this series of powerful heterogeneous electrocatalysts are also highlighted.

Eight Weeks of Intermittent Exercise in Hypoxia, with or without a Low-Carbohydrate Diet, Improves Bone Mass and Functional and Physiological Capacity in Older Adults with Type 2 Diabetes.

In an increasingly aging and overweight population, osteoporosis and type 2 diabetes (T2DM) are major public health concerns. T2DM patients experience prejudicial effects on their bone health, affecting their physical capacity. Exercise in hypoxia (EH) and a low-carbohydrate diet (LCD) have been suggested for therapeutic benefits in T2DM, improving bone mineral content (BMC) and glycemic control. This study investigated the effects of EH combined with an LCD on body composition and functional and physiologic capacity in T2DM patients. Older T2DM patients (n = 42) were randomly assigned to the following groups: (1) control group: control diet + exercise in normoxia; (2) EH group: control diet + EH; (3) intervention group: LCD + EH. Cardiopulmonary tests (BRUCE protocol), body composition (DEXA), and functional capacity (6MWT, handgrip strength) were evaluated. Body mass index (kg/m2) and body fat (%) decreased in all groups (p < 0.001). BMC (kg) increased in all groups (p < 0.001) and was significantly higher in the EH and EH + LCD groups (p < 0.001). VO2peak improved in all groups (p < 0.001), but more so in the hypoxia groups (p = 0.019). Functional capacity was increased in all groups (p < 0.001), but more so in the EH group in 6MWT (p = 0.030). EH with and without an LCD is a therapeutic strategy for improving bone mass in T2DM, which is associated with cardiorespiratory and functional improvements.

Photoredox C(2)-Arylation of Indole- and Tryptophan-Containing Biomolecules.

We introduce a novel and straightforward methodology for photoredox arylation of an indole scaffold using aryldiazonium salts under mild and metal-free conditions. Our approach enables the regioselective and chemoselective introduction of several aryl groups to the C(2) position of indoles and tryptophan, even in competition with other amino acids. This approach extends to the late-stage functionalization of peptides and lysozyme, heralding the unprecedented arylation of tryptophan residues in wild-type proteins and offering broad utility in chemical biology.

Cryoprotective Polysaccharides with Ordered Gel Structures Induce Ice Growth Anticipation and Survival Enhancement during Cell Cryopreservation.

This work cross-correlated rheological, thermodynamic, and conformational features of several natural polysaccharides to their cryoprotective performance. The basis of cryoprotection of FucoPol, pectin, and agar revealed a causal combination of (i) an emerging sol-gel transition (p = 0.014) at near-hypothermia (4 °C), (ii) noncolligative attenuated supercooling of the kinetic freezing point of water (p = 0.026) supporting ice growth anticipation, and (iii) increased conformational order (p < 0.0001), where helix-/sheet-like features boost cryoprotection. FucoPol, of highest cryoprotective performance, revealed a predominantly helical structure (α/ß = 1.5) capable of forming a gel state at 4 °C and the highest degree of supercooling attenuation (TH = 6.2 °C). Ice growth anticipation with gel-like polysaccharides suggests that the gel matrix neutralizes elastic deformations and lethal cell volumetric fluctuations during freezing, thus preventing the loss of homeostasis and increasing post-thaw viability. Ultimately, structured gels capable of attenuated supercooling enable cryoprotective action at the polymer-cell interface, in addition to polymer-ice interactions. This rationale potentiates implementing alternative, biobased, noncytotoxic polymers in cryobiology.

Alterations in the pro-resolving lipid mediator machinery within first trimester maternal tissue: Implications in decidualization and miscarriage risk.

A pivotal event in uterine receptivity and human reproduction is the differentiation of endometrial stromal cells into decidual cells, known as decidualization. Decidualization is interlinked with its inflammatory environment. Our study aimed to investigate the presence and role of pro-resolving lipid mediators in first trimester maternal tissue. We assessed the levels of LXA4 and RvD1, along with their metabolic LOX enzymes, in elective (control) and sporadic miscarriage samples. We investigated the effects of LXA4 and RvD1 on decidualization using primary endometrial stromal cells and the immortalized endometrial stromal St-T1b cell line. The upregulation of 12- and 15-LOX expression was observed in pregnancy tissue after sporadic miscarriage, suggesting an inflammatory imbalance. Furthermore, incubation with these lipid mediators led to a decrease in decidualization biomarkers PRL and IGFBP-1, accompanied by morphological changes indicative of aberrant differentiation. The expression of LOX enzymes in decidual natural killer cells suggests their involvement in regulating the inflammatory surroundings and the extent of decidualization.

On the Determination of Elastic Properties of Single-Walled Nitride Nanotubes Using Numerical Simulation.

In recent years, tubular nanostructures have been related to immense advances in various fields of science and technology. Considerable research efforts have been centred on the theoretical prediction and manufacturing of non-carbon nanotubes (NTs), which meet modern requirements for the development of novel devices and systems. In this context, diatomic inorganic nanotubes formed by atoms of elements from the 13th group of the periodic table (B, Al, Ga, In, Tl) and nitrogen (N) have received much research attention. In this study, the elastic properties of single-walled boron nitride, aluminium nitride, gallium nitride, indium nitride, and thallium nitride nanotubes were assessed numerically using the nanoscale continuum modelling approach (also called molecular structural mechanics). The elastic properties (rigidities, surface Young's and shear moduli, and Poisson's ratio) of nitride nanotubes are discussed with respect to the bond length of the corresponding diatomic hexagonal lattice. The results obtained contribute to a better understanding of the mechanical response of nitride compound-based nanotubes, covering a broad range, from the well-studied boron nitride NTs to the hypothetical thallium nitride NTs.

Learning nonparametric ordinary differential equations from noisy data.

Learning nonparametric systems of Ordinary Differential Equations (ODEs) x˙=f(t,x) from noisy data is an emerging machine learning topic. We use the well-developed theory of Reproducing Kernel Hilbert Spaces (RKHS) to define candidates for f for which the solution of the ODE exists and is unique. Learning f consists of solving a constrained optimization problem in an RKHS. We propose a penalty method that iteratively uses the Representer theorem and Euler approximations to provide a numerical solution. We prove a generalization bound for the L2 distance between x and its estimator. Experiments are provided for the FitzHugh-Nagumo oscillator, the Lorenz system, and for predicting the Amyloid level in the cortex of aging subjects. In all cases, we show competitive results compared with the state-of-the-art.

The Potential of the Fibronectin Inhibitor Arg-Gly-Asp-Ser in the Development of Therapies for Glioblastoma.

Glioblastoma (GBM) is the most lethal and common malignant primary brain tumor in adults. An important feature that supports GBM aggressiveness is the unique composition of its extracellular matrix (ECM). Particularly, fibronectin plays an important role in cancer cell adhesion, differentiation, proliferation, and chemoresistance. Thus, herein, a hydrogel with mechanical properties compatible with the brain and the ability to disrupt the dynamic and reciprocal interaction between fibronectin and tumor cells was produced. High-molecular-weight hyaluronic acid (HMW-HA) functionalized with the inhibitory fibronectin peptide Arg-Gly-Asp-Ser (RGDS) was used to produce the polymeric matrix. Liposomes encapsulating doxorubicin (DOX) were also included in the hydrogel to kill GBM cells. The resulting hydrogel containing liposomes with therapeutic DOX concentrations presented rheological properties like a healthy brain. In vitro assays demonstrated that unmodified HMW-HA hydrogels only caused GBM cell killing after DOX incorporation. Conversely, RGDS-functionalized hydrogels displayed per se cytotoxicity. As GBM cells produce several proteolytic enzymes capable of disrupting the peptide-HA bond, we selected MMP-2 to illustrate this phenomenon. Therefore, RGDS internalization can induce GBM cell apoptosis. Importantly, RGDS-functionalized hydrogel incorporating DOX efficiently damaged GBM cells without affecting astrocyte viability, proving its safety. Overall, the results demonstrate the potential of the RGDS-functionalized hydrogel to develop safe and effective GBM treatments.

Reservoir displacement by an invasive rodent reduces Lassa virus zoonotic spillover risk.

The black rat (Rattus rattus) is a globally invasive species that has been widely introduced across Africa. Within its invasive range in West Africa, R. rattus may compete with the native rodent Mastomys natalensis, the primary reservoir host of Lassa virus, a zoonotic pathogen that kills thousands annually. Here, we use rodent trapping data from Sierra Leone and Guinea to show that R. rattus presence reduces M. natalensis density within the human dwellings where Lassa virus exposure is most likely to occur. Further, we integrate infection data from M. natalensis to demonstrate that Lassa virus zoonotic spillover risk is lower at sites with R. rattus. While non-native species can have numerous negative effects on ecosystems, our results suggest that R. rattus invasion has the indirect benefit of decreasing zoonotic spillover of an endemic pathogen, with important implications for invasive species control across West Africa.

Risk of Eating Disorders and Social Desirability among Higher Education Students: Comparison of Nutrition Students with Other Courses.

The transition to college is a period of higher risk of the development of eating disorders, with nutrition/dietetics students representing a group of particular vulnerability. Hence, it is interesting to assess eating disorders, taking into consideration potential sources of bias, including social desirability. Our aims were to compare the risk of eating disorders between students of nutrition/dietetics and those attending other courses and to study potential social desirability biases. A total of 799 higher education students (81.7% females) aged 18 to 27 years old completed a questionnaire assessing the risk of eating disorders (EAT-26) and social desirability (composite version of the Marlowe-Crowne Social Desirability Scale). The proportion of students with a high risk of eating disorders was higher among females (14.5% vs. 8.2%, p = 0.044). Nutrition/dietetics students did not differ from those attending other courses regarding the risk of eating disorders. The social desirability bias when assessing the risk of eating disorders was overall low (EAT-26 total score: r = -0.080, p = 0.024). Social desirability correlated negatively with the Diet (r = -0.129, p < 0.001) and Bulimia and food preoccupation subscales (r = -0.180, p < 0.001) and positively with Oral self-control (r = 0.139, p < 0.001).

Coding, Decoding and Retrieving a Message Using DNA: An Experience from a Brazilian Center Research on DNA Data Storage.

DNA data storage based on synthetic oligonucleotides is a major attraction due to the possibility of storage over long periods. Nowadays, the quantity of data generated has been growing exponentially, and the storage capacity needs to keep pace with the growth caused by new technologies and globalization. Since DNA can hold a large amount of information with a high density and remains stable for hundreds of years, this technology offers a solution for current long-term data centers by reducing energy consumption and physical storage space. Currently, research institutes, technology companies, and universities are making significant efforts to meet the growing need for data storage. DNA data storage is a promising field, especially with the advancement of sequencing techniques and equipment, which now make it possible to read genomes (i.e., to retrieve the information) and process this data easily. To overcome the challenges associated with developing new technologies for DNA data storage, a message encoding and decoding exercise was conducted at a Brazilian research center. The exercise performed consisted of synthesizing oligonucleotides by the phosphoramidite route. An encoded message, using a coding scheme that adheres to DNA sequence constraints, was synthesized. After synthesis, the oligonucleotide was sequenced and decoded, and the information was fully recovered.

Nitrogen-containing andrographolide derivatives with multidrug resistance reversal effects in cancer cells.

Multidrug resistance (MDR) remains a challenging issue in cancer treatment. Aiming at finding anticancer agents to overcome MDR, the triacetyl derivative (2) of the labdane diterpenoid lactone andrographolide (1) underwent the Michael-type addition reaction followed by elimination, yielding twenty-three new derivatives, bearing nitrogen-containing substituents (3-25). Their structures were assigned, mainly, by 1D and 2D NMR experiments. The MDR reversal potential of compounds 1-25 was assessed, by functional and chemosensitivity assays, using resistant human ABCB1-gene transfected L5178Y mouse lymphoma cells as a model. Several derivatives exhibited remarkable P-glycoprotein (P-gp) inhibitory ability. Compounds 13 and 20, bearing thiosemicarbazide moieties, were the most active exhibiting a strong MDR reversal effect at 2 µM. Some compounds showed selectivity towards the resistant cells, with compound 5 exhibiting a collateral sensitivity effect associated with significant antiproliferative activity (IC50 = 5.47 ± 0.22 µM). Moreover, all selected compounds displayed synergistic interaction with doxorubicin, with compound 3 being the most active. In the ATPase assay, selected compounds exhibited characteristics of P-gp inhibitors.

Taxonomic study of Hymenochaetaceae species (Agaricomycetes, Basidiomycota) in the municipalities of Tomé-Açu and Bujaru, Pará, Brazil.

The family Hymenochaetaceae includes a diversity of 893 species described around the world. Its representatives are known by their usually rusty colored basidiomes with a poroid hymenial surface, hydnoid or smooth, woody consistency, and wide morphological variation regarding the arrangement on the substrate. They behave as saprophytic, parasitic, ectomycorrhizal and play a fundamental role in the decomposition of wood in forest ecosystems. In the Brazilian Amazonia region, approximately 40 species of Hymenochaetaceae are currently recorded. The main goal of this study was to increase the knowledge on Hymenochaetaceae from the Brazilian Amazonia. Collections were carried out between October 2021 and April 2022 in the state of Pará, municipalities of Tomé-Açu and Bujaru, to expanding the knowledge of this fungal family to the Brazilian Amazonia. A total of 15 specimens were identified, distributed in seven genera and 12 species. Four species are new records for the state of Pará (Fomitiporia apiahyna, Phellinus neocallimorphus, Phellinus sancti-georgii, and Sclerotus extensus) and two of them are new records for the Brazilian Amazonia (P. neocallimorphus and P. sancti-georgii). Our findings contribute to taxonomic knowledge of this family in the Brazilian Amazonia and reduce the information gaps about the diversity of species.

A search strategy for detecting duodenoscope-associated infections: a retrospective observational study.

BACKGROUND: Duodenoscope-associated infections (DAIs) are exogenous infections resulting from the use of contaminated duodenoscopes. Though numerous outbreaks of DAI have involved multidrug-resistant micro-organisms (MDROs), outbreaks involving non-MDROs are also likely to occur. Detection challenges arise as these infections often resolve before culture or because causative strains are not retained for comparison with duodenoscope strains. AIM: To identify and analyse DAIs spanning a seven-year period in a tertiary care medical centre. METHODS: This was a retrospective observational study. Duodenoscope cultures positive for gastrointestinal flora between March 2015 and September 2022 were paired with duodenoscope usage data to identify patients exposed to contaminated duodenoscopes. Analysis encompassed patients treated after a positive duodenoscope culture and those treated within the interval from a negative to a positive culture. Patient identification numbers were cross-referenced with a clinical culture database to identify patients developing infections with matching micro-organisms within one year of their procedure. A 'pair' was established upon a species-level match between duodenoscope and patient cultures. Pairs were further analysed via antibiogram comparison, and by whole-genome sequencing (WGS) to determine genetic relatedness. FINDINGS: Sixty-eight pairs were identified; of these, 21 exhibited matching antibiograms which underwent WGS, uncovering two genetically closely related pairs categorized as DAIs. Infection onset occurred up to two months post procedure. Both causative agents were non-MDROs. CONCLUSION: This study provides crucial insights into DAIs caused by non-MDROs and it highlights the challenge of DAI recognition in daily practice. Importantly, the delayed manifestation of the described DAIs suggests a current underestimation of DAI risk.

Gonioscopy-Assisted Transluminal Trabeculotomy Outcomes Under Different Levels of Glaucoma Severity: A Multicenter, Comparative Study.

PURPOSE: To evaluate the outcomes of gonioscopy-assisted transluminal trabeculotomy (GATT) under different levels of glaucoma severity. DESIGN: Retrospective, multicenter, before-and-after study. METHODS: One eye from all primary open-angle glaucoma patients who underwent GATT combined with cataract surgery (Phaco-GATT) or GATT stand-alone with 12 months of follow-up were included and divided according to glaucoma severity (mild = GI, moderate = GII, and advanced = GIII) and the outcomes compared. RESULTS: A total of 270 eyes were included: 90 in GI, 75 in GII, and 105 in GIII. The IOP was reduced from 18.6 ± 6.0 mm Hg in GI, 19.7 ± 6.4 mm Hg in GII, and 21.0 ± 7.9 mm Hg in GIII, preoperatively, to 11.9 ± 2.6 mm Hg in GI, 11.8 ± 2.1 mm Hg in GII, and 11.9 ± 3.0 mm Hg in GIII at 12 months postoperatively (P < .001 for all). The number of hypotensive ocular medications were reduced from 2.7 ± 1.0 in GI, 3.1 ± 0.8 in GII, and 3.2 ± 1.2 in GIII to 0.6 ± 0.9 in GI, 1.0 ± 1.1 in GII, and 1.2 ± 1.1 in GIII at the last postoperative visit (P < .001 for all). Relative success was achieved, at 1 year, in 93.8% of the eyes in GI, 89.0% in GII, and 88.1% in GIII (P = .3). Complete success was achieved in 61.8% of the eyes in GI, 43.8% in GII, and 37.6% in GIII (P = .007). No serious adverse event was observed in any group. CONCLUSIONS: GATT is a safe and effective procedure in glaucoma, regardless of its preoperative severity.