Supplementary Information File Research Articles

Effects of Tcte1 knockout on energy chain transportation and spermatogenesis: implications for male infertility.

Is the Tcte1 mutation causative for male infertility? Our collected data underline the complex and devastating effect of the single-gene mutation on the testicular molecular network, leading to male reproductive failure. Recent data have revealed mutations in genes related to axonemal dynein arms as causative for morphology and motility abnormalities in spermatozoa of infertile males, including dysplasia of fibrous sheath (DFS) and multiple morphological abnormalities in the sperm flagella (MMAF). The nexin-dynein regulatory complex (N-DRC) coordinates the dynein arm activity and is built from the DRC1-DRC7 proteins. DRC5 (TCTE1), one of the N-DRC elements, has already been reported as a candidate for abnormal sperm flagella beating; however, only in a restricted manner with no clear explanation of respective observations. Using the CRISPR/Cas9 genome editing technique, a mouse Tcte1 gene knockout line was created on the basis of the C57Bl/6J strain. The mouse reproductive potential, semen characteristics, testicular gene expression levels, sperm ATP, and testis apoptosis level measurements were then assessed, followed by visualization of N-DRC proteins in sperm, and protein modeling in silico. Also, a pilot genomic sequencing study of samples from human infertile males (n = 248) was applied for screening of TCTE1 variants. To check the reproductive potential of KO mice, adult animals were crossed for delivery of three litters per caged pair, but for no longer than for 6 months, in various combinations of zygosity. All experiments were performed for wild-type (WT, control group), heterozygous Tcte1+/- and homozygous Tcte1-/- male mice. Gross anatomy was performed on testis and epididymis samples, followed by semen analysis. Sequencing of RNA (RNAseq; Illumina) was done for mice testis tissues. STRING interactions were checked for protein-protein interactions, based on changed expression levels of corresponding genes identified in the mouse testis RNAseq experiments. Immunofluorescence in situ staining was performed to detect the N-DRC complex proteins: Tcte1 (Drc5), Drc7, Fbxl13 (Drc6), and Eps8l1 (Drc3) in mouse spermatozoa. To determine the amount of ATP in spermatozoa, the luminescence level was measured. In addition, immunofluorescence in situ staining was performed to check the level of apoptosis via caspase 3 visualization on mouse testis samples. DNA from whole blood samples of infertile males (n = 137 with non-obstructive azoospermia or cryptozoospermia, n = 111 samples with a spectrum of oligoasthenoteratozoospermia, including n = 47 with asthenozoospermia) was extracted to perform genomic sequencing (WGS, WES, or Sanger). Protein prediction modeling of human-identified variants and the exon 3 structure deleted in the mouse knockout was also performed. No progeny at all was found for the homozygous males which were revealed to have oligoasthenoteratozoospermia, while heterozygous animals were fertile but manifested oligozoospermia, suggesting haploinsufficiency. RNA-sequencing of the testicular tissue showed the influence of Tcte1 mutations on the expression pattern of 21 genes responsible for mitochondrial ATP processing or linked with apoptosis or spermatogenesis. In Tcte1-/- males, the protein was revealed in only residual amounts in the sperm head nucleus and was not transported to the sperm flagella, as were other N-DRC components. Decreased ATP levels (2.4-fold lower) were found in the spermatozoa of homozygous mice, together with disturbed tail:midpiece ratios, leading to abnormal sperm tail beating. Casp3-positive signals (indicating apoptosis) were observed in spermatogonia only, at a similar level in all three mouse genotypes. Mutation screening of human infertile males revealed one novel and five ultra-rare heterogeneous variants (predicted as disease-causing) in 6.05% of the patients studied. Protein prediction modeling of identified variants revealed changes in the protein surface charge potential, leading to disruption in helix flexibility or its dynamics, thus suggesting disrupted interactions of TCTE1 with its binding partners located within the axoneme. All data generated or analyzed during this study are included in this published article and its supplementary information files. RNAseq data are available in the GEO database (https://www.ncbi.nlm.nih.gov/geo/) under the accession number GSE207805. The results described in the publication are based on whole-genome or exome sequencing data which includes sensitive information in the form of patient-specific germline variants. Information regarding such variants must not be shared publicly following European Union legislation, therefore access to raw data that support the findings of this study are available from the corresponding author upon reasonable request. In the study, the in vitro fertilization performance of sperm from homozygous male mice was not checked. This study contains novel and comprehensive data concerning the role of TCTE1 in male infertility. The TCTE1 gene is the next one that should be added to the 'male infertility list' because of its crucial role in spermatogenesis and proper sperm functioning. This work was supported by National Science Centre in Poland, grants no.: 2015/17/B/NZ2/01157 and 2020/37/B/NZ5/00549 (to M.K.), 2017/26/D/NZ5/00789 (to A.M.), and HD096723, GM127569-03, NIH SAP #4100085736 PA DoH (to A.N.Y.). The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Corrigendum to “Iron complexes of [2 + 2] and [6 + 6] Schiff-base macrocycles derived from 2,2′-oxydianiline and their applications” [Inorg. Chem. Commun. 139 (2022) 109376

• The correct formula of 3 is [Fe 2 (L 2 H 4 )][FeBr 3 OFeBr 3 ] 2 ‧8MeCN. • The revised CIF has been deposited with the CSD • An updated version of the supplementary information file is provided.

Probing the randomness of the local current distributions of 316 L stainless steel corrosion in NaCl solution

This investigation proposes using Scanning Electrochemical Cell Microscopy (SECCM) as a high throughput tool to collect corrosion activity from randomly probed locations on 316 L SS. In the presence of chloride, potentiodynamic polarisation tests triggered the development of pitting corrosion. Data science methods were deployed to handle and explore 955 j Vs E curves. Normality tests and fitting with theoretical functions were used to understand the conditional log(j) distributions at different potentials. Unimodal and uniform distributions were assigned to the passive and pitting regions. Our “big-data” local strategy revealed a potential-dependent distribution of log(j), with the randomness increasing with testing aggressiveness. Data availabilityAll data generated or analysed during this study are included in this published article (and its supplementary information files) and are available in the Mendeley Data repository, [https://data.mendeley.com/datasets/78rz8vw46x/2]. Code availabilityThe code required to reproduce these findings is included in this published article (and its supplementary information files) and is available to download from GitHub: https://github.com/bcoelho-leonardo/Data-driven-analysis-of-the-local-current-distributions-of-316L-corrosion-in-NaCl-solution/blob/4efff485b115468840b25ea56ad81b31711c0f51/local%20current%20distributions%20of%20316L%20corrosion.ipynb.

Seventy years of evidence on the efficacy and safety of drugs for treating leprosy: a network meta-analysis

The World Health Organization (WHO) recommends multidrug therapy (MDT) with rifampicin, dapsone, and clofazimine for treating leprosy, which is based on very low-quality evidence. Here, we performed a network meta-analysis (NMA) to produce quantitative evidence to strengthen current WHO recommendations. All studies were obtained from Embase and PubMed from the date of establishment to October 9, 2021. Data were synthesized with frequentist random-effects network meta-analyses. Outcomes were assessed using odds ratios (ORs), 95% confidence intervals (95% CIs), and P score. Sixty controlled clinical trials and 9256 patients were included. MDT was effective (range of OR: 1.06-1255584.25) for treating leprosy and multibacillary leprosy. Six treatments (Range of OR: 1.199-4.50) were more effective than MDT. Clofazimine (P score=0.9141) and dapsone+rifampicin (P score=0.8785) were effective for treating type 2 leprosy reaction. There were no significant differences in the safety of any of the tested drug regimens. The WHO MDT is effective for treating leprosy and multibacillary leprosy, but it may not be effective enough. Pefloxacin and ofloxacin may be good adjunct drugs for increasing MDT efficacy. Clofazimine and dapsone+rifampicin can be used in the treatment of a type 2 leprosy reaction. Single-drug regimens are not efficient enough to treat leprosy, multibacillary leprosy, or a type 2 leprosy reaction. All data generated or analyzed during this study are included in this published article [and its supplementary information files].

Nature can still be the strongest help against aging and neurodegeneration: the sirtuins way.

Nature can still be the strongest help against aging and neurodegeneration: the sirtuins way.

Eradication of human immunodeficiency virus-1 reservoir in the brain microglia.

Eradication of human immunodeficiency virus-1 reservoir in the brain microglia.

Emerging non-invasive therapeutic approaches targeting hypocholinergic neural systems in Parkinson's disease.

Emerging non-invasive therapeutic approaches targeting hypocholinergic neural systems in Parkinson's disease.

Molecular mechanisms of lesion-induced axonal sprouting in the corticofugal projection: the role of glial cells.

Molecular mechanisms of lesion-induced axonal sprouting in the corticofugal projection: the role of glial cells.

CD34+ progenitor cells as diagnostic and therapeutic targets in Alzheimer's disease.

CD34+ progenitor cells as diagnostic and therapeutic targets in Alzheimer's disease.

Developmental exposure to thyroid disruptors: misprogramming of the brain's stem cells in later life?

Developmental exposure to thyroid disruptors: misprogramming of the brain's stem cells in later life?

Spontaneous Thoracic Spinal Epidural Hematoma During Pregnancy

Spontaneous Thoracic Spinal Epidural Hematoma During Pregnancy

Deferasirox and vitamin D3 co-therapy mitigates iron-induced renal injury by enhanced modulation of cellular anti-inflammatory, anti-oxidative stress, and iron regulatory pathways in rat

BackgroundChronic iron overload could induce nephropathy via oxidative stress and inflammation, and chelating therapy has limited efficacy in removing excess intracellular iron. Although vitamin D (VD) has shown potent antioxidant and anti-inflammatory effects, as well contribute to iron homeostasis, none of the previous studies measured its potential remedial effects against chronic iron toxicity. AimsTo measure the alleviating effects of deferasirox (DFX) and/or vitamin D (VD) single and combined therapies against nephrotoxicity induced by chronic iron overload. MethodsForty male rats were divided into negative (NC) and positive (PC) controls, DFX, VD, and DFX/VD groups. The designated groups received iron for six weeks followed by DFX and/or VD for another six weeks. Then, the expression pattern of renal genes and proteins including hepcidin, ferroportin (FPN), megalin, transferrin receptor 1 (TfR1), ferritin heavy and light chains, VD receptor (VDR), VD synthesizing (Cyp27b1) and catabolizing (Cyp24a1) enzymes were measured alongside serum markers of renal function and iron biochemical parameters. Additionally, several markers of oxidative stress (MDA/H2O2/GSH/SOD1/CAT/GPx4) and inflammation (IL-1β/IL-6/TNF-α/IL-10) together with renal cell apoptosis and expression of caspase-3 (Casp-3) were measured. ResultsThe PC rats showed pathological iron and renal biochemical markers, hypovitaminosis D, increased renal tissue iron contents with increased Cyp24a1/Megalin/ferritin-chains/hepcidin, and decreased Cyp27b1/VDR/TfR1/FPN expression than the NC group. The PC renal tissues also showed abnormal histology, increased inflammatory (IL-1β/IL-6/TNF-α), oxidative stress (MDA/H2O2), and apoptosis markers with decreased IL-10/GSH/SOD1/CAT/GPx4. Although DFX monotherapy reduced serum iron levels, it was comparable to the PC group in renal iron concentrations, VD and iron-homeostatic molecules, alongside markers of oxidative stress, inflammation, and apoptosis. On the other hand, VD monotherapy markedly modulated renal iron and VD-related molecules, reduced renal tissue iron concentrations, and preserved renal tissue relative to the PC and DFX groups. However, serum iron levels were equal in the VD and PC groups. In contrast, the best significant improvements in serum and renal iron levels, expression of renal iron-homeostatic molecules, oxidative stress, inflammation, and apoptosis were seen in the co-therapy group. Conclusionsiron-induced nephrotoxicity was associated with dysregulations in renal VD-system together with renal oxidative stress, inflammation, and apoptosis. While DFX reduced systemic iron, VD monotherapy showed better attenuation of renal iron concentrations and tissue damage. Nonetheless, the co-therapy approach exhibited the maximal remedial effects, possibly by enhanced modulation of renal iron-homeostatic molecules alongside reducing systemic iron levels. Availability of data and materialsAll data generated or analysed during this study are included in this published article [and its Supplementary information files].

Facile biosynthesis of taxadiene by a newly constructed Escherichia coli strain fusing enzymes taxadiene synthase and geranylgeranyl pyrophosphate synthase

Taxadiene has received extensive attention as the hydrocarbon backbone of a well-known anti-cancer drug, Paclitaxel. In this study, a de novo pathway for taxadiene biosynthesis from cheap carbon sources was newly constructed using Escherichia coli BL21 (DE3) as a chassis cell. The total biosynthesis pathway of taxadiene was divided into upstream and downstream modules for respective optimization. To facilitate the cyclization of the diterpene substrate geranylgeranyl pyrophosphate, two of the key downstream module enzymes, taxadiene synthase and geranylgeranyl pyrophosphate synthase, were genetically expressed in the form of fusion protein. After a series of optimization, the best recombinant strain, designated as E. coli strain ECU5008, achieved a titer of 93.5 mg/L taxadiene in shake flask cultivation. In addition, a commercially available macroporous adsorption resin was employed for the extraction and purification of taxadiene, in which each gram of resin Hz-816 could adsorb about 13.2 mg of taxadiene from the methanol extract of the cultured E. coli cells. The application of macroporous adsorption resin effecctively improved the isolation yield of taxadiene from fermentation broth. Availability data and materialsAll data generated or analyzed during this study are included in this article and its Supplementary information file.

Just a Grand Duke who Loves Chemistry. Peter Leopold of Habsburg-Lorraine (1747–1792) and his Chemical Cabinet at the Imperial and Royal Museum of Physics and Natural History

This article dealt with the history of the chemical cabinet established by the Grand Duke of Tuscany, Peter Leopold of Habsburg-Lorraine (1747–1792), at the Imperial and Royal Museum of Physics and Natural History in Firenze during his regency. To achieve this goal, it investigated untapped archival sources (e.g., administrative and commercial documents, minutes, correspondences, inventories) concerning the museum management from its foundation in 1775 to the departure of the Grand Duke for Vienna to be crowned as Holy Roman Emperor Leopold II in 1790. The article analyzed the chemical cabinet’s manuscript catalog, whose entire transcription is presented in the Supplementary Information Files. The work then examined the connections between the activities performed at the chemical laboratory and Peter Leopold’s interests in experimental chemistry. Concerning this research question, the scientific relationship he held with the naturalist Giovanni Valentino Mattia Fabbroni (1752–1822) – Vice-director and then Director of the Imperial and Royal Museum of Physics and Natural History – who helped the Grand Duke navigate all aspects of his interests in chemistry and natural sciences, was also discussed.

Hebbian plasticity: the elusive missing link at the heart of Alzheimer's disease pathogenesis?

Hebbian plasticity: the elusive missing link at the heart of Alzheimer's disease pathogenesis?

Emerging role of neuregulin-1beta1 in pathogenesis and progression of multiple sclerosis

Emerging role of neuregulin-1beta1 in pathogenesis and progression of multiple sclerosis

The neuroprotective effects of oxygen therapy in Alzheimer’s disease: a narrative review

Alzheimer’s disease (AD) is a degenerative neurological disease that primarily affects the elderly. Drug therapy is the main strategy for AD treatment, but current treatments suffer from poor efficacy and a number of side effects. Non-drug therapy is attracting more attention and may be a better strategy for treatment of AD. Hypoxia is one of the important factors that contribute to the pathogenesis of AD. Multiple cellular processes synergistically promote hypoxia, including aging, hypertension, diabetes, hypoxia/obstructive sleep apnea, obesity, and traumatic brain injury. Increasing evidence has shown that hypoxia may affect multiple pathological aspects of AD, such as amyloid-beta metabolism, tau phosphorylation, autophagy, neuroinflammation, oxidative stress, endoplasmic reticulum stress, and mitochondrial and synaptic dysfunction. Treatments targeting hypoxia may delay or mitigate the progression of AD. Numerous studies have shown that oxygen therapy could improve the risk factors and clinical symptoms of AD. Increasing evidence also suggests that oxygen therapy may improve many pathological aspects of AD including amyloid-beta metabolism, tau phosphorylation, neuroinflammation, neuronal apoptosis, oxidative stress, neurotrophic factors, mitochondrial function, cerebral blood volume, and protein synthesis. In this review, we summarized the effects of oxygen therapy on AD pathogenesis and the mechanisms underlying these alterations. We expect that this review can benefit future clinical applications and therapy strategies on oxygen therapy for AD.

Evaluation of the efficacy and toxicity of oral and topical pumpkin oil on the hair growth of mice

This study aimed to evaluate the efficacy and safety of a topical and oral administration of pumpkin seed oil (PSO) on the hair growth of BALB/c male mice. The animals had their dorsal area shaved (2 ×2 cm) and they were divided into 6 experimental groups. They received orally saline (OS), finasteride (F), or PSO (OP) for 14 days; or topically saline (TS), minoxidil (M), or PSO (TP) for 7 days. The euthanasia of all of the mice occurred on the 22nd day, and the histological slides from the skin area were analyzed. Lipoperoxidation in the liver was assessed through the TBARS method and was also evaluated by the antioxidant enzymes (SOD and CAT). The comet assay and the micronucleus tests were performed for genotoxic/mutagenic safety analyses. A significant increase in the number of hair follicles in the TP group was seen (8.8 ± 0.8) but it was disorganized, with loose dermal collagen. Finasteride presented a significant increase in the levels of the TBARS, SOD, and CAT in the liver, and M increased the DNA damage in the blood and the liver tissues. PSO did not induce any significant changes. In addition, PSO did not induce genotoxic or mutagenic effects. In conclusion, the oral PSO for 14 days acted in the proliferation of the hair follicles, without toxicity signals in the liver. Data availabilityThe authors confirm that all of the relevant data is included in the article and/or in the supplementary information file.

Exploiting Caenorhabditis elegans to discover human gut microbiota-mediated intervention strategies in protein conformational diseases.

Exploiting Caenorhabditis elegans to discover human gut microbiota-mediated intervention strategies in protein conformational diseases.

Transcription factors promote neural regeneration after spinal cord injury.

Transcription factors promote neural regeneration after spinal cord injury.