Encondroma osificado en fémur. Una localización atípica. A propósito de un caso / Ossified enchondroma in femur. An atypical location. Case study

Presentamos el caso de un hombre de 61 años en el que se halló de forma incidental un encondroma a nivel proximal de fémur. Tras seguimiento, se observó la estabilidad de la lesión. El encondroma es un tumor de origen cartilaginoso benigno. Se localiza principalmente en las falanges de las manos y los pies, aunque puede observarse en húmero o fémur. Por lo general, es una lesión asintomática y se halla de manera incidental. En las radiografías suelen verse lesiones redondeadas bien definidas con radiolucidez central. Se recomienda el seguimiento con radiografías seriadas para comprobar la progresión o estabilidad de la lesión y hacer su diagnóstico diferencial con el condrosarcoma.(AU)

We report the case of a 61-year-old man in whom an enchondroma was incidentally detected at the proximal level of the femur. After follow-up the lesion was stable. Enchondroma is a benign cartilaginous tumor. It is located mainly in the phalanges of the hands and feet, although it can be seen in the humerus or femur. It is usually an asymptomatic lesion, found incidentally. On x-rays, well-defined round lesions with central radiolucency are usually observed. Follow-up with serial x-rays is recommended to verify the lesion’s course or stability and make its differential diagnosis with chondrosarcoma.(AU)

Reduction-Responsive Cationic Vesicles from Bolaamphiphiles with Ionizable Amino Acid or Dipeptide Polar Heads.

This paper presents a study of the aggregation of cationic bolaamphiphilic molecules into vesicles. These molecules are based on a cystamine core with protonated terminal dipeptide groups. The study found that vesicles can be formed at pH 4 for all of the dipeptide-terminated bolaamphiphiles containing different combinations of l-valine, l-phenylalanine, and l-tryptophan. The concentration for aggregation onset was determined by using pyrene as a fluorescent probe or light dispersion for compounds with tryptophan. Dynamic light scattering (DLS) studies and transmission electron microscopy (TEM) reveal that the vesicles have diameters ranging from 140 to 500 nm and show the capability of loading hydrophobic cargos, such as Nile red, and their liberation in reductive environments. Furthermore, the bolaamphiphiles are only fully protonated and prone to vesicle formation at acidic pH, making them a promising alternative for gastrointestinal delivery.

Consensus document on acute-on-chronic liver failure (ACLF) established by the Mexican Association of Hepatology.

Acute-on chronic liver failure (ACLF) has been an intensively debated topic mainly due to the lack of a unified definition and diagnostic criteria. The growing number of publications describing the mechanisms of ACLF development, the progression of the disease, outcomes and treatment has contributed to a better understanding of the disease, however, it has also sparked the debate about this condition. As an attempt to provide medical professionals with a more uniform definition that could be applied to our population, the first Mexican consensus was performed by a panel of experts in the area of hepatology in Mexico. We used the most relevant and impactful publications along with the clinical and research experience of the consensus participants. The consensus was led by 4 coordinators who provided the most relevant bibliography by doing an exhaustive search on the topic. The entire bibliography was made available to the members of the consensus for consultation at any time during the process and six working groups were formed to develop the following sections: 1.- Generalities, definitions, and criteria, 2.- Pathophysiology of cirrhosis, 3.- Genetics in ACLF, 4.- Clinical manifestations, 5.- Liver transplantation in ACLF, 6.- Other treatments.

Greenhouse Gas Emissions and Crossbred Cow Milk Production in a Silvopastoral System in Tropical Mexico.

In Mexico, pasture degradation is associated with extensive pastures; additionally, under these conditions, livestock activities contribute considerably to greenhouse gas (GHG) emissions. Among the options to improve grazing systems and reduce GHG emissions, silvopastoral systems (SPS) have been recommended. The objectives of this work were to quantify the N outflow in a soil-plant-animal interface, as well as the CH4 emissions and milk production in an SPS with woody legumes (Leucaena leucocephala) that is associated with stargrass (Cynodon nlemfuensis). This was then compared with stargrass in a monoculture system (MS) in the seasons (dry and rainy period) over a two-year period. Dung was collected from the animals of each of the grazing systems and applied fresh to the land plots. Fresh dung and urine were collected from the cows of each grazing system and were applied to the experimental plots. In addition, the soil CH4 and N2O contents were measured to quantify the emissions. Average milk yield by seasons was similar: MS (7.1 kg per animal unit (AU)/day-1) and SPS (6.31 kg per AU/day-1). Cows in the MS had a mean N intake of 171.9 g/UA day-1 without seasonal variation, while the SPS animals' mean N intake was 215.7 g/UA day-1 for both seasons. For the urine applied to soil, the N2O outflow was higher in the MS (peak value = 1623.9 µg N-N2O m-2 h-1). The peak value for the SPS was 755.9 µg of N-N2O m-2 h-1. The N2O emissions were higher in the rainy season (which promotes denitrification). The values for the feces treatment were 0.05% (MS) and 0.01% (SPS). The urine treatment values were 0.52% (MS) and 0.17% (SPS). The emissions of CH4 showed that the feces of the SPS systems resulted in a higher accumulation of gas in the rainy season (29.8 g C ha-1), followed by the feces of the MS system in the dry season (26.0 g C ha-1). Legumes in the SPS helped to maintain milk production, and the N2O emissions were lower than those produced by the MS (where the pastures were fertilized with N).

Gold nanoparticle-based two-photon fluorescent nanoprobe for monitoring intracellular nitric oxide levels.

Nitric oxide (NO) plays an important role in the regulation of the immune, cardiovascular and nervous systems. Consequently, being able to monitor and quantify intracellular NO levels would provide a greater understanding of the implications of this molecule in the different biological processes, including, for example, in cancer. Here, we report a broadly applicable two-photon excitable fluorescent nanoprobe able to detect and potentially quantify NO levels in an extensive range of cellular environments. The nanoprobe consists of a thiolated photoinduced electron transfer-based two=photon fluorescent probe attached onto the surface of 2.4 ± 0.7 nm gold nanoparticles (DANPY-NO@AuNPs). The nanoprobe, which can be synthesised in a reproducible manner and exhibits great stability when stored at room temperature, is able to selectively detect NO in solution, with a dynamic range up to 150 µM, and at pH values of biological relevance. DANPY-NO@AuNPs were able to selectively detect endogenous NO in RAW264.7γ NO- macrophages and THP-1 human leukemic cells; and endogenous and exogenous NO in endothelial cells. The nanoprobe accumulated in the acidic organelles of the tested cell lines showing negligible toxicity. Importantly, DANPY-NO@AuNPs showed potential to quantify intracellular NO concentrations in MDA-MB-231 breast cancer cells. The biological evaluation of the nanoprobe was undertaken using confocal laser scanning (images and intracellular emission spectra) and multiphoton microscopies, and flow cytometry. Based on their excellent sensitivity and stability, and outstanding versatility, DANPY-NO@AuNPs can be applied for the spatiotemporal monitoring of in vitro and in vivo NO levels.

Reduction-triggered Disassembly of Organic Cationic Nanorods Produces a Cysteine Protease Mimic (Miravet et†al.).

The emergence of catalytic activity associated with a disassembly process is reported, reminiscent of complex biological systems. A cystine derivative with pendant imidazole groups self-assembles into cationic nanorods in the presence of the cationic surfactants cetylpyridinium chloride (CPC) or cetyltrimethylammonium bromide (CTAB). Disulfide reduction triggers nanorod disassembly and the generation of a simple cysteine protease mimic, which shows a dramatically improved catalytic efficiency in the hydrolysis of p-nitrophenyl acetate (PNPA).

Animal welfare in Latin America: Trends and characteristics of scientific publications.

The present study constitutes a review of the scientific articles about animal welfare in terrestrial farmed animals, published in 19 countries of Latin America. The main objectives were to quantify and characterize articles produced between 1992 and 2021 in farm animals' welfare using "Web of Science [v.5.32]" and "CAB Abstracts" databases. A total of 663 articles were found for the period analyzed, which were mainly in English (87%). The countries with the most publications were Brazil (43%), México (25%), Chile (12%), Uruguay (10%), Colombia (4%) and Argentina (2%). Cattle was the farm species most considered in the publications (41%), and the studies addressed mostly the on-farm production stage (76%). There was a rapid increase in the number of articles published in the last 15 years, accounting for 95% of the publications. This could be related to the publication of welfare standards by the World Organization for Animal Health (WOAH) since 2005, the creation of the Collaborating Center for Animal Welfare and Sustainable Livestock Systems-Chile-Uruguay-México in 2009, a Regional Strategy of Animal Welfare prompted by the WOAH in 2012 and the inclusion of animal welfare in the veterinary curriculum. The fact that most articles were in English shows that Latin American researchers have somehow overcome the challenge of publishing in a non-native language and their research can be read/cited worldwide. However considerable gaps in scientific productivity were identified in comparison to European and North American countries. Scientific research concerning the livestock industry in Latin America faces new challenges arising from the need to move toward more sustainable production systems within the One Welfare and One Health frame.

Photodynamic inactivation of Staphylococcus aureus in the presence of aggregation-prone photosensitizers based on BODIPY used at submicromolar concentrations.

Two new brominated BODIPYs (1 and 2) bearing amino acid-based chains (l-valine for 1, and dimethyl-l-lysine for 2) were synthesized and characterized. In organic solvents, 1 and 2 were fully soluble and showed the photophysical properties expected for brominated BODIPY dyes, including efficient generation of singlet oxygen (1O2), upon irradiation. In contrast, in aqueous media, both compounds were prone to aggregation and the photo-induced generation of 1O2 was halted. Despite the lack of generation of this reactive species in aqueous media (in cuvette), both 1 and 2 have positive antimicrobial Photodynamic Inactivation (aPDI) effect. The activity against gram-positive Staphylococcus aureus and gram-negative Escherichia coli was determined through the inactivation curves, with a total energy dose of 5.3 J/cm2 (white light LED used as an energy source). Compound 2 was highly active against both gram-positive and gram-negative bacteria (3 log CFU/mL reduction was obtained at 0.16 µM for S. aureus and 2.5-5.0 µM for E. coli), whereas 1 was less effective to kill S. aureus (3 log CFU/mL at 0.32 µM) and ineffective for E. coli. The higher efficiency of 2, as compared to 1, to reduce the population of bacteria, can reside in the presence of a protonatable residue in 2, allowing a more effective interaction of this molecule with the cell walls of the microorganisms. In order to explain the lack of reactivity in pure aqueous media (in cuvette) and the contrasting good activity in the presence of bacterial cells it can be hypothesized that upon interaction with the walls of the microorganisms, the aggregated photosensitizers suffer a disaggregation process restoring the ability to generate 1O2, and hence leading to efficient photodynamic activity against these pathogenic microorganisms, in agreement with the similar effect observed recently for porphyrinoid photosensitizers.

Development of a Polymeric Film Entrapping Rose Bengal and Iodide Anion for the Light-Induced Generation and Release of Bactericidal Hydrogen Peroxide.

A series of poly(2-hydroxyethyl methacrylate) (PHEMA) thin films entrapping photosensitizer Rose Bengal (RB) and tetrabutylammonium iodide (TBAI) have been synthetized. The materials have been characterized by means of Thermogravimetric Analysis (TGA), Attenuated Total Reflectance Fourier Transform Infrared Spectroscopy (ATR-FTIR) and UV-vis Absorption spectroscopy. Irradiation of the materials with white light led to the generation of several bactericidal species, including singlet oxygen (1O2), triiodide anion (I3-) and hydrogen peroxide (H2O2). 1O2 production was demonstrated spectroscopically by reaction with the chemical trap 2,2'-(anthracene-9,10-diylbis(methylene))dimalonic acid (ABDA). In addition, the reaction of iodide anion with 1O2 yielded I3- inside the polymeric matrix. This reaction is accompanied by the formation of H2O2, which diffuses out the polymeric matrix. Generation of both I3- and H2O2 was demonstrated spectroscopically (directly in the case of triiodide by the absorption at 360 nm and indirectly for H2O2 using the xylenol orange test). A series of photodynamic inactivation assays were conducted with the synthesized polymers against Gram-negative bacteria Escherichia coli and Pseudomonas aeruginosa. Complete eradication (7 log10 CFU/mL) of both bacteria occurred after only 5 min of white light irradiation (400-700 nm; total energy dose 24 J/cm2) of the polymer containing both RB and TBAI. The control polymer without embedded iodide (only RB) showed only marginal reductions of ca. 0.5 log10 CFU/mL. The main novelty of the present investigation is the generation of three bactericidal species (1O2, I3- and H2O2) at the same time using a single polymeric material containing all the elements needed to produce such a bactericidal cocktail, although the most relevant antimicrobial activity is shown by H2O2. This experimental approach avoids multistep protocols involving a final step of addition of I-, as described previously for other assays in solution.

Enhancement of photoactivity and cellular uptake of (Bu4N)2[Mo6I8(CH3COO)6] complex by loading on porous MCM-41 support. Photodynamic studies as an anticancer agent.

The incorporation by ionic assembly of the hexanuclear molybdenum cluster (Bu4N)2[Mo6I8(CH3CO2)6] (1) in amino-decorated mesoporous silica nanoparticles MCM-41, has yielded the new molybdenum-based hybrid photosensitizer 1@MCM-41. The new photoactive material presents a high porosity, due to the intrinsic high specific surface area of MCM-41 nanoparticles (989 m2 g-1) which is responsible for the good dispersion of the hexamolybdenum clusters on the nanoparticles surface, as observed by STEM analysis. The hybrid photosensitizer can generate efficiently singlet oxygen, which was demonstrated by using the benchmark photooxygenation reaction of 9,10-anthracenediyl-bis(methylene)dimalonic acid (ABDA) in water. The photodynamic therapy activity has been tested using LED light as an irradiation source (λirr ~ 400-700 nm; 15.6 mW/cm2). The results show a good activity of the hybrid photosensitizer against human cervical cancer (HeLa) cells, reducing up to 70 % their viability after 20 min of irradiation, whereas low cytotoxicity is detected in the darkness. The main finding of this research is that the incorporation of molybdenum complexes at porous MCM-41 supports enhances their photoactivity and improves cellular uptake, compared to free clusters.

C. elegans as an Animal Model to Study the Intersection of DNA Repair, Aging and Neurodegeneration.

Since its introduction as a genetic model organism, Caenorhabditis elegans has yielded insights into the causes of aging. In addition, it has provided a molecular understanding of mechanisms of neurodegeneration, one of the devastating effects of aging. However, C. elegans has been less popular as an animal model to investigate DNA repair and genomic instability, which is a major hallmark of aging and also a cause of many rare neurological disorders. This article provides an overview of DNA repair pathways in C. elegans and the impact of DNA repair on aging hallmarks, such as mitochondrial dysfunction, telomere maintenance, and autophagy. In addition, we discuss how the combination of biological characteristics, new technical tools, and the potential of following precise phenotypic assays through a natural life-course make C. elegans an ideal model organism to study how DNA repair impact neurodegeneration in models of common age-related neurodegenerative diseases.

A highly photostable and versatile two-photon fluorescent probe for the detection of a wide range of intracellular nitric oxide concentrations in macrophages and endothelial cells.

Nitric oxide (NO) is involved in many biological processes affecting the cardiovascular, nervous and immune systems. Intracellular NO can be monitored using fluorescent probes in combination with fluorescence imaging techniques. Most of the currently available NO fluorescent molecular probes are excited via one-photon excitation using UV or Vis light, which results in poor penetration and high photodamage to living tissues. Here, we report a two-photon fluorescent molecular probe, DANPY-NO, able to detect NO in live cells. The probe consists of an o-phenylenediamine linked to a naphthalimide core; and operates via photoinduced electron transfer. DANPY-NO exhibits good sensitivity (LOD of 77.8 nM) and high selectivity towards NO, and is stable over a broad range of pHs. The probe targeted acidic organelles within macrophages and endothelial cells, and demonstrated enhanced photostability over a commercially available NO probe. DANPY-NO was used to selectively detect endogenous NO in RAW264.7ϒ NO- macrophages, THP-1 human leukemic cells, primary mouse (bone marrow-derived) macrophages and endothelial cells. The probe was also able to detect exogenous NO in endothelial cells and distinguish between increasing concentrations of NO. The NO detection was evidenced using confocal laser scanning and two-photon microscopies, and flow cytometry. Further evidence was obtained by recording the changes in the intracellular fluorescence emission spectrum of the probe. Importantly, the probe displayed negligible toxicity to the analysed biological samples. The excellent sensitivity, selectivity, stability and versatility of DANPY-NO confirm its potential for in vitro and in vivo imaging of NO.

Context-dependent effects of IL-2 rewire immunity into distinct cellular circuits.

Interleukin 2 (IL-2) is a key homeostatic cytokine, with therapeutic applications in both immunogenic and tolerogenic immune modulation. Clinical use has been hampered by pleiotropic functionality and widespread receptor expression, with unexpected adverse events. Here, we developed a novel mouse strain to divert IL-2 production, allowing identification of contextual outcomes. Network analysis identified priority access for Tregs and a competitive fitness cost of IL-2 production among both Tregs and conventional CD4 T cells. CD8 T and NK cells, by contrast, exhibited a preference for autocrine IL-2 production. IL-2 sourced from dendritic cells amplified Tregs, whereas IL-2 produced by B cells induced two context-dependent circuits: dramatic expansion of CD8+ Tregs and ILC2 cells, the latter driving a downstream, IL-5-mediated, eosinophilic circuit. The source-specific effects demonstrate the contextual influence of IL-2 function and potentially explain adverse effects observed during clinical trials. Targeted IL-2 production therefore has the potential to amplify or quench particular circuits in the IL-2 network, based on clinical desirability.

[Sustained virologic response in patients with hepatitis C and chronic kidney disease]. / Respuesta viral sostenida en pacientes con hepatitis C y enfermedad renal crónica.

Background: Patients with chronic kidney disease (CKD) have a higher prevalence of hepatitis C virus (HCV) infection compared to the general population, and they also present higher morbidity and mortality if they are not treated. Current treatment is based on different direct-acting antiviral (DAA) schemes, which are available in the Mexican health system. However, the efficacy and safety of DAA treatment in patients with CKD on hemodialysis and HCV infection are unknown in Mexican population. Objective: To determine the efficacy through sustained viral response (SVR) and the safety of DAAs in patients with CKD on hemodialysis and chronic HCV infection in the Mexican population. Material and methods: Real-life cohort study. Patients with CKD on hemodialysis and HCV infection treated with DAAs from a third level hospital were included. Descriptive statistics of the clinical characteristics were performed, efficacy was determined by SVR and safety with the global frequency of adverse effects associated with treatment. Results: 25 patients were included. All of them received treatment with glecaprebir/pibrentasvir for 8 weeks. The mean age was 57.8 years and the median time of CKD on hemodialysis was 5 years. 96% of patients had HCV genotype 1B. 100% of the patients presented SVR and the most frequent adverse effects were headache, nausea and fatigue. Conclusions: In the Mexican population studied, patients with HCV and CKD on hemodialysis presented a sustained viral response of 100% with glecaprevir/pibrentasvir with mild adverse effects.

Introducción: los pacientes con enfermedad renal crónica (ERC) tienen una mayor prevalencia de infección por virus de hepatitis C (VHC) en comparación con la población general y presentan mayor morbimortalidad si no se tratan. El tratamiento actual se basa en diferentes esquemas de antivirales de acción directa (ADD), disponibles en el sistema de salud mexicano; sin embargo, se desconoce su eficacia y seguridad en pacientes con ERC en hemodiálisis e infección por VHC en población mexicana. Objetivo: determinar la eficacia mediante respuesta viral sostenida (RVS) y la seguridad de los AAD en pacientes con ERC en hemodiálisis e infección crónica por VHC en población mexicana. Material y métodos: estudio de cohorte de vida real. Se incluyeron pacientes con ERC en hemodiálisis e infección por VHC tratados con AAD en un hospital de tercer nivel. Se usó estadística descriptiva de las características clínicas, se determinó eficacia mediante RVS y seguridad con la frecuencia global de efectos adversos asociados al tratamiento. Resultados: se incluyeron 25 pacientes. Todos recibieron tratamiento con glecaprebir/pibrentasvir durante ocho semanas. La media de edad fue 57.8 años y la mediana de tiempo de ERC en hemodiálisis fue de 5 años. El 96% de los pacientes presentó genotipo 1B de VHC. El 100% de los pacientes presentaron RVS y los efectos adversos más frecuentes fueron cefalea, náuseas y fatiga. Conclusiones: en la población mexicana estudiada, los pacientes con VHC y ERC en hemodiálisis presentaron respuesta viral sostenida del 100% con glecaprevir/pibrentasvir con efectos adversos leves.

Glutathione-responsive molecular nanoparticles from a dianionic bolaamphiphile and their use as carriers for targeted delivery.

The formation in aqueous media of molecular nanoparticles from a bolaamphiphile (SucIleCsa) incorporating a disulfide moiety is described. The particles can be loaded efficiently with the lipophilic mitochondrial marker DiOC6(3), quenching its fluorescence, which is recovered upon reductive particle disassembly. DiOC6(3) transport into human colorectal adenocarcinoma cells (HT-29) is demonstrated using flow cytometry and confocal scanning fluorescence microscopy. A significant increase in intracellular fluorescence is observed when the cells are stimulated to produce glutathione (GSH). These new molecular nanoparticles can be considered a theranostic tool that simultaneously achieves targeted delivery of lipophilic substances and signals high levels of GSH.

Detection of subcellular nitric oxide in mitochondria using a pyrylium probe: assays in cell cultures and peripheral blood.

Fluorescent probes for the detection of intracellular nitric oxide (NO) are abundant, but those targeted to the mitochondria are scarce. Among those molecules targeting mitochondrial NO (mNO), the majority use a triphenylphosphonium (TPP) cation as a vector to reach such organelles. Here we describe a simple molecule (mtNOpy) based on the pyrylium structure, made in a few synthetic steps, capable of detecting selectively NO (aerated medium) over other reactive species. The calculated detection limit for mtNOpy is 88 nM. The main novelty of this probe is that it has a simple molecular architecture and can act both as a fluorogenic and as a mitochondriotropic agent, without using TPP. mtNOpy has been tested in two different scenarios: (a) in a controlled environment of cell line cultures (human colon carcinoma HT-29 cells and mouse macrophage RAW 264.7 cells), using confocal laser scanning microscopy, and (b) on a much more complex sample of peripheral blood, using flow cytometry. In the first context, mtNOpy has been found to be responsive (turn-on fluorescence) to exogenous and endogenous NO stimuli (via SNAP donor and LPS stimulation, respectively). In the second area, mtNOpy has been able to discriminate between NO-generating phagocytes (neutrophils and monocytes) from other leukocytes (NK, B and T cells).

Fluorescent styrylpyrylium probes for the imaging of mitochondria in live cells.

Eight styrylpyrylium tetrafluoroborate salts have been synthesized and fully optically characterized by UV-vis absorption and fluorescence steady-state/time-resolved spectroscopies. The new dyes exhibit strong emission bands with yellow-orange colours, depending on the substituents present in the structure. Notably, the Stokes shift recorded for some of them exceeds 100 nm, a very valuable feature for biological imaging. Four of them have been assayed as biological imaging agents by confocal laser scanning microscopy (CLSM) in the human hepatoma cell line Hep3B. It has been found that all the compounds efficiently stain intracellular structures which have been identified as mitochondria through colocalization assays with MitoView (a well-known mitochondrial marker) and using carbonyl cyanide m-chlorophenyl hydrazone (CCCP) as a mitochondrial membrane potential uncoupler. Additionally, the potential ability of the studied dyes as cytotoxic drugs has been explored. The inhibitory concentration (IC50) against Hep3B was found to be in the range of 4.2 µM-11.5 µM, similar to other described anticancer drugs for the same hepatoma cell line. The combined features of a good imaging agent and potential anticancer drug make the family of the studied pyrylium salts good candidates for further theranostic studies. Remarkably, despite the extensive use of pyrylium dyes in several scientific areas (from photocatalysis to optics), there is no precedent description of a styrylpyrylium salt with potential theranostic applications.

Photoreversible formation of nanotubes in water from an amphiphilic azobenzene derivative.

An anionic azobenzene-appended derivative of L-ValylGlycine self-assembles into nanotubes in water. Irradiation with 365 nm light provokes trans-cis isomerization of the azobenzene unit and subsequent tube disassembly. Thermal or photoinduced (457 nm light) recovery of the trans isomer restores the nanotubes.

Base excision repair causes age-dependent accumulation of single-stranded DNA breaks that contribute to Parkinson disease pathology.

Aging, genomic stress, and mitochondrial dysfunction are risk factors for neurodegenerative pathologies, such as Parkinson disease (PD). Although genomic instability is associated with aging and mitochondrial impairment, the underlying mechanisms are poorly understood. Here, we show that base excision repair generates genomic stress, promoting age-related neurodegeneration in a Caenorhabditis elegans PD model. A physiological level of NTH-1 DNA glycosylase mediates mitochondrial and nuclear genomic instability, which promote degeneration of dopaminergic neurons in older nematodes. Conversely, NTH-1 deficiency protects against α-synuclein-induced neurotoxicity, maintaining neuronal function with age. This apparent paradox is caused by modulation of mitochondrial transcription in NTH-1-deficient cells, and this modulation activates LMD-3, JNK-1, and SKN-1 and induces mitohormesis. The dependance of neuroprotection on mitochondrial transcription highlights the integration of BER and transcription regulation during physiological aging. Finally, whole-exome sequencing of genomic DNA from patients with idiopathic PD suggests that base excision repair might modulate susceptibility to PD in humans.