Understanding Pressure Effects on Structural, Optical, and Magnetic Properties of CsMnF4 and Other 3dn Compounds.

The pressure dependence of structural, optical, and magnetic properties of the layered compound CsMnF4 are explored through first-principles calculations. The structure at ambient pressure does not arise from a Jahn-Teller effect but from an orthorhombic instability on MnF63- units in the tetragonal parent phase, while there is a P4/n → P4 structural phase transition at P = 40 GPa discarding a spin crossover transition from S = 2 to S = 1. The present results reasonably explain the evolution of spin-allowed d-d transitions under pressure, showing that the first transition undergoes a red-shift under pressure following the orthorhombic distortion in the layer plane. The energy of such a transition at zero pressure is nearly twice that observed in Na3MnF6 due to the internal electric field and the orthorhombic distortion also involved in K2CuF4. The reasons for the lack of orthorhombic distortion in K2MF4 (M = Ni, Mn) or CsFeF4 are also discussed in detail. The present calculations confirm the ferromagnetic ordering of layers in CsMnF4 at zero pressure and predict a shift to an antiferromagnetic phase for pressures above 15 GPa consistent with the reduction of the orthorhombicity of the MnF63- units. This study underlines the usefulness of first-principles calculations for a right interpretation of experimental findings.

Asymmetric multi-task learning for interpretable gaze-driven grasping action forecasting.

This work tackles the problem of automatically predicting the grasping intention of humans observing their environment, with eye-tracker glasses and video cameras recording the scene view. Our target application is the assistance to people with motor disabilities and potential cognitive impairments, using assistive robotics. Our proposal leverages the analysis of human attention captured in the form of gaze fixations recorded by an eye-tracker on the first person video, as the anticipation of prehension actions is a well studied and well known phenomenon. We propose a multi-task system that simultaneously addresses the prediction of human attention in the near future, and the anticipation of grasping actions. In our model, visual attention is modeled as a competitive process between a discrete set of states, each one associated to a well-known gaze movement pattern from visual psychology. We additionally consider an asymmetric multitask problem, where attention modeling is an auxiliary task that helps to regularize the learning process of the main action prediction task, and propose a constrained multi-task loss that naturally deals with this asymmetry. Our model shows superior performance than other losses for dynamic multi-task learning, current dominant deep architectures for general action forecasting and particularly-tailored models for predicting grasping intention. In particular, it provides state-of-the-art performance in three datasets for egocentric action anticipation, with an average precision of 0.569 and 0.524 in GITW and Sharon datasets, respectively, and an accuracy of 89.2% and a success rate of 51.7% in Invisible dataset.

Molecular pathways in mitochondrial disorders due to a defective mitochondrial protein synthesis.

Mitochondria play a central role in cellular metabolism producing the necessary ATP through oxidative phosphorylation. As a remnant of their prokaryotic past, mitochondria contain their own genome, which encodes 13 subunits of the oxidative phosphorylation system, as well as the tRNAs and rRNAs necessary for their translation in the organelle. Mitochondrial protein synthesis depends on the import of a vast array of nuclear-encoded proteins including the mitochondrial ribosome protein components, translation factors, aminoacyl-tRNA synthetases or assembly factors among others. Cryo-EM studies have improved our understanding of the composition of the mitochondrial ribosome and the factors required for mitochondrial protein synthesis and the advances in next-generation sequencing techniques have allowed for the identification of a growing number of genes involved in mitochondrial pathologies with a defective translation. These disorders are often multisystemic, affecting those tissues with a higher energy demand, and often present with neurodegenerative phenotypes. In this article, we review the known proteins required for mitochondrial translation, the disorders that derive from a defective mitochondrial protein synthesis and the animal models that have been established for their study.

Acute Responses to Different Velocity Loss Thresholds during Squat Exercise with Blood-Flow Restriction in Strength-Trained Men.

(1) Background: The aim of this paper is to analyze the acute effects of different velocity loss (VL) thresholds during a full squat (SQ) with blood-flow restriction (BFR) on strength performance, neuromuscular activity, metabolic response, and muscle contractile properties. (2) Methods: Twenty strength-trained men performed four protocols that differed in the VL achieved within the set (BFR0: 0% VL; BFR10: 10% VL; BFR20: 20% VL; and BFR40: 40% VL). The relative intensity (60% 1RM), recovery between sets (2 min), number of sets (3), and level of BFR (50% of arterial occlusion pressure) were matched between protocols. Tensiomyography (TMG), blood lactate, countermovement jump (CMJ), maximal voluntary isometric SQ contraction (MVIC), and performance with the absolute load required to achieve 1 m·s-1 at baseline measurements in SQ were assessed before and after the protocols. (3) Results: BFR40 resulted in higher EMG alterations during and after exercise than the other protocols (p < 0.05). BFR40 also induced greater impairments in TMG-derived variables and BFR10 decreased contraction time. Higher blood lactate concentrations were found as the VL within the set increased. BFR0 and BFR10 showed significantly increased median frequencies in post-exercise MVIC. (4) Conclusions: High VL thresholds (BFR40) accentuated metabolic and neuromuscular stress, and produced increased alterations in muscles' mechanical properties. Low VL could potentiate post-exercise neuromuscular activity and muscle contractile properties.

Strain-Phonon Cooperation as a Necessary Ingredient to Understand the Jahn-Teller Effect in Solids.

Spatial degeneracy is the cause of the complex electronic, geometrical, and magnetic structures found in a number of materials whose more representative example is KCuF3. In the literature the properties of this lattice are usually explained through the Kugel--Khomskii model, based on superexchange interactions. Here we provide rigorous theoretical and computational arguments against this view proving that structural and magnetic properties essentially arise from electron-vibration (vibronic) interactions. Moreover, based on the work of Öpik and Pryce, we show that the coupling between lattice (homogeneous strain) and motif (phonons) distortions is essential to understand the main stable configurations of the lattice. Using this information, we predict a new low-energy phase in KCuF3 that could strongly alter its properties and provide guidance on how to stabilize it through strain engineering.

Mediation effect of body mass index on the association between serum magnesium level and insulin resistance in children from Mexico City.

BACKGROUND/OBJECTIVES: Reduced serum magnesium (Mg) levels have been associated with obesity, insulin resistance (IR), type 2 diabetes, and metabolic syndrome in adults. However, in the children population, the evidence is still limited. In this cross-sectional study, we aimed to analyze the association of serum Mg levels with the frequency of overweight and obesity and cardiometabolic traits in 189 schoolchildren (91 girls and 98 boys) between 6 and 12 years old from Mexico City. SUBJECTS/METHODS: Anthropometrical data were collected and biochemical parameters were measured by enzymatic colorimetric assay. Serum Mg level was analyzed by inductively coupled plasma mass spectrometry (ICP-MS). The triglyceride-glucose (TyG) index was used as a surrogate marker to evaluate IR. RESULTS: Serum Mg level was negatively associated with overweight (Odds ratio [OR] = 0.377, 95% confidence interval [CI] 0.231-0.614, p < 0.001) and obesity (OR = 0.345, 95% CI 0.202-0.589, p < 0.001). Serum Mg level resulted negatively associated with body mass index (BMI, ß = -1.16 ± 0.26, p < 0.001), BMI z-score (ß = -0.48 ± 0.10, p < 0.001) and TyG index (ß = -0.04 ± 0.04, p = 0.041). Through a mediation analysis was estimated that BMI z-score accounts for 60.5% of the negative association of serum Mg level with IR (Sobel test: z = 2.761; p = 0.005). CONCLUSION: Our results evidence that BMI z-score mediate part of the negative association of serum Mg level and IR in Mexican schoolchildren.

Overweight, Obesity, Hypertriglyceridemia, and Insulin Resistance Are Positively Associated with High Serum Copper Levels in Mexican Adults.

Recently, the role of trace elements in the pathophysiology of obesity, insulin resistance (IR), and metabolic diseases has been explored. In this cross-sectional study, we aimed to assess the association of overweight, obesity, and cardiometabolic traits with serum copper (Cu) levels in 346 Mexican adults. Serum Cu level was measured by inductively coupled plasma mass spectrometry (ICP-MS). Anthropometrical data were collected, and biochemical parameters were measured. The triglyceride-glucose (TyG) index was used as a surrogate marker to evaluate IR. Overweight and obesity status was positively associated with the serum Cu level (ß = 19.434 ± 7.309, p = 0.008). Serum Cu level was observed to have a positive association with serum triglycerides level (ß = 0.160 ± 0.045, p < 0.001) and TyG (ß = 0.001 ± 0.001, p < 0.001). Additionally, high serum Cu level was positively associated with overweight and obesity status (odds ratio [OR] = 1.9, 95% confidence interval [95% CI] 1.1-3.4, p = 0.014), hypertriglyceridemia (OR = 3.0, 95% CI 1.7-5.3, p < 0.001), and IR (OR = 2.6, 95% CI 1.4-4.6, p = 0.001). In conclusion, our results suggest that overweight, obesity, hypertriglyceridemia, and IR are positively associated with serum Cu levels in Mexican adults.

Genetic variability of Aedes aegypti (Diptera: Culicidae) in El Salvador and Honduras: presence of a widespread haplotype and implications for mosquito control.

BACKGROUND: This study examined population genetics of Aedes aegypti in El Salvador and Honduras, two adjacent countries in Central America. Aedes aegypti is associated with yellow fever, dengue, chikungunya, and Zika. Each year, thousands of cases of dengue are typically reported in El Salvador and Honduras. METHODS: In El Salvador, collections were obtained from five Departments. In Honduras, samples were obtained from six municipalities in four Departments. Mitochondrial DNA cytochrome oxidase I (COI) was sequenced, and consensus sequences were combined with available sequences from El Salvador to determine haplotype number, haplotype diversity, nucleotide diversity, and Tajima's D. A haplotype network was produced to examine the relationship between genotypes. RESULTS: In El Salvador, there were 17 haplotypes, while in Honduras there were 4 haplotypes. In both El Salvador and Honduras, Haplotype 1 is most abundant and widespread. In El Salvador, haplotype H2 was also widespread in 10 of 11 sampled municipalities, but it was not present in Honduras. The capital of El Salvador (San Salvador) and the eastern region of ES had the highest haplotype diversity of regions sampled. CONCLUSIONS: Haplotype 1 and H2 each belong to different phylogenetic lineages of Ae. aegypti. The most geographically widespread haplotype (H1) may have been present the longest and could be a remnant from previous eradication programs. These data may contribute to future control programs for Ae. aegypti in the two countries.

Chemical Bonding, 10Dq Parameter and Superexchange in the Model Compound KNiF3.

The cubic field splitting parameter, 10Dq, plays a central role in the ligand field theory on insulating transition metal compounds. Experimental data obtained in the last 50 years prove that 10Dq is highly dependent on changes of the metal-ligand distance, R, induced by chemical or applied pressures. Despite this fact has important consequences on optical and magnetic properties of such compounds, its actual origin is still controversial. Seeking to clarify that crucial issue, this work is focused on KNiF3, a reference system among insulating transition metal compounds. By means of first principles calculations we show that, contrary to what is usually thought, the R-dependence of 10Dq arises neither from the crystal field contribution nor from the covalent admixture of 3d(Ni) with valence 2p(F) orbitals. Indeed, we prove that it is mainly due to the residual covalency with deep 2s(F) orbitals, highly sensitive to R variations. As a salient feature the present calculations show that the 3d-2pσ and 3d-2pπ admixtures raise practically equal the energy of antibonding eg and t2g orbitals of NiF6 4- units in KNiF3 thus leading to a null contribution to 10Dq. This conclusion is not significantly altered when considering the change of covalency on passing from the ground state 3A2(t2g 6eg 2) to the excited state 3T2(t2g 5eg 3). The different influence of chemical bonding on the superexchange constant, J, and 10Dq is also discussed in a second step. It is pointed out that the strong dependence of J upon R can hardly be explained through the behavior of the 3d-2pσ covalency derived for a single NiF6 4- unit. For the sake of clarity, the meaning of 10Dq is also briefly analyzed.

Obesity Is Associated with Oxidative Stress Markers and Antioxidant Enzyme Activity in Mexican Children.

The relationship between metabolic disorders and oxidative stress is still controversial in the child population. The present cross-sectional study aimed to analyze the associations between obesity, cardiometabolic traits, serum level of carbonylated proteins (CPs), malondialdehyde (MDA), and the enzyme activity of catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) in children from Mexico City (normal weight: 120; obesity: 81). Obesity resulted in being positively associated with CAT (ß = 0.05 ± 0.01, p = 5.0 × 10-3) and GPx (ß = 0.13 ± 0.01, p = 3.7 × 10-19) enzyme activity. A significant interaction between obesity and sex was observed in MDA and SOD enzymatic activity (PMDA = 0.03; PSOD = 0.04). The associations between obesity, MDA level, and SOD enzyme activity were only significant in boys (boys: PMDA = 3.0 × 10-3; PSOD = 7.0 × 10-3; girls: p ≥ 0.79). In both children with normal weight and those with obesity, CP levels were positively associated with SOD enzyme activity (PNormal-weight = 2.2 × 10-3; PObesity = 0.03). In conclusion, in Mexican children, obesity is positively associated with CAT and GPx enzyme activity, and its associations with MDA levels and SOD enzyme activity are sex-specific. Therefore, CP level is positively related to SOD enzyme activity independently of body weight.

Biochelates from Spent Coffee Grounds Increases Iron Levels in Dutch Cucumbers but Affects Their Antioxidant Capacity.

Spent coffee grounds (SCG) are a type of food waste and are produced in abundance around the world. However, their utilization as a soil organic amendment is challenging due to their phytotoxic effect. In the present work, the impact of agronomic biofortification on Dutch cucumbers was investigated using different chemically modified SCG and analyzing their effects on iron contents, their capacity for releasing antioxidants, and the production of short-chain fatty acids after in vitro digestion-fermentation. The results indicated variations in the iron contents and chemical compositions of cucumbers according to the treatment groups. Functionalized and activated hydrochar from SCG increased Fe levels in cucumbers. Although activated hydrochar obtained at 160 °C and functionalized with Fe showed the highest iron supply per serving, differences in antioxidant capacity and short-chain fatty acid production were observed between the groups. It is concluded that growing conditions and the presence of iron may significantly influence the contribution of these cucumbers to the dietary intake of nutrients and antioxidants, which could have important implications for human health and nutrition.

Implementing a Bundle for Evidence-based Cesarean Delivery May Not Be As Beneficial as Expected: A Multi-center, Pre- and Post- Study.

BACKGROUND: Standardization of procedures improves outcomes. Though systematic reviews have summarized the evidence-based steps (EBS) of cesarean delivery (CD), their bundled implementation has not been investigated. OBJECTIVE: In this pre- and post-implementation trial, we sought to ascertain if bundled EBS of CD, compared to surgeon's preference, improves outcomes. STUDY DESIGN: A StaRI (Standards for Reporting Implementation Studies) compliant, multi-center pre- and post-implementation trial at 4 teaching hospitals was conducted. The pre-implementation period consisted of CD done based on the physicians' preferences for 3 months; educational intervention (e.g., didactics, badge cards, posters, video) occurred at the 4th month. CDs in post-implementation period employed the bundled EBS. A pre-planned 10% randomized audit of both groups assessed adherence and uptake of EBS. The primary outcome was a composite maternal morbidity (CMM), which included estimated blood loss > 1,000 mL, blood transfusion, endometritis, post-partum fever, wound complications, sepsis, thrombosis, ICU admission, hysterectomy, or death. The secondary outcome was a composite neonatal morbidity (CNM) and some of its components were 5-min Apgar score < 7, positive pressure oxygen use, hypoglycemia, or sepsis. A priori Bayesian sample size calculation indicated 700 CD in each group was needed to demonstrate 20% relative reduction (from 15% to 12%) of CMM with 75% certainty. Bayesian logistic regression with neutral priors was used to calculate likelihood of net-improvement in adjusted relative risk (aRR) with 95% credible intervals (CrI). RESULTS: A total of 1,425 consecutive CD (721 in pre- and 704 in post-implementation group) were examined. Audited data indicated that the baseline EBS utilization rate during the pre-implementation period was 79%; after the implementation bundled EBS of CD the audited adherence was 89%-an uptake of 10.0% of the EBS. In four aspects, the maternal characteristics differed significantly in the pre- and post-implementation periods: race/ethnicity, hypertensive disorder, and the relative contribution of the 4 centers to the cohorts and the gestational age at delivery, but the indications for CD and whether its duration was < versus > 60 min did not. The rates of CMM in the pre- and post-implementation groups were 26% and 22%, respectively (aRR, 0.88; 95% CrI, 0.73-1.04), with a 94 % Bayesian probability of a reduction in CMM. The CNM occurred in 37% of the pre- and in 41% of the post-implementation group (aRR, 1.12; 95% CrI 0.98-1.39), with a 95% Bayesian probability of worsening in CNM. When CMM were segregated by preterm (<37 wks) and term (> 37 weeks) CD, the improvement in maternal outcomes persisted; when CNM were segregated by gestational age subgroupsthe potential for worsening neonatal outcomes persisted as well. CONCLUSIONS: Standardization of the evidence-based bundled steps of cesarean delivery resulted in a modest reduction of the composite maternal outcome; however, a paradoxical increase in neonatal composite morbidity was noted. Although individual evidence-based steps may be of value, while awaiting additional intervention trials a formal bundling of such steps is currently not recommended.

Retromer-mediated recruitment of the WASH complex involves discrete interactions between VPS35, VPS29, and FAM21.

Endosomal trafficking ensures the proper distribution of lipids and proteins to various cellular compartments, facilitating intracellular communication, nutrient transport, waste disposal, and the maintenance of cell structure. Retromer, a peripheral membrane protein complex, plays an important role in this process by recruiting the associated actin-polymerizing WASH complex to establish distinct sorting domains. The WASH complex is recruited through the interaction of the VPS35 subunit of retromer with the WASH complex subunit FAM21. Here, we report the identification of two separate fragments of FAM21 that interact with VPS35, along with a third fragment that binds to the VPS29 subunit of retromer. The crystal structure of VPS29 bound to a peptide derived from FAM21 shows a distinctive sharp bend that inserts into a conserved hydrophobic pocket with a binding mode similar to that adopted by other VPS29 effectors. Interestingly, despite the network of interactions between FAM21 and retromer occurring near the Parkinson's disease-linked mutation (D620N) in VPS35, this mutation does not significantly impair the direct association with FAM21 in vitro.

Zn Biofortification of Dutch Cucumbers with Chemically Modified Spent Coffee Grounds: Zn Enrichment and Nutritional Implications.

Spent coffee grounds (SCGs) are a food waste with a large generation around the world. However, their utilization as a soil organic amendment is difficult due to their phytotoxic effect. In the present work, the impact of agronomic biofortification on Dutch cucumbers was studied by using different chemically modified SCGs, analyzing their effects on Zn content, the release of antioxidant capacity and the production of short-chain fatty acids after in vitro digestion-fermentation. The results indicated variations in the Zn content and chemical composition of cucumbers according to the treatment groups. The functionalized with Zn and activated SCGs were able to increase Zn levels in cucumbers. Meanwhile, the activated hydrochar obtained at 160 °C and the activated and functionalized with Zn SCGs showed the highest Zn supply per serving. Differences in the antioxidant capacity and short-chain fatty acid production were observed between the groups. It is concluded that the growing conditions and the presence of Zn may significantly influence the contribution of these cucumbers to the dietary intake of nutrients and antioxidants, which could have important implications for human health and nutrition.

[Use of clinical ultrasound in primary care: Multicenter prospective study]. / Uso de la ecografía clínica en Atención Primaria. Estudio prospectivo multicéntrico.

OBJECTIVE: The objective was to describe the characteristics of the use of clinical ultrasound in two health centers (SC) of Health Area VII of the Region of Murcia (CS Murcia-Sur and CS Floridablanca). DESIGN: Observational, descriptive, longitudinal, prospective and multicenter study. SITE: CS Murcia-Sur and CS Floridablanca (Health Area VII of the Region of Murcia). PARTICIPANTS: One hundred and thirty-five patients were included. INTERVENTIONS: Performance of clinical ultrasound in the primary care (PC) consultation. MAIN MEASUREMENTS: Demographic variables (age, sex), as well as clinical variables (reason for consultation, type of ultrasound, results, referrals to the second hospital level, degree of diagnostic agreement) were collected. RESULTS: One hundred and thirty-five patients were included, more than 50% were female. The main reason for consultation was musculoskeletal and soft tissue symptoms (44.4%), followed by digestive symptoms (21.5%). 44.4% of the ultrasounds were classified as normal, while pathological findings were found in 55.6%. Confirmatory tests were requested in 43.7% and the findings were confirmed in 67% of the patients. CONCLUSIONS: The use of ultrasound in PC allows to show the high prevalence of pathological findings in the examination of patients. In a technique that helps the clinician in his diagnostic-therapeutic process. The integration of clinical ultrasound in the PC consultation can save complementary studies and referrals to a second level of care. Its implementation in PC requires proper training of professionals.

SARS-CoV-2 Vaccine-Elicited Immunity after B Cell Depletion in Multiple Sclerosis.

The impact of B cell deficiency on the humoral and cellular responses to SARS-CoV2 mRNA vaccination remains a challenging and significant clinical management question. We evaluated vaccine-elicited serological and cellular responses in 1) healthy individuals who were pre-exposed to SARS-CoV-2 (n = 21), 2) healthy individuals who received a homologous booster (mRNA, n = 19; or Novavax, n = 19), and 3) persons with multiple sclerosis on B cell depletion therapy (MS-αCD20) receiving mRNA homologous boosting (n = 36). Pre-exposure increased humoral and CD4 T cellular responses in immunocompetent individuals. Novavax homologous boosting induced a significantly more robust serological response than mRNA boosting. MS-α CD20 had an intact IgA mucosal response and an enhanced CD8 T cell response to mRNA boosting compared with immunocompetent individuals. This enhanced cellular response was characterized by the expansion of only effector, not memory, T cells. The enhancement of CD8 T cells in the setting of B cell depletion suggests a regulatory mechanism between B and CD8 T cell vaccine responses.

GrimAge is elevated in older adults with mild COVID-19 an exploratory analysis.

COVID-19 has been contained; however, the side effects associated with its infection continue to be a challenge for public health, particularly for older adults. On the other hand, epigenetic status contributes to the inter-individual health status and is associated with COVID-19 severity. Nevertheless, current studies focus only on severe COVID-19. Considering that most of the worldwide population developed mild COVID-19 infection. In the present exploratory study, we aim to analyze the association of mild COVID-19 with epigenetic ages (HorvathAge, HannumAge, GrimAge, PhenoAge, SkinAge, and DNAmTL) and clinical variables obtained from a Mexican cohort of older adults. We found that all epigenetic ages significantly differ from the chronological age, but only GrimAge is elevated. Additionally, both the intrinsic epigenetic age acceleration (IEAA) and the extrinsic epigenetic age acceleration (EEAA) are accelerated in all patients. Moreover, we found that immunological estimators and DNA damage were associated with PhenoAge, SkinBloodHorvathAge, and HorvathAge, suggesting that the effects of mild COVID-19 on the epigenetic clocks are mainly associated with inflammation and immunology changes. In conclusion, our results show that the effects of mild COVID-19 on the epigenetic clock are mainly associated with the immune system and an increase in GrimAge, IEAA, and EEAA.

URI-CADS: A Fully Automated Computer-Aided Diagnosis System for Ultrasound Renal Imaging.

Ultrasound is a widespread imaging modality, with special application in medical fields such as nephrology. However, automated approaches for ultrasound renal interpretation still pose some challenges: (1) the need for manual supervision by experts at various stages of the system, which prevents its adoption in primary healthcare, and (2) their limited considered taxonomy (e.g., reduced number of pathologies), which makes them unsuitable for training practitioners and providing support to experts. This paper proposes a fully automated computer-aided diagnosis system for ultrasound renal imaging addressing both of these challenges. Our system is based in a multi-task architecture, which is implemented by a three-branched convolutional neural network and is capable of segmenting the kidney and detecting global and local pathologies with no need of human interaction during diagnosis. The integration of different image perspectives at distinct granularities enhanced the proposed diagnosis. We employ a large (1985 images) and demanding ultrasound renal imaging database, publicly released with the system and annotated on the basis of an exhaustive taxonomy of two global and nine local pathologies (including cysts, lithiasis, hydronephrosis, angiomyolipoma), establishing a benchmark for ultrasound renal interpretation. Experiments show that our proposed method outperforms several state-of-the-art methods in both segmentation and diagnosis tasks and leverages the combination of global and local image information to improve the diagnosis. Our results, with a 87.41% of AUC in healthy-pathological diagnosis and 81.90% in multi-pathological diagnosis, support the use of our system as a helpful tool in the healthcare system.

Targeting cancer stem cell OXPHOS with tailored ruthenium complexes as a new anti-cancer strategy.

BACKGROUND: Previous studies by our group have shown that oxidative phosphorylation (OXPHOS) is the main pathway by which pancreatic cancer stem cells (CSCs) meet their energetic requirements; therefore, OXPHOS represents an Achille's heel of these highly tumorigenic cells. Unfortunately, therapies that target OXPHOS in CSCs are lacking. METHODS: The safety and anti-CSC activity of a ruthenium complex featuring bipyridine and terpyridine ligands and one coordination labile position (Ru1) were evaluated across primary pancreatic cancer cultures and in vivo, using 8 patient-derived xenografts (PDXs). RNAseq analysis followed by mitochondria-specific molecular assays were used to determine the mechanism of action. RESULTS: We show that Ru1 is capable of inhibiting CSC OXPHOS function in vitro, and more importantly, it presents excellent anti-cancer activity, with low toxicity, across a large panel of human pancreatic PDXs, as well as in colorectal cancer and osteosarcoma PDXs. Mechanistic studies suggest that this activity stems from Ru1 binding to the D-loop region of the mitochondrial DNA of CSCs, inhibiting OXPHOS complex-associated transcription, leading to reduced mitochondrial oxygen consumption, membrane potential, and ATP production, all of which are necessary for CSCs, which heavily depend on mitochondrial respiration. CONCLUSIONS: Overall, the coordination complex Ru1 represents not only an exciting new anti-cancer agent, but also a molecular tool to dissect the role of OXPHOS in CSCs. Results indicating that the compound is safe, non-toxic and highly effective in vivo are extremely exciting, and have allowed us to uncover unprecedented mechanistic possibilities to fight different cancer types based on targeting CSC OXPHOS.