Breed and non-genetic risk factors associated with the prevalence of subclinical mastitis in livestock systems of Arauca, Colombian orinoquia.

Subclinical Mastitis (SCM) is caused by several factors associated with the interaction of the individual cow, cow management, and the environment. The aim of this study was to assess the breed and non-genetic risk factors on the prevalence of SCM in cows from the dual-purpose livestock system on the floodplain of Arauca, Colombian Orinoquia. Milk samples were taken from the individual mammary quarters of 481 cows representing 28 different farms where the electrical conductivity (EC) test applied. To determine the factors associated with SCM, a multiple logistic regression analysis was used. The response variable was the SCM presence (1), or absence (0) obtained with the EC test. Breed was included as a genetic risk factor, and as non- genetic risk factors: number of cows in production, daily milk production, lactation month, cow age, climatic period, body condition, and calving number. The factors that were significantly associated with the SCM presence were body condition, climatic period, and breed (p < 0.05). Odds ratio (OR) analysis of significant effects indicates that for each unit increase in body condition, the OR of having animals with SCM is reduced by 71%. In the dry period the OR of animals with SCM increases by 150% compared to the rainy period. Composite breeds reduce the OR of SCM animals by 73%, compared with Indicus-predominance animals. In this study, the occurrence of SCM in extensive management systems in Arauca, Colombian Orinoquia, is determined by the risk factors of breed, climatic period, and body condition.

High-throughput virtual search of small molecules for controlling the mechanical stability of human CD4.

Protein mechanical stability determines the function of a myriad of proteins, especially proteins from the extracellular matrix. Failure to maintain protein mechanical stability may result in diseases and disorders such as cancer, cardiomyopathies, or muscular dystrophy. Thus, developing mutation-free approaches to enhance and control the mechanical stability of proteins using pharmacology-based methods may have important implications in drug development and discovery. Here, we present the first approach that employs computational high-throughput virtual screening and molecular docking to search for small molecules in chemical libraries that function as mechano-regulators of the stability of human cluster of differentiation 4, receptor of HIV-1. Using single-molecule force spectroscopy, we prove that these small molecules can increase the mechanical stability of CD4D1D2 domains over 4-fold in addition to modifying the mechanical unfolding pathways. Our experiments demonstrate that chemical libraries are a source of mechanoactive molecules and that drug discovery approaches provide the foundation of a new type of molecular function, that is, mechano-regulation, paving the way toward mechanopharmacology.

Environmental and Breed Risk Factors Associated with the Prevalence of Subclinical Mastitis in Dual-Purpose Livestock Systems in the Arauca Floodplain Savannah, Colombian Orinoquia.

The aim of this study was to assess the environmental and breed risk factors associated with the prevalence of subclinical mastitis (SCM) in cows in the dual-purpose livestock system of Arauca, Colombian Orinoquia. Milk samples were taken from 1924 mammary quarters, corresponding to 481 cows on 28 different farms, and the California Mastitis Test (CMT) was applied. Risk factors associated with SCM were determined using multiple logistic regression analysis. The response variable was the presence (1) or absence (0) of SCM. Breed was included as a genetic risk factor, and daily milk production, number of cows in production, lactation month, calving number, cow age, climatic period, and body condition were included as environmental risk factors. The analysis of the odds ratio (OR) of significant effects indicated that the factors significantly associated with the presence of SCM were the number of cows (OR = 2.29; p = 0.005), milk production (OR = 0.88; p = 0.045), and the Taurus-Indicus breeds (OR = 1.79; p = 0.009) and composite breed (OR = 3.95; p = 0.005). In this study, the occurrence of SCM was determined by the following risk factors: number of cows, milk production, and breed. Likewise, the highest prevalence seemed to occur on farms with less technological development and sanitary management of producers from the lowest socioeconomic stratum.

Evolution of CRISPR-associated endonucleases as inferred from resurrected proteins.

Clustered regularly interspaced short palindromic repeats (CRISPR)-associated Cas9 is an effector protein that targets invading DNA and plays a major role in the prokaryotic adaptive immune system. Although Streptococcus pyogenes CRISPR-Cas9 has been widely studied and repurposed for applications including genome editing, its origin and evolution are poorly understood. Here, we investigate the evolution of Cas9 from resurrected ancient nucleases (anCas) in extinct firmicutes species that last lived 2.6 billion years before the present. We demonstrate that these ancient forms were much more flexible in their guide RNA and protospacer-adjacent motif requirements compared with modern-day Cas9 enzymes. Furthermore, anCas portrays a gradual palaeoenzymatic adaptation from nickase to double-strand break activity, exhibits high levels of activity with both single-stranded DNA and single-stranded RNA targets and is capable of editing activity in human cells. Prediction and characterization of anCas with a resurrected protein approach uncovers an evolutionary trajectory leading to functionally flexible ancient enzymes.

Net CO2 assimilation rate response of tomato seedlings (Solanum lycopersicum L.) to the interaction between light intensity, spectrum and ambient CO2 concentration.

Artificial lighting is complementary and single-source lighting for controlled Environment Agriculture (CEA) to increase crop productivity. Installations to control CO2 levels and luminaires with variable spectrum and intensity are becoming increasingly common. In order to see the net assimilation of CO2 based on the relationship between the three factors: intensity, spectrum and CO2 concentration, tests are proposed on tomatoes seedling with combinations of ten spectra (100B, 80B20G, 20B80G, 100G, 80G20R, 20G80R, 100R, 80R20B, 20R80B, 37R36G27B) seven light intensities (30, 90, 200, 350, 500, 700 and 1000 µmol·m-2 s-1) and nine CO2 concentrations (200, 300, 400, 500, 600, 700, 800 and 900 ppm). These tomato seedlings grew under uniform conditions with no treatments applied up to the moment of measurement by a differential gas analyzer. We have developed a model to evaluate and determine under what spectrum and intensity of light photosynthesis the Net assimilation of CO2 (An) is more significant in the leaves of tomato plants, considering the CO2 concentration as an independent variable in the model. The evaluation of the model parameters for each spectrum and intensity shows that the intensity has a more decisive influence on the maximum An rate than the spectra. For intensities lower than 350 µmol·m-2 s-1, it is observed that the spectrum has a greater influence on the variable An. The spectra with the best behaviour were 80R20B and 80B20R, which maintained An values between 2 and 4 (µmol CO2·m-2·s-1) above the spectra with the worst behaviour (100G, 80G20R, 20G80R and 37B36G27R) in practically all situations. Photosynthetic Light-Use Efficiency (PLUE) was also higher for the 80B20R and 20R80B spectra with values of 36,07 and 33,84 mmol CO2·mol photon-1, respectively, for light intensities of 200 µmol·m-2 s-1 and 400 ppm of CO2that increased to values of 49,65 and 48,38 mmol CO2·mol photon-1 for the same light intensity and concentrations of 850 ppm. The choice of spectrum is essential, as indicated by the data from this study, to optimize the photosynthesis of the plant species grown in the plant factory where light intensities are adjusted for greater profitability.

Basal oxidation of conserved cysteines modulates cardiac titin stiffness and dynamics.

Titin, as the main protein responsible for the passive stiffness of the sarcomere, plays a key role in diastolic function and is a determinant factor in the etiology of heart disease. Titin stiffness depends on unfolding and folding transitions of immunoglobulin-like (Ig) domains of the I-band, and recent studies have shown that oxidative modifications of cryptic cysteines belonging to these Ig domains modulate their mechanical properties in vitro. However, the relevance of this mode of titin mechanical modulation in vivo remains largely unknown. Here, we describe the high evolutionary conservation of titin mechanical cysteines and show that they are remarkably oxidized in murine cardiac tissue. Mass spectrometry analyses indicate a similar landscape of basal oxidation in murine and human myocardium. Monte Carlo simulations illustrate how disulfides and S-thiolations on these cysteines increase the dynamics of the protein at physiological forces, while enabling load- and isoform-dependent regulation of titin stiffness. Our results demonstrate the role of conserved cysteines in the modulation of titin mechanical properties in vivo and point to potential redox-based pathomechanisms in heart disease.

Unraveling the molecular determinants of the anti-phagocytic protein cloak of plague bacteria.

The pathogenic bacterium Yersina pestis is protected from macrophage engulfment by a capsule like antigen, F1, formed of long polymers of the monomer protein, Caf1. However, despite the importance of this pathogen, the mechanism of protection was not understood. Here we demonstrate how F1 protects the bacteria from phagocytosis. First, we show that Escherichia coli expressing F1 showed greatly reduced adherence to macrophages. Furthermore, the few cells that did adhere remained on the macrophage surface and were not engulfed. We then inserted, by mutation, an "RGDS" integrin binding motif into Caf1. This did not change the number of cells adhering to macrophages but increased the fraction of adherent cells that were engulfed. Therefore, F1 protects in two separate ways, reducing cell adhesion, possibly by acting as a polymer brush, and hiding innate receptor binding sites needed for engulfment. F1 is very robust and we show that E. coli expressing weakened mutant polymers are engulfed like the RGDS mutant. This suggests that innate attachment sites on the native cell surface are exposed if F1 is weakened. Single-molecule force spectroscopy (SMFS) experiments revealed that wild-type F1 displays a very high mechanical stability of 400 pN. However, the mechanical resistance of the destabilised mutants, that were fully engulfed, was only 20% weaker. By only marginally exceeding the mechanical force applied to the Caf1 polymer during phagocytosis it may be that the exceptional tensile strength evolved to resist the forces applied at this stage of engulfment.

Prenatal Diagnosis of Fetal Lymphangioma: A Case Series.

Fetal lymphangioma is an uncommon congenital malformation that is mainly comprised of the subcutaneous tissue of the neck. This malformation can develop in other areas like the thoracic and axillary regions, though rarely. We report 6 consecutive cases of lymphatic malformation in a fetal center in Dominican Republic. In our case series fetal chest lymphangiomas were present in 2 fetuses. In addition, 2 cases of axillary lymphangiomas also involved the thoracic region. Adequate management by a multidiciplinary team is necessary to provide a better approach to delivery.

Mechanochemical Evolution of Disulfide Bonds in Proteins.

Disulfide bonds play a pivotal role in the mechanical stability of proteins. Numerous proteins that are known to be exposed to mechanical forces in vivo contain disulfide bonds. The presence of cryptic disulfide bonds in a protein structure may be related to its resistance to an applied mechanical force. Disulfide bonds in proteins tend to be highly conserved but their evolution might be directly related to the evolution of the protein mechanical stability. Hence, tracking the evolution of disulfide bonds in a protein can help to derive crucial stability/function correlations in proteins that are exposed to mechanical forces. Phylogenic analysis and ancestral sequence reconstruction (ASR) allow tracking the evolution of proteins from the past ancestors to our modern days and also establish correlations between proteins from different species. In addition, ASR can be combined with single-molecule force spectroscopy (smFS) to investigate the mechanical properties of proteins including the occurrence and function of disulfide bonds. Here we present a detailed protocol to study the mechanochemical evolution of proteins using a fragment of the giant muscle protein titin as example. The protocol can be easily adapted to AFS studies of any resurrected mechanical force bearing protein of interest.

Fibrosis pulmonar idiopática. Características clínicas de un registro en Panamá. 2017-2020

Introducción: La fibrosis pulmonar idiopática es una enfermedad rara, asociada al envejecimiento, con una alta tasa de mortalidad entre los 2.5 a 3 años. El diagnóstico se realiza con la sospecha clínica y la confirmación del patrón de neumonía intersticial usual, en tomografía del tórax o en biopsia pulmonar; el tratamiento actual se basa en fármacos anti fibróticos. Material y método: Se llevó a cabo un estudio descriptivo y prospectivo tipo registro, de pacientes con fibrosis pulmonar idiopática, que estuviesen en seguimiento por médicos especialistas en neumología en 4 consultorios privados de la ciudad de Panamá entre el 2017 y el 2020. Resultado: Se evaluaron 32 pacientes, edad media de 69 años (rango 53 ­ 91); 18/32 (56.3%) fueron masculinos, y de estos, 16/18 (88.9%) eran fumadores. Los crepitantes tipo velcro subescapulares se encontraron en 29/32 (90.6%). El patrón de neumonía intersticial usual en tomografía se encontró en 30/32 (93.7%), y 2/32 (6.3%) en biopsia. Los medicamentos anti fibróticos fueron usados en 6/32 (18.6%); el 50% usó nintedanib y el 50% pirfenidona. Fallecieron 4/32 (12.5%) pacientes en el periodo de estudio. Conclusión: La fibrosis pulmonar idiopática es frecuente en mayores de 50 años, principalmente varones, con historial de tabaquismo y reflujo gastroesofágico. Los crepitantes tipo velcro subescapulares son un hallazgo frecuente. El diagnóstico se realizó en su mayoría con tomografía de tórax de alta resolución; la difusión de monóxido de carbono y la saturación en la caminata de 6 minutos son las pruebas funcionales más alteradas. Menos de un tercio de los pacientes recibe tratamiento con anti fibróticos. (provisto por Infomedic International)

Introduction: Idiopathic pulmonary fibrosis is a rare disease, associated with aging, with a high mortality rate between 2.5 to 3 years. Diagnosis is made with clinical suspicion and confirmation of the usual interstitial pneumonia pattern in chest tomography or lung biopsy; current treatment is based on antifibrotic drugs. Methods: A descriptive and prospective registry-type study was carried out on patients with idiopathic pulmonary fibrosis who were being followed up by pulmonology specialists in 4 private practices in Panama City between 2017 and 2020. Results: 32 patients were evaluated, mean age 69 years (range 53 - 91); 18/32 (56.3%) were male, and of these, 16/18 (88.9%) were smokers. Subscapularis velcro-type crackles were found in 29/32 (90.6%). The usual interstitial pneumonia pattern on CT was found in 30/32 (93.7%), and 2/32 (6.3%) on biopsy. Antifibrotic drugs were used in 6/32 (18.6%); 50% used nintedanib and 50% pirfenidone. Four/32 (12.5%) patients died during the study period. Conclusion: Idiopathic pulmonary fibrosis is frequent in patients older than 50 years, mainly males, with a history of smoking and gastroesophageal reflux. Subscapular Velcro-like crackles are a frequent finding. Diagnosis was mostly made with high-resolution chest CT; carbon monoxide diffusion and 6-minute walk saturation are the most altered functional tests. Less than one third of patients receive treatment with antifibrotic drugs. (provided by Infomedic International)

Development of Sterile Insect Technique for Control of the European Grapevine Moth, Lobesia botrana, in Urban Areas of Chile.

The European grapevine moth, a Palearctic pest, was first detected in the Americas in 2008. Its establishment in Chile presented production and export issues for grapes and other fruits, and a national control campaign was launched. Urban areas next to agricultural production areas were recognized as a challenge for effective control. In 2015, a SIT laboratory was established in Arica, Chile to evaluate its potential for urban control. Progress included the development and evaluation of artificial diets, a mass-rearing of 75,000 moths/week, confirmation of 150 Gy as an operational dose for inherited sterility, and releases of sterile moths in a 25 ha urban area next to fruit production areas. Season-long releases demonstrated that high overflooding ratios were achieved early in the season but decreased with a large increase in the wild moth population. Sterile moth quality was consistently high, and moths were observed living in the field up to 10 days and dispersing up to 800 m. Recommendations for further development of the SIT include conducting cage and field studies to evaluate overflooding ratios and mating competitiveness, measuring of infestation densities in release and no-release areas, and conducting trials to evaluate combining SIT with compatible integrated pest management (IPM) tactics such as fruit stripping and use of mating disruption.

Enzymatically produced cellulose nanocrystals as reinforcement for waterborne polyurethane and its applications.

Waterborne polyurethanes (WBPUs) have been proposed as ecofriendly elastomers with several applications in coatings and adhesives. WBPU's physicochemical properties can be enhanced by the addition of cellulose nanocrystals (CNCs). The way CNCs are isolated has a strong effect on their properties and can determine their role as reinforcement. In this work, CNCs produced using ancestral endoglucanase (EnCNCs) were used as reinforcement for WBPU and compared with CNC produced by sulfuric acid hydrolysis (AcCNC). The enzymatic method produced highly thermostable and crystalline CNCs. The addition of small contents of EnCNCs improved the thermomechanical stability and mechanical properties of WBPUs, even better than commercial AcCNCs. Besides, WBPU reinforced by adding EnCNCs was studied as a coating for paper materials, increasing its abrasion resistance and as electrospun nanocomposite mats where EnCNCs helped maintaining the morphology of the fibers.

Manifestaciones trombóticas en la neumonía viral por SARS-CoV-2 pacientes hospitalizados en el Hospital «Irma de Lourdes Tzanetatos¼, Panamá, Panamá. De marzo de 2020 a septiembre de 2020 / Thrombotic manifestations in viral neumonia by CoV-2-SARS hospitalized patients at «Irma Lourdes Tzanetatos¼ Hospital, Panama, Panama. March 2020 to September 2020

La respuesta a la infección viral produce un estado de trombosis o hipercoagulabilidad que, unido a la inflamación de las células endoteliales, puede generar disfunción plaquetaria y predisposición a la formación de trombos que, aunque con frecuencia son más venosos, también pueden aparecer en el sistema arterial y producir infartos a cualquier nivel así como tromboembolia e hipertensión pulmonar. Estas manifestaciones han sido captadas hospitalariamente y al egreso de los pacientes detectados por SARS-CoV-2 habiendo ya cumplido el tiempo establecido de virulencia. Los criterios diagnósticos de respuesta inmunológica trombótica asociada a COVID-19 (RITAC) ayudan a seleccionar al paciente que está predispuesto a esta condición; a esto se añade que el paciente ya tiene un diagnóstico de infección por SARS-CoV-2 (AU)

The response to viral infection produces a prothrombotic state of hypercoagulability , united with an inflammation of endothelial cells, It can generate platelet dysfunction and predisposition to the formation of thrombus, that, although, are more frequently venous, Also, it can appear in the arterial system and cause heart attacks at any level; thromboembolism and pulmonary hypertension, as well. These manifestations have been captured hospitably and with the egress of patients detected by SARS-CoV-2. The diagnostic criteria of RITAC (abbreviation in Spanish of Thrombotic Immune Response Associated to COVID-19), help to select the patient who is predisposed to this condition; adding that the patient already has a diagnosis of SARS-CoV-2 infection (AU)

Entropic bonding of the type 1 pilus from experiment and simulation.

The type 1 pilus is a bacterial filament consisting of a long coiled proteic chain of subunits joined together by non-covalent bonding between complementing ß -strands. Its strength and structural stability are critical for its anchoring function in uropathogenic Escherichia coli bacteria. The pulling and unravelling of the FimG subunit of the pilus was recently studied by atomic force microscopy experiments and steered molecular dynamics simulations (Alonso-Caballero et al. 2018 Nat. Commun. 9, 2758. (doi:10.1038/s41467-018-05107-6)). In this work, we perform a quantitative comparison between experiment and simulation, showing a good agreement in the underlying work values for the unfolding. The simulation results are then used to estimate the free energy difference for the detachment of FimG from the complementing strand of the neighbouring subunit in the chain, FimF. Finally, we show that the large free energy difference for the unravelling and detachment of the subunits which leads to the high stability of the chain is entirely entropic in nature.

CDCA7 finely tunes cytoskeleton dynamics to promote lymphoma migration and invasion.

Metastases, the major cause of death from cancer, require cells' acquisition of the ability to migrate and involve multiple steps, including local tumor cell invasion and basement membrane penetration. Certain lymphoid tumors are highly metastatic, but the mechanisms of invasion by lymphoma cells are poorly understood. We recently showed that CDCA7, a protein induced by MYC, is overexpressed in lymphoid tumors and that its knockdown decreases lymphoid tumor growth without inhibiting the proliferation of normal cells. Here we show that CDCA7 is critical for invasion and migration of lymphoma cells. Indeed, CDCA7 knockdown in lymphoma cells limited tumor cell invasion in matrigel-coated transwell plates and tumor invasion of neighboring tissues in a mouse xenograft model and in a zebrafish model of cell invasion. CDCA7 silencing markedly inhibited lymphoma cell migration on fibronectin without modifying cell adhesion to this protein. Instead, CDCA7 knockdown markedly disrupted the precise dynamic reorganization of actomyosin and tubulin cytoskeletons required for efficient migration. In particular, CDCA7 silencing impaired tubulin and actomyosin cytoskeleton polarization, increased filamentous actin formation, and induced myosin activation. Of note, inhibitors of actin polymerization, myosin II, or ROCK reestablished the migration capacity of CDCA7-silenced lymphoma cells. Given the critical role of CDCA7 in lymphoma-genesis and invasion, therapies aimed at inhibiting its expression or activity might provide significant control of lymphoma growth, invasion, and metastatic dissemination.

Forensic analysis of Turkish elections in 2017-2018.

With a majority of 'Yes' votes in the Constitutional Referendum of 2017, Turkey continued its drift towards an autocracy. By the will of the Turkish people, this referendum transferred practically all executive power to president Erdogan. However, the referendum was confronted with a substantial number of allegations of electoral misconducts and irregularities, ranging from state coercion of 'No' supporters to the controversial validity of unstamped ballots. Here we report the results of an election forensic analysis of recent Turkish elections to clarify to what extent it is plausible that these voting irregularities were present and able to influence the outcome of the referendum. We apply statistical forensics tests to identify the specific nature of the alleged electoral malpractices. In particular, we test whether the data contains fingerprints for ballot stuffing (submission of multiple ballots per person during the vote) and voter rigging (coercion and intimidation of voters). Additionally, we perform tests to identify numerical anomalies in the election results. For the 2017 Constitutional Referendum we find systematic and highly significant statistical support for the presence of both ballot stuffing and voter rigging. In 11% of stations we find signs for ballot stuffing with a standard deviation (uncertainty of ballot stuffing probability) of 2.7% (4 sigma event). Removing such ballot-stuffing-characteristic anomalies from the data would tip the overall balance from 'No' to a majority of 'Yes' votes. The 2017 election was followed by early elections in 2018 to directly vote for a new president who would now be head of state and government. We find statistical irregularities in the 2018 presidential and parliamentary elections similar in size and direction to those in 2017. These findings validate that our results unveil systematic and potentially even fraudulent biases that require further attention in order to combat electoral malpractices.

Instrumental Effects in the Dynamics of an Ultrafast Folding Protein under Mechanical Force.

The analysis and interpretation of single molecule force spectroscopy (smFS) experiments is often complicated by hidden effects from the measuring device. Here we investigate these effects in our recent smFS experiments on the ultrafast folding protein gpW, which has been previously shown to fold without crossing a free energy barrier in the absence of force (i.e., downhill folding). Using atomic force microscopy (AFM) smFS experiments, we found that a very small force of ∼5 pN brings gpW near its unfolding midpoint and results in two-state (un)folding patterns that indicate the emergence of a force-induced free energy barrier. The change in the folding regime is concomitant with a 30,000-fold slowdown of the folding and unfolding times, from a few microseconds that it takes gpW to (un)fold at the midpoint temperature to seconds in the AFM. These results are puzzling because the barrier induced by force in the folding free energy landscape of gpW is far too small to account for such a difference in time scales. Here we use recently developed theoretical methods to resolve the origin of the strikingly slow dynamics of gpW under mechanical force. We find that, while the AFM experiments correctly capture the equilibrium distance distribution, the measured dynamics are entirely controlled by the response of the cantilever and polyprotein linker, which is much slower than the protein conformational dynamics. This interpretation is likely applicable to the folding of other small biomolecules in smFS experiments, and becomes particularly important in the case of systems with fast folding dynamics and small free energy barriers, and for instruments with slow response times.

Mechanical architecture and folding of E. coli type 1 pilus domains.

Uropathogenic Escherichia coli attach to tissues using pili type 1. Each pilus is composed by thousands of coiled FimA domains followed by the domains of the tip fibrillum, FimF-FimG-FimH. The domains are linked by non-covalent ß-strands that must resist mechanical forces during attachment. Here, we use single-molecule force spectroscopy to measure the mechanical contribution of each domain to the stability of the pilus and monitor the oxidative folding mechanism of a single Fim domain assisted by periplasmic FimC and the oxidoreductase DsbA. We demonstrate that pilus domains bear high mechanical stability following a hierarchy by which domains close to the tip are weaker than those close to or at the pilus rod. During folding, this remarkable stability is achieved by the intervention of DsbA that not only forms strategic disulfide bonds but also serves as a chaperone assisting the folding of the domains.

The life of proteins under mechanical force.

Although much of our understanding of protein folding comes from studies of isolated protein domains in bulk, in the cellular environment the intervention of external molecular machines is essential during the protein life cycle. During the past decade single molecule force spectroscopy techniques have been extremely useful to deepen our understanding of these interventional molecular processes, as they allow for monitoring and manipulating mechanochemical events in individual protein molecules. Here, we review some of the critical steps in the protein life cycle, starting with the biosynthesis of the nascent polypeptide chain in the ribosome, continuing with the folding supported by chaperones and the translocation into different cell compartments, and ending with proteolysis in the proteasome. Along these steps, proteins experience molecular forces often combined with chemical transformations, affecting their folding and structure, which are measured or mimicked in the laboratory by the application of force with a single molecule apparatus. These mechanochemical reactions can potentially be used as targets for fighting against diseases. Inspired by these insightful experiments, we devise an outlook on the emerging field of mechanopharmacology, which reflects an alternative paradigm for drug design.

Testing for voter rigging in small polling stations.

Nowadays, a large number of countries combine formal democratic institutions with authoritarian practices. Although in these countries the ruling elites may receive considerable voter support, they often use several manipulation tools to control election outcomes. A common practice of these regimes is the coercion and mobilization of large numbers of voters. This electoral irregularity is known as voter rigging, distinguishing it from vote rigging, which involves ballot stuffing or stealing. We develop a statistical test to quantify the extent to which the results of a particular election display traces of voter rigging. Our key hypothesis is that small polling stations are more susceptible to voter rigging because it is easier to identify opposing individuals, there are fewer eyewitnesses, and interested parties might reasonably expect fewer visits from election observers. We devise a general statistical method for testing whether voting behavior in small polling stations is significantly different from the behavior in their neighbor stations in a way that is consistent with the widespread occurrence of voter rigging. On the basis of a comparative analysis, the method enables third parties to conclude that an explanation other than simple variability is needed to explain geographic heterogeneities in vote preferences. We analyze 21 elections in 10 countries and find significant statistical anomalies compatible with voter rigging in Russia from 2007 to 2011, in Venezuela from 2006 to 2013, and in Uganda in 2011. Particularly disturbing is the case of Venezuela, where the smallest polling stations were decisive to the outcome of the 2013 presidential elections.