Metabolic Engineering: Methodologies and Applications.

Metabolic engineering aims to improve the production of economically valuable molecules through the genetic manipulation of microbial metabolism. While the discipline is a little over 30 years old, advancements in metabolic engineering have given way to industrial-level molecule production benefitting multiple industries such as chemical, agriculture, food, pharmaceutical, and energy industries. This review describes the design, build, test, and learn steps necessary for leading a successful metabolic engineering campaign. Moreover, we highlight major applications of metabolic engineering, including synthesizing chemicals and fuels, broadening substrate utilization, and improving host robustness with a focus on specific case studies. Finally, we conclude with a discussion on perspectives and future challenges related to metabolic engineering.

Risk of lung disease in the PI*SS genotype of alpha-1 antitrypsin: an EARCO research project.

BACKGROUND: The PI*S variant is one of the most prevalent mutations within alpha-1 antitrypsin deficiency (AATD). The risk of developing AATD-related lung disease in individuals with the PI*SS genotype is poorly defined despite its substantial prevalence. Our study aimed to characterize this genotype and its risk for lung disease and compare it with the PI*ZZ and PI*SZ genotypes using data from the European Alpha-1 antitrypsin Deficiency Research Collaboration international registry. METHOD: Demographic, clinical, functional, and quality of life (QoL) parameters were assessed to compare the PI*SS characteristics with the PI*SZ and PI*ZZ controls. A propensity score with 1:3 nearest-neighbour matching was performed for the most important confounding variables. RESULTS: The study included 1007 individuals, with PI*SS (n = 56; 5.6%), PI*ZZ (n = 578; 57.4%) and PI*SZ (n = 373; 37.0%). The PI*SS population consisted of 58.9% men, with a mean age of 59.2 years and a mean FEV1(% predicted) of 83.4%. Compared to PI*ZZ individuals they had less frequent lung disease (71.4% vs. 82.2%, p = 0.037), COPD (41.4% vs. 60%, p = 0.002), and emphysema (23.2% vs. 51.9%, p < 0.001) and better preserved lung function, fewer exacerbations, lower level of dyspnoea, and better QoL. In contrast, no significant differences were found in the prevalence of lung diseases between PI*SS and PI*SZ, or lung function parameters, exacerbations, dyspnoea, or QoL. CONCLUSIONS: We found that, as expected, the risk of lung disease associated with the PI*SS genotype is significantly lower compared with PI*ZZ, but does not differ from that observed in PI*SZ individuals, despite having higher serum AAT levels. TRIAL REGISTRATION: www. CLINICALTRIALS: gov (ID: NCT04180319).

[Ethical and legal aspects of violence against women]. / Aspectos éticos y legales de la violencia sobre la mujer.

Caring for female victims of violence presents health professionals with situations that require careful consideration due to the conflicts raised between the fundamental principles of bioethics. During this process, intermediate courses of action should be adopted in which none of the affected principles is totally compromised, yet always take into account due compliance with legal and deontological regulations. Within these conflicts, the possible impact on the autonomy of the victim must be taken into consideration, conditioned by the relationship of dominance with respect to their aggressor, a fundamental characteristic of gender violence. However, the fact that there is a legal obligation to issue an injury report or to communicate a well-founded suspicion of abuse is not enough to ignore the fact that the person, in this case the victim, must be a participant in the process. As such, the doctor has the obligation to inform his or her patient about this legal requirement, dedicating all the time and attention necessary to ensure that the victim understands the purpose and benefits of complying with this. In any case, and beyond the appropriate adaptation of the professional's conduct to current precepts, the ethical principle of care must be adhered to, by which the best thing the professional can do is to provide the victim with the means to avoid the repetition of new attacks, implementing prevention measures that have their origin in the accurate diagnosis of the situation of violence and in the communication of this to the authorities.

Molecular phylogeny, historical biogeography and revised classification of andrenine bees (Hymenoptera: Andrenidae).

The mining bee subfamily Andreninae (Hymenoptera: Andrenidae) is a widely distributed and diverse group of ground-nesting solitary bees, including numerous species known to be important pollinators. Most of the species diversity of Andreninae is concentrated in the mainly Holarctic genus Andrena, comprising ca. 1550 described species. The subfamily and especially the genus have remained relatively neglected by recent molecular phylogenetic studies, with current classifications relying largely on morphological characters. We sampled ultraconserved element (UCE) sequences from 235 taxa, including all andrenine genera and 98 out of 104 currently recognized Andrena subgenera. Using 419,858 aligned nucleotide sites from 1009 UCE loci, we present a comprehensive molecular phylogenetic analysis of the subfamily. Our analysis supports the recognition of seven distinct genera in the Andreninae: Alocandrena, Ancylandrena, Andrena, Cubiandrena, Euherbstia, Megandrena, and Orphana. Within the genus Andrena, present-day subgeneric concepts revealed high degrees of paraphyly and polyphyly, due to strong homoplasy of morphological characters, necessitating a thorough, extensive revision of the higher classification of the genus. Based on our findings, we place the subgenus Calcarandrena in synonymy with Andrena (Lepidandrena); Hyperandrena, Nemandrena, Scoliandrena, Tylandrena and Zonandrena with A. (Melandrena); Distandrena, Fumandrena and Proxiandrena with A. (Micrandrena); Carandrena with A. (Notandrena); Agandrena with A. (Plastandrena); Geandrena and Xanthandrena with A. (Ptilandrena); Xiphandrena with A. (Scrapteropsis); and Platygalandrena and Poliandrena with A. (Ulandrena) (new synonymies). We additionally reestablish the groups known as Opandrena and Truncandrena as valid subgenera of Andrena. Our results also show that the MRCA of Andrena + Cubiandrena dispersed from the New World to the Palaearctic probably during the Eocene-early Oligocene, followed by 10-14 Neogene dispersal events from the Palaearctic to the Nearctic and 1-6 Neogene dispersals back into the Palaearctic, all within the genus Andrena.

Quality of life of patients with metastatic pancreatic adenocarcinoma initiating first-line chemotherapy in routine practice.

BACKGROUND: Despite advances in surgery, radiotherapy, and chemotherapy, pancreatic adenocarcinoma often progresses rapidly and causes death. The physical decline of these patients is expected to impact their quality of life (QoL). Therefore, in addition to objective measures of effectiveness, the evaluation of health-related QoL should be considered a matter of major concern when assessing therapy outcomes. METHODS: Observational, prospective, multicenter study including patients with metastatic pancreatic adenocarcinoma who started first-line chemotherapy in 12 Spanish centers. Treatment and clinical characteristics were recorded at baseline. Patients' health-related quality of life, ECOG, and Karnofsky index were measured at baseline, at Days 15 and 30, and every four weeks up to 6 months of chemotherapy. Health-related quality of life was measured using the EORTC-QLQ-C30 and EQ-5D questionnaires. Other endpoints included overall survival and progression-free survival. RESULTS: The study sample included 116 patients (median age of 65 years). Mean (SD) scores for the QLQ-C30 global health status scale showed a significant increasing trend throughout the treatment (p = 0.005). Patients with either a Karnofsky index of 70-80 or ECOG 2 showed greater improvement in the QLQ-C30 global health status score than the corresponding groups with better performance status (p ≤ 0.010). Pain, appetite, sleep disturbance, nausea, and constipation significantly improved throughout the treatment (p < 0.005). Patients with QLQ-C30 global health status scores ≥50 at baseline had significantly greater overall survival and progression-free survival (p = 0.005 and p = 0.021, respectively). No significant associations were observed regarding the EQ-5D score. CONCLUSIONS: Most metastatic pancreatic adenocarcinoma patients receiving first-line chemotherapy showed an increase in health-related quality of life scores throughout the treatment. Patients with lower performance status and health-related quality of life at baseline tended to greater improvement. The EORTC QLQ-C30 scale allowed us to measure the health-related quality of life of metastatic pancreatic adenocarcinoma patients receiving first-line chemotherapy.

Satisfaction of patients and primary care professionals with a teleophthalmology-based screening programme for diabetic retinopathy in a rural area in Castilla y León, Spain.

INTRODUCTION: Diabetic retinopathy (DR) is the leading cause of blindness in working-age adults in most developed countries. Early diagnosis and early treatment for retinopathy can reduce the incidence of severe loss of vision in a high percentage of sight-threatening DR. However, sight-threatening DR is asymptomatic in a high percentage of patients and no more than 50% of the diabetic patients are reviewed periodically in ophthalmology, mainly in rural areas. Telemedicine facilitates the exchange of information among professionals, reducing unnecessary journeys for patients who live in rural or remote areas. The survey of satisfaction is a highly useful quantitative instrument to obtain information directly from the users of a screening program. One aim of this study has been to determine the prevalence of DR in a sample of diabetic patients from a rural area of Spain and to classify DR patients according to the type and severity of this complication of the disease. The other main target was to evaluate the degree of satisfaction in both diabetic patients and professionals with a teleophthalmology-based screening program of DR. METHODS: A sample of 114 diabetic patients included in a new teleophthalmology program for the screening of DR in Castilla y León, Spain, were asked to take part in an in-person survey designed to evaluate the degree of satisfaction. This sample was obtained through a consecutive non-probability sampling technique, out of a total of 752 diabetic patients who underwent a retinography screening program in a distant rural healthcare center. The survey assessed aspects related to the information about the program the patients received, the organization of the center, the way the test was conducted and the reception of the results. All the included participants consented to participate in this study. Additionally, an anonymous survey was conducted via email. The sample was made up of 10 professionals responsible for taking the retinal images from the patients included in the study. This survey assessed their degree of satisfaction with their training, the way the test was carried out, the support from their managers and how this activity influenced their relationship with their patients. RESULTS: A high percentage of patients with DR in the study sample had a form of sight-threatening retinopathy (29.4%), which in this program is a criterion of referral to be assessed by an ophthalmologist. Of the surveyed patients, 93.8% scored eight points or higher for their degree of general satisfaction with the activity. All of them claimed they would prefer to continue their exploration at the healthcare center instead of going to the hospital. As regards the professionals, 70% scored eight points or more in terms of their degree of general satisfaction with the activity, whereas 20% scored between five and seven. One professional did not respond to the question. Finally, 90% stated that they would continue performing the activity, while the remaining 10% answered no. CONCLUSION: According to the high percentage of patients diagnosed with vision-threatening DR in this study, an early diagnosis of this complication of diabetes seems to be important. Teleophthalmology enhances patient accessibility to the healthcare system, making early diagnosis of DR easier, with a high degree of satisfaction among patients and healthcare professionals.

Confirmatory factor analysis of the Revised UCLA Loneliness Scale (UCLA LS-R) in individuals over 65.

GOALS: The UCLA LS-R is the most extensively used scale to assess loneliness. However, few studies examine the scale's use on older individuals. The goal of the study is to analyse the suitability of the scale´s structure for assessing older individuals. METHOD: The UCLA LS-R scale was administered to a random sample of 409 community-dwelling residents of Madrid (53% women) aged 65-84 years (obtained from the MentDis_ICF65+ study). Confirmatory factor analysis was used to assess the factor structure of the UCLA LS-R. RESULTS: The internal consistency of the scale obtained a Cronbach's alpha of .85. All the analysed models of factor structure of the UCLA LS-R achieved a fairly good fit and RMSEA values over .80. The models that best fit the empirical data are those of Hojat (1982) and Borges et al. (2008). CONCLUSION: The data suggest an equivalent effectiveness of UCLA LS-R in adults under 65 and over 65, which may indicate a similar structure of the loneliness construct in both populations. This outcome is consistent with the idea that loneliness has two dimensions: emotional loneliness and social loneliness. The use of short measures that are easy to apply and interpret should help primary care professionals identify loneliness problems in older individuals sooner and more accurately.

High fat diet blunts the effects of leptin on ventilation and on carotid body activity.

KEY POINTS: Leptin plays a role in the control of breathing, acting mainly on central nervous system; however, leptin receptors have been recently shown to be expressed in the carotid body (CB), and this finding suggests a physiological role for leptin in the regulation of CB function. Leptin increases minute ventilation in both basal and hypoxic conditions in rats. It increases the frequency of carotid sinus nerve discharge in basal conditions, as well as the release of adenosine from the CB. However, in a metabolic syndrome animal model, the effects of leptin in ventilatory control, carotid sinus nerve activity and adenosine release by the CB are blunted. Although leptin may be involved in triggering CB overactivation in initial stages of obesity and dysmetabolism, resistance to leptin signalling and blunting of responses develops in metabolic syndrome animal models. ABSTRACT: Leptin plays a role in the control of breathing, acting mainly on central nervous system structures. Leptin receptors are expressed in the carotid body (CB) and this finding has been associated with a putative physiological role of leptin in the regulation of CB function. Since, the CBs are implicated in energy metabolism, here we tested the effects of different concentrations of leptin administration on ventilatory parameters and on carotid sinus nerve (CSN) activity in control and high-fat (HF) diet fed rats, in order to clarify the role of leptin in ventilation control in metabolic disease states. We also investigated the expression of leptin receptors and the neurotransmitters involved in leptin signalling in the CBs. We found that in non-disease conditions, leptin increases minute ventilation in both basal and hypoxic conditions. However, in the HF model, the effect of leptin in ventilatory control is blunted. We also observed that HF rats display an increased frequency of CSN discharge in basal conditions that is not altered by leptin, in contrast to what is observed in control animals. Leptin did not modify intracellular Ca2+ in CB chemoreceptor cells, but it produced an increase in the release of adenosine from the whole CB. We conclude that CBs represent an important target for leptin signalling, not only to coordinate peripheral ventilatory chemoreflexive drive, but probably also to modulate metabolic variables. We also concluded that leptin signalling is mediated by adenosine release and that HF diets blunt leptin responses in the CB, compromising ventilatory adaptation.

Does Migrant Background Matter for Adolescents' Fertility Preferences? The Latin American 1.5 Generation in Spain.

This article examines the fertility preferences of Latin American adolescents of the 1.5 generation and their native peers in Spain. We compare their expected age at first birth as well as their expected family size. The fertility preferences of the 1.5 generation are likely to reflect the family values of two different socialization environments as well as the adaptation process to the childbearing norms of the host society. The analysis is based on the Chances Survey, which collected data from 2700 adolescents in secondary schools in Madrid in 2011. Results indicate that fertility timing preferences of Latin American adolescents reflect socialization influences from the society of origin, but also a quick adaptation to the childbearing norms in the host society, since their expected age at first birth is somewhat earlier than that of their Spanish peers but considerably later than that prevailing in their country of origin. The degree of social integration, measured by the number of the respondent's best friends who were Spanish, seems more important than age at migration for diminishing the gap between Latin Americans and Spaniards. Moreover, higher educational expectations are associated with preferences for postponed entry into parenthood. With regard to family size expectations, we find no significant variation between adolescents of migrant and native origin, confirming the argument that the "two-child norm" currently prevails in both middle- and high-income countries.

Tauopathy induced by low level expression of a human brain-derived tau fragment in mice is rescued by phenylbutyrate.

Human neurodegenerative tauopathies exhibit pathological tau aggregates in the brain along with diverse clinical features including cognitive and motor dysfunction. Post-translational modifications including phosphorylation, ubiquitination and truncation, are characteristic features of tau present in the brain in human tauopathy. We have previously reported an N-terminally truncated form of tau in human brain that is associated with the development of tauopathy and is highly phosphorylated. We have generated a new mouse model of tauopathy in which this human brain-derived, 35 kDa tau fragment (Tau35) is expressed in the absence of any mutation and under the control of the human tau promoter. Most existing mouse models of tauopathy overexpress mutant tau at levels that do not occur in human neurodegenerative disease, whereas Tau35 transgene expression is equivalent to less than 10% of that of endogenous mouse tau. Tau35 mice recapitulate key features of human tauopathies, including aggregated and abnormally phosphorylated tau, progressive cognitive and motor deficits, autophagic/lysosomal dysfunction, loss of synaptic protein, and reduced life-span. Importantly, we found that sodium 4-phenylbutyrate (Buphenyl®), a drug used to treat urea cycle disorders and currently in clinical trials for a range of neurodegenerative diseases, reverses the observed abnormalities in tau and autophagy, behavioural deficits, and loss of synapsin 1 in Tau35 mice. Our results show for the first time that, unlike other tau transgenic mouse models, minimal expression of a human disease-associated tau fragment in Tau35 mice causes a profound and progressive tauopathy and cognitive changes, which are rescued by pharmacological intervention using a clinically approved drug. These novel Tau35 mice therefore represent a highly disease-relevant animal model in which to investigate molecular mechanisms and to develop novel treatments for human tauopathies.

Spontaneous nasal perforation in a bevacizumab-treated patient with metastatic breast cancer.

Nasal septum perforation in patients with cancer receiving systemic therapy is rare, and its association with bevacizumab use has described recently in the literature. Here, we report the case of a 34-year-old woman with hormone-sensitive, HER-2/neu negative, metastatic breast cancer who develope a nasal septum perforation during the treatment with paclitaxel and bevacizumab.

Long-term care in Spain: Difficulties in professionalizing services.

The aim of this article is to analyze the difficulties in professionalizing the long-term care system in Spain. Since 2006, the new Spanish law has recognized care as a subjective right, and regulations are being designed to create a framework for its professionalization. Nowadays, family remains the most important group of providers who care for their elders, and women remain the main informal caregivers. Why do families resist using public long-term care services and professional carers included in the new law? The hypothesis highlights sociocultural factors as an obstacle to professionalization of long-term care services in addition to political and economic factors. The results show qualitative data about expectations, preferences, and discourses that women caregivers have in relation to their responsibility. The empirical material includes 25 interviews with different profiles of caregivers and six focus groups with family caregivers. The article suggests that the Spanish ideal of care is a problem for the professionalization of services because the family remains as the main provider of care-without specific skills, knowledge, and abilities.

Reduced number of axonal mitochondria and tau hypophosphorylation in mouse P301L tau knockin neurons.

Expression of the frontotemporal dementia-related tau mutation, P301L, at physiological levels in adult mouse brain (KI-P301L mice) results in overt hypophosphorylation of tau and age-dependent alterations in axonal mitochondrial transport in peripheral nerves. To determine the effects of P301L tau expression in the central nervous system, we examined the kinetics of mitochondrial axonal transport and tau phosphorylation in primary cortical neurons from P301L knock-in (KI-P301L) mice. We observed a significant 50% reduction in the number of mitochondria in the axons of cortical neurons cultured from KI-P301L mice compared to wild-type neurons. Expression of murine P301L tau did not change the speed, direction of travel or likelihood of movement of mitochondria. Notably, the angle that defines the orientation of the mitochondria in the axon, and the volume of individual moving mitochondria, were significantly increased in neurons expressing P301L tau. We found that murine tau phosphorylation in KI-P301L mouse neurons was diminished and the ability of P301L tau to bind to microtubules was also reduced compared to tau in wild-type neurons. The P301L mutation did not influence the ability of murine tau to associate with membranes in cortical neurons or in adult mouse brain. We conclude that P301L tau is associated with mitochondrial changes and causes an early reduction in murine tau phosphorylation in neurons coupled with impaired microtubule binding of tau. These results support the association of mutant tau with detrimental effects on mitochondria and will be of significance for the pathogenesis of tauopathies.

Trans-splicing correction of tau isoform imbalance in a mouse model of tau mis-splicing.

Abnormal metabolism of the tau protein is central to the pathogenesis of a number of dementias, including Alzheimer's disease. Aberrant alternative splicing of exon 10 in the tau pre-mRNA resulting in an imbalance of tau isoforms is one of the molecular causes of the inherited tauopathy, FTDP-17. We showed previously in heterologous systems that exon 10 inclusion in tau mRNA could be modulated by spliceosome-mediated RNA trans-splicing (SMaRT). Here, we evaluated the potential of trans-splicing RNA reprogramming to correct tau mis-splicing in differentiated neurons in a mouse model of tau mis-splicing, the htau transgenic mouse line, expressing the human MAPT gene in a null mouse Mapt background. Trans-splicing molecules designed to increase exon 10 inclusion were delivered to neurons using lentiviral vectors. We demonstrate reprogramming of tau transcripts at the RNA level after transduction of cultured neurons or after direct delivery and long-term expression of viral vectors into the brain of htau mice in vivo. Tau RNA trans-splicing resulted in an increase in exon 10 inclusion in the mature tau mRNA. Importantly, we also show that the trans-spliced product is translated into a full-length chimeric tau protein. These results validate the potential of SMaRT to correct tau mis-splicing and provide a framework for its therapeutic application to neurodegenerative conditions linked to aberrant RNA processing.

Neural-Network Scoring Functions Identify Structurally Novel Estrogen-Receptor Ligands.

The magnitude of the investment required to bring a drug to the market hinders medical progress, requiring hundreds of millions of dollars and years of research and development. Any innovation that improves the efficiency of the drug-discovery process has the potential to accelerate the delivery of new treatments to countless patients in need. "Virtual screening," wherein molecules are first tested in silico in order to prioritize compounds for subsequent experimental testing, is one such innovation. Although the traditional scoring functions used in virtual screens have proven useful, improved accuracy requires novel approaches. In the current work, we use the estrogen receptor to demonstrate that neural networks are adept at identifying structurally novel small molecules that bind to a selected drug target, ultimately allowing experimentalists to test fewer compounds in the earliest stages of lead identification while obtaining higher hit rates. We describe 39 novel estrogen-receptor ligands identified in silico with experimentally determined Ki values ranging from 460 nM to 20 µM, presented here for the first time.

Mechanisms enforcing the estrogen receptor ß selectivity of botanical estrogens.

Because little is known about the actions of botanical estrogens (BEs), widely consumed by menopausal women, we investigated the mechanistic and cellular activities of some major BEs. We examined the interactions of genistein, daidzein, equol, and liquiritigenin with estrogen receptors ERα and ERß, with key coregulators (SRC3 and RIP140) and chromatin binding sites, and the regulation of gene expression and proliferation in MCF-7 breast cancer cells containing ERα and/or ERß. Unlike the endogenous estrogen, estradiol (E2), BEs preferentially bind to ERß, but their ERß-potency selectivity in gene stimulation (340- to 830-fold vs. E2) is enhanced at several levels (coregulator recruitment, chromatin binding); nevertheless, at high (0.1 or 1 µM) concentrations, BEs also fully activate ERα. Because ERα drives breast cancer cell proliferation and ERß dampens this, the relative levels of these two ERs in target cells and the BE dose greatly affect gene expression and proliferative response and will be crucial determinants of the potential benefits vs. risks of BEs. Our findings reveal key and novel mechanistic differences in the estrogenic activities of BEs vs. E2, with BEs displaying patterns of activity distinctly different from those seen with E2 and provide valuable information to inform future studies.

Epigenetics modifications and Subclinical Atherosclerosis in Obstructive Sleep Apnea: The EPIOSA study.

BACKGROUND: Obstructive sleep apnea (OSA) is associated with increased risk for cardiovascular morbidity and mortality. Epidemiological and animal models studies generate hypotheses for innovative strategies in OSA management by interfering intermediates mechanisms associated with cardiovascular complications. We have thus initiated the Epigenetics modification in Obstructive Sleep Apnea (EPIOSA) study (ClinicalTrials.gov identifier: NCT02131610). METHODS/DESIGN: EPIOSA is a prospective cohort study aiming to recruit 350 participants of caucasian ethnicity and free of other chronic or inflammatory diseases: 300 patients with prevalent OSA and 50 non-OSA subjects. All of them will be follow-up for at least 5 years. Recruitment and study visits are performed in single University-based sleep clinic using standard operating procedures. At baseline and at each one year follow-up examination, patients are subjected to a core phenotyping protocol. This includes a standardized questionnaire and physical examination to determine incident comorbidities and health resources utilization, with a primary focus on cardiovascular events. Confirmatory outcomes information is requested from patient records and the regional Department of Health Services. Every year, OSA status will be assessed by full sleep study and blood samples will be obtained for immediate standard biochemistry, hematology, inflammatory cytokines and cytometry analysis. For biobanking, aliquots of serum, plasma, urine, mRNA and DNA are also obtained. Bilateral carotid echography will be performed to assess subclinical atherosclerosis and atherosclerosis progression. OSA patients are treated according with national guidelines. DISCUSSION: EPIOSA will enable the prospective evaluation of inflammatory and epigenetics mechanism involved in cardiovascular complication of treated and non-treated patients with OSA compared with non OSA subjects.

Living apart together in contemporary Spain: Diverse motivations across life stages.

Living-apart-together (LAT) partnerships are gaining prominence in many high-income societies, prompting ongoing discussions about their significance and their role in the family formation process. This study provides a contemporary update on LAT relationships in Spain, with a specific emphasis on variations across different life stages. The study focuses on several key aspects: (1) recent trends in the prevalence of LAT relationships, (2) socio-demographic factors associated with being in a LAT relationship, (3) joint influence of both partners' characteristics, and (4) short-term intentions to co-reside. Using data from the 2018 Spanish Fertility Survey, we employ logistic regression models to analyze the factors influencing individuals' likelihood of being in a LAT relationship as opposed to a co-residential partnership. Our findings reveal a noticeable rise in LAT partnerships in Spain over the past two decades, except among the youngest age group. Personal motivations and socially attributed meanings of LAT relationships, however, differ depending on an individual's life stage. Among young adults, LAT partnerships largely serve as a transitional phase in the family formation process, preceding co-residence with a partner. In this early adulthood stage, unemployment and temporary work contracts - affecting any of the partners - often hinder household formation, but intentions to co-reside in the near future remain strong. In contrast, LAT partnerships in the mid-life stage often stem from a desire to maintain personal independence and are frequently linked to prior partnership and reproductive biographies.

Development of amino-pyrimidine inhibitors of c-Jun N-terminal kinase (JNK): kinase profiling guided optimization of a 1,2,3-benzotriazole lead.

A series of amino-pyrimidines was developed based upon an initial kinase cross-screening hit from a CDK2 program. Kinase profiling and structure-based drug design guided the optimization from the initial 1,2,3-benzotriazole hit to a potent and selective JNK inhibitor, compound 24f (JNK1 and 2 IC(50)=16 and 66 nM, respectively), with bioavailability in rats and suitable for further in vivo pharmacological evaluation.