Protein Science Meets Artificial Intelligence: A Systematic Review and a Biochemical Meta-Analysis of an Inter-Field.

Proteins are some of the most fascinating and challenging molecules in the universe, and they pose a big challenge for artificial intelligence. The implementation of machine learning/AI in protein science gives rise to a world of knowledge adventures in the workhorse of the cell and proteome homeostasis, which are essential for making life possible. This opens up epistemic horizons thanks to a coupling of human tacit-explicit knowledge with machine learning power, the benefits of which are already tangible, such as important advances in protein structure prediction. Moreover, the driving force behind the protein processes of self-organization, adjustment, and fitness requires a space corresponding to gigabytes of life data in its order of magnitude. There are many tasks such as novel protein design, protein folding pathways, and synthetic metabolic routes, as well as protein-aggregation mechanisms, pathogenesis of protein misfolding and disease, and proteostasis networks that are currently unexplored or unrevealed. In this systematic review and biochemical meta-analysis, we aim to contribute to bridging the gap between what we call binomial artificial intelligence (AI) and protein science (PS), a growing research enterprise with exciting and promising biotechnological and biomedical applications. We undertake our task by exploring "the state of the art" in AI and machine learning (ML) applications to protein science in the scientific literature to address some critical research questions in this domain, including What kind of tasks are already explored by ML approaches to protein sciences? What are the most common ML algorithms and databases used? What is the situational diagnostic of the AI-PS inter-field? What do ML processing steps have in common? We also formulate novel questions such as Is it possible to discover what the rules of protein evolution are with the binomial AI-PS? How do protein folding pathways evolve? What are the rules that dictate the folds? What are the minimal nuclear protein structures? How do protein aggregates form and why do they exhibit different toxicities? What are the structural properties of amyloid proteins? How can we design an effective proteostasis network to deal with misfolded proteins? We are a cross-functional group of scientists from several academic disciplines, and we have conducted the systematic review using a variant of the PICO and PRISMA approaches. The search was carried out in four databases (PubMed, Bireme, OVID, and EBSCO Web of Science), resulting in 144 research articles. After three rounds of quality screening, 93 articles were finally selected for further analysis. A summary of our findings is as follows: regarding AI applications, there are mainly four types: 1) genomics, 2) protein structure and function, 3) protein design and evolution, and 4) drug design. In terms of the ML algorithms and databases used, supervised learning was the most common approach (85%). As for the databases used for the ML models, PDB and UniprotKB/Swissprot were the most common ones (21 and 8%, respectively). Moreover, we identified that approximately 63% of the articles organized their results into three steps, which we labeled pre-process, process, and post-process. A few studies combined data from several databases or created their own databases after the pre-process. Our main finding is that, as of today, there are no research road maps serving as guides to address gaps in our knowledge of the AI-PS binomial. All research efforts to collect, integrate multidimensional data features, and then analyze and validate them are, so far, uncoordinated and scattered throughout the scientific literature without a clear epistemic goal or connection between the studies. Therefore, our main contribution to the scientific literature is to offer a road map to help solve problems in drug design, protein structures, design, and function prediction while also presenting the "state of the art" on research in the AI-PS binomial until February 2021. Thus, we pave the way toward future advances in the synthetic redesign of novel proteins and protein networks and artificial metabolic pathways, learning lessons from nature for the welfare of humankind. Many of the novel proteins and metabolic pathways are currently non-existent in nature, nor are they used in the chemical industry or biomedical field.

What can we learn from ß-cell failure biomarker application in diabetes in childhood? A systematic review.

BACKGROUND: The prevalence of diabetes as a catastrophic disease in childhood is growing in the world. The search for novel biomarkers of ß-cell failure has been an elusive task because it requires several clinical and biochemical measurements in order to integrate the risk of metabolic syndrome. AIM: To determine which biomarkers are currently used to identify ß-cell failure among children and adolescents with high risk factors for diabetes mellitus. METHODS: This systematic review was carried out using a modified version of the PICO protocol (Participants/Intervention/Comparison/Outcome). Once our research question was established, terms were individually researched on three different databases (PubMed, BIREME and Web of Science). The total articles obtained underwent a selection process from which the 78 most relevant articles were retrieved to undergo further analysis. They were assessed individually according to quality criteria. RESULTS: First, we made the classification of the ß-cell-failure biomarkers by the target tissue and the evolution of the disease, separating the biomarkers in relation to the types of diabetes. Second, we demonstrated that most biomarkers currently used as early signs of ß-cell failure are those that concern local or systemic inflammation processes and oxidative stress as well as those related to endothelial dysfunction processes. Third, we explored the novelties of diabetes as a protein conformational disease and the novel biomarker called real human islet amyloid polypeptide amyloid oligomers. Finally, we ended with a discussion about the best practice of validation and individual control of using different types of biomarkers in type 1 and type 2 diabetes in order to assess the role they play in the progress of diabetes in childhood. CONCLUSION: This review makes widely evident that most biomarkers currently used as early signs of ß-cell failure are those that concern local or systemic inflammation processes and oxidative stress as well as those related to endothelial dysfunction processes. Landing in the clinical practice we propose that real human islet amyloid polypeptide amyloid oligomers is good for identifying patients with ß-cell damage and potentially could substitute many biomarkers.

The L125F MATE1 variant enriched in populations of Amerindian origin is associated with increased plasma levels of metformin and lactate.

Genetic factors that affect variability in metformin response have been poorly studied in the Latin American population, despite its being the initial drug therapy for type 2 diabetes, one of the most prevalent diseases in that region. Metformin pharmacokinetics is carried out by members of the membrane transporters superfamily (SLCs), being the multidrug and toxin extrusion protein 1 (MATE1), one of the most studied. Some genetic variants in MATE1 have been associated with reduced in vitro metformin transport. They include rs77474263 p.[L125F], a variant present at a frequency of 13.8% in Latin Americans, but rare worldwide (less than 1%). Using exome sequence data and TaqMan genotyping, we revealed that the Mexican population has the highest frequency of this variant: 16% in Mestizos and 27% in Amerindians, suggesting a possible Amerindian origin. To elucidate the metformin pharmacogenetics, a children cohort was genotyped, allowing us to describe, for the first time, a MATE1 rs77474263 TT homozygous individual. An additive effect of the L125F variant was observed on blood metformin accumulation, revealing the highest metformin and lactate serum levels in the TT homozygote, and intermediate metformin values in the heterozygotes. Moreover, a molecular dynamics analysis suggested that the genetic variant effect on metformin efflux could be due to a decreased protein permeability. We conclude that pharmacogenetics could be useful in enhancing metformin pharmacovigilance in populations having a high frequency of the risk genotype, especially considering that these populations also have a higher susceptibility to the diseases for which metformin is the first-choice drug.

Bibliotherapy as a Non-pharmaceutical Intervention to Enhance Mental Health in Response to the COVID-19 Pandemic: A Mixed-Methods Systematic Review and Bioethical Meta-Analysis.

Background: A non-pharmaceutical treatment offered as psychological support is bibliotherapy, which can be described as the process of reading, reflecting, and discussing literature to further a cognitive shift. The coronavirus disease 2019 (COVID-19) pandemic demands a response to prevent a peak in the prevalence of mental health problems and to avoid the collapse of mental health services, which are scarce and inaccessible due to the pandemic. Thus, this study aimed to review articles on the effectiveness of bibliotherapy on different mental health problems. Methods: A systematic review was conducted to examine relevant studies that assess the effectiveness of bibliotherapy in different clinical settings as a treatment capable of enhancing a sense of purpose and its surrounding values. To achieve this, a systematic review, including a bioethical meta-analysis, was performed. A variant of the PICO (Participants, Intervention, Comparison, and Outcome) model was used for the search strategy, and the systematic review was conducted in three databases: PubMed, Bireme, and OVID. Inclusion criteria were relevant studies that included the keywords, excluding documents with irrelevant topics, studies on subjects 15 years or younger, and in languages besides Spanish or English. Starting with 707 studies, after three rounds of different quality criteria, 13 articles were selected for analysis, including a hermeneutic analysis, which was followed by a fourth and final recovery round assessing bibliotherapy articles concerning healthcare workers. Results: Our findings showed that through bibliotherapy, patients developed several capacities, including the re-signification of their own activities through a new outlook of their moral horizon. There are no research road maps serving as guides to conduct research on the use of bibliotherapy to enhance mental health. Additionally, values such as autonomy and justice were closely linked with positive results in bibliotherapy. This implies that bibliotherapy has the potential to have a positive impact in different settings. Conclusions: Our contribution is to offer a road map that presents state-of-the-art bibliotherapy research, which will assist institutions and healthcare professionals to plan clinical and specific interventions with positive outcomes.

Protein-conformational diseases in childhood: Naturally-occurring hIAPP amyloid-oligomers and early ß-cell damage in obesity and diabetes.

BACKGROUND AND AIMS: This is the first time that obesity and diabetes mellitus (DM) as protein conformational diseases (PCD) are reported in children and they are typically diagnosed too late, when ß-cell damage is evident. Here we wanted to investigate the level of naturally-ocurring or real (not synthetic) oligomeric aggregates of the human islet amyloid polypeptide (hIAPP) that we called RIAO in sera of pediatric patients with obesity and diabetes. We aimed to reduce the gap between basic biomedical research, clinical practice-health decision making and to explore whether RIAO work as a potential biomarker of early ß-cell damage. MATERIALS AND METHODS: We performed a multicentric collaborative, cross-sectional, analytical, ambispective and blinded study; the RIAO from pretreated samples (PTS) of sera of 146 pediatric patients with obesity or DM and 16 healthy children, were isolated, measured by sound indirect ELISA with novel anti-hIAPP cytotoxic oligomers polyclonal antibody (MEX1). We carried out morphological and functional studied and cluster-clinical data driven analysis. RESULTS: We demonstrated by western blot, Transmission Electron Microscopy and cell viability experiments that RIAO circulate in the blood and can be measured by ELISA; are elevated in serum of childhood obesity and diabetes; are neurotoxics and works as biomarkers of early ß-cell failure. We explored the range of evidence-based medicine clusters that included the RIAO level, which allowed us to classify and stratify the obesity patients with high cardiometabolic risk. CONCLUSIONS: RIAO level increases as the number of complications rises; RIAOs > 3.35 µg/ml is a predictor of changes in the current indicators of ß-cell damage. We proposed a novel physio-pathological pathway and shows that PCD affect not only elderly patients but also children. Here we reduced the gap between basic biomedical research, clinical practice and health decision making.

Unpacking the aggregation-oligomerization-fibrillization process of naturally-occurring hIAPP amyloid oligomers isolated directly from sera of children with obesity or diabetes mellitus.

The formation of amyloid oligomers and fibrils of the human islet amyloid polypeptide (hIAPP) has been linked with ß- cell failure and death which causes the onset, progression, and comorbidities of diabetes. We begin to unpack the aggregation-oligomerization-fibrillization process of these oligomers taken from sera of pediatric patients. The naturally occurring or real hIAPP (not synthetic) amyloid oligomers (RIAO) were successfully isolated, we demonstrated the presence of homo (dodecamers, hexamers, and trimers) and hetero-RIAO, as well as several biophysical characterizations which allow us to learn from the real phenomenon taking place. We found that the aggregation/oligomerization process is active in the sera and showed that it happens very fast. The RIAO can form fibers and react with anti-hIAPP and anti-amyloid oligomers antibodies. Our results opens the epistemic horizon and reveal real differences between the four groups (Controls vs obesity, T1DM or T2DM) accelerating the process of understanding and discovering novel and more efficient prevention, diagnostic, transmission and therapeutic pathways.

Diabetes Drug Discovery: hIAPP1-37 Polymorphic Amyloid Structures as Novel Therapeutic Targets.

Human islet amyloid peptide (hIAPP1-37) aggregation is an early step in Diabetes Mellitus. We aimed to evaluate a family of pharmaco-chaperones to act as modulators that provide dynamic interventions and the multi-target capacity (native state, cytotoxic oligomers, protofilaments and fibrils of hIAPP1-37) required to meet the treatment challenges of diabetes. We used a cross-functional approach that combines in silico and in vitro biochemical and biophysical methods to study the hIAPP1-37 aggregation-oligomerization process as to reveal novel potential anti-diabetic drugs. The family of pharmaco-chaperones are modulators of the oligomerization and fibre formation of hIAPP1-37. When they interact with the amino acid in the amyloid-like steric zipper zone, they inhibit and/or delay the aggregation-oligomerization pathway by binding and stabilizing several amyloid structures of hIAPP1-37. Moreover, they can protect cerebellar granule cells (CGC) from the cytotoxicity produced by the hIAPP1-37 oligomers. The modulation of proteostasis by the family of pharmaco-chaperones A-F is a promising potential approach to limit the onset and progression of diabetes and its comorbidities.

Amyloid Biomarkers in Conformational Diseases at Face Value: A Systematic Review.

Conformational diseases represent a new aspect of proteomic medicine where diagnostic and therapeutic paradigms are evolving. In this context, the early biomarkers for target cell failure (neurons, ß-cells, etc.) represent a challenge to translational medicine and play a multidimensional role as biomarkers and potential therapeutic targets. This systematic review, which follows the PICO and Prisma methods, analyses this new-fangled multidimensionality, its strengths and limitations, and presents the future possibilities it opens up. The nuclear diagnosis methods are immunoassays: ELISA, immunodot, western blot, etc., while the therapeutic approach is focused on pharmaco- and molecular chaperones.

Smoothed Body Composition Percentiles Curves for Mexican Children Aged 6 to 12 Years.

Overweight children and childhood obesity are a public health problem in Mexico. Obesity is traditionally assessed using body mass index (BMI), but an excess of adiposity does not necessarily reflect a high BMI. Thus, body composition indexes are a better alternative. Our objective was to generate body composition percentile curves in children from Mexico City. A total of 2026 boys and 1488 girls aged 6 to 12 years old were studied in Mexico City. Body weight, height, and BMI calculation were measured. Total body fat percentage (TBFP) was derived from the skinfold thicknesses, and fat mass (FMI) and free fat mass indexes (FFMI) were calculated. Finally, age- and gender-specific smoothed percentile curves were generated with Cole's Lambda, Mu, and Sigma (LMS) method. In general, height, weight, waist circumference (WC), and TBFP were higher in boys, but FFM was higher in girls. TBFP appeared to increase significantly between ages 8 and 9 in boys (+2.9%) and between ages 10 and 11 in girls (+1.2%). In contrast, FFM% decreased noticeably between ages 8 and 9 until 12 years old in boys and girls. FMI values peaked in boys at age 12 (P97 = 14.1 kg/m²) and in girls at age 11 (P97 = 8.8 kg/m²). FFMI percentiles increase at a steady state reaching a peak at age 12 in boys and girls. Smoothed body composition percentiles showed a different pattern in boys and girls. The use of TBFP, FMI, and FFMI along with BMI provides valuable information in epidemiological, nutritional, and clinical research.

Novel insight into streptozotocin-induced diabetic rats from the protein misfolding perspective.

Protein folding is a process of self-assembly defined by the sequence of the amino acids of the protein involved. Additionally, proteins tend to unfold, misfold and aggregate due to both intrinsic and extrinsic causes. Human islet amyloid polypeptide (hIAPP) aggregation is an early step in diabetes mellitus. However, the aggregation of rat IAPP (rIAPP) remains an open question. Adult female Sprague-Dawley rats weighing 150-250 g were divided into two groups. The experimental group (streptozotocin [STZ]) (n = 21) received an intraperitoneal injection of a single dose of 40 mg/kg STZ. We used the mouse anti-IAPP antibody and the anti-amyloid oligomer antibody to study the temporal course of rIAPP oligomerization during STZ-induced diabetes using a wide array of methods, strategies and ideas derived from biochemistry, cell biology, and proteomic medicine. Here, we demonstrated the tendency of rIAPP to aggregate and trigger cooperative processes of self-association or hetero-assembly that lead to the formation of amyloid oligomers (trimers and hexamers). Our results are the first to demonstrate the role of rIAPP amyloid oligomers in the development of STZ-induced diabetes in rats. The IAPP amyloid oligomers are biomarkers of the onset and progression of diabetes and could play a role as therapeutic targets.

Today´s medical self and the other: Challenges and evolving solutions for enhanced humanization and quality of care.

BACKGROUND: Recent scientific developments, along with growing awareness of cultural and social diversity, have led to a continuously growing range of available treatment options; however, such developments occasionally lead to an undesirable imbalance between science, technology and humanism in clinical practice. This study explores the understanding and practice of values and value clusters in real-life clinical settings, as well as their role in the humanization of medicine and its institutions. The research focuses on the values of clinical practice as a means of finding ways to enhance the pairing of Evidence-Based Medicine (EBM) with Values-based Medicine (VBM) in daily practice. METHODS AND FINDINGS: The views and representations of clinical practice in 15 pre-CME and 15 post-CME interviews were obtained from a random sampling of active healthcare professionals. These views were then identified and qualitatively analyzed using a three-step hermeneutical approach. A clinical values space was identified in which ethical and epistemic values emerge, grow and develop within the biomedical, ethical, and socio-economic dimensions of everyday health care. Three main values-as well as the dynamic clusters and networks that they tend to form-were recognized: healthcare personnel-patient relationships, empathy, and respect. An examination of the interviews suggested that an adequate conceptualization of values leads to the formation of a wider axiological system. The role of clinician-as-consociate emerged as an ideal for achieving medical excellence. CONCLUSIONS: By showing the intricate clusters and networks into which values are interwoven, our analysis suggests methods for fine-tuning educational interventions so they can lead to demonstrable changes in attitudes and practices.

Drug Development in Conformational Diseases: A Novel Family of Chemical Chaperones that Bind and Stabilise Several Polymorphic Amyloid Structures.

The increasing prevalence of conformational diseases, including Alzheimer's disease, type 2 Diabetes Mellitus and Cancer, poses a global challenge at many different levels. It has devastating effects on the sufferers as well as a tremendous economic impact on families and the health system. In this work, we apply a cross-functional approach that combines ideas, concepts and technologies from several disciplines in order to study, in silico and in vitro, the role of a novel chemical chaperones family (NCHCHF) in processes of protein aggregation in conformational diseases. Given that Serum Albumin (SA) is the most abundant protein in the blood of mammals, and Bovine Serum Albumin (BSA) is an off-the-shelf protein available in most labs around the world, we compared the ligandability of BSA:NCHCHF with the interaction sites in the Human Islet Amyloid Polypeptide (hIAPP):NCHCHF, and in the amyloid pharmacophore fragments (Aß17-42 and Aß16-21):NCHCHF. We posit that the merging of this interaction sites is a meta-structure of pharmacophore which allows the development of chaperones that can prevent protein aggregation at various states from: stabilizing the native state to destabilizing oligomeric state and protofilament. Furthermore to stabilize fibrillar structures, thus decreasing the amount of toxic oligomers in solution, as is the case with the NCHCHF. The paper demonstrates how a set of NCHCHF can be used for studying and potentially treating the various physiopathological stages of a conformational disease. For instance, when dealing with an acute phase of cytotoxicity, what is needed is the recruitment of cytotoxic oligomers, thus chaperone F, which accelerates fiber formation, would be very useful; whereas in a chronic stage it is better to have chaperones A, B, C, and D, which stabilize the native and fibril structures halting self-catalysis and the creation of cytotoxic oligomers as a consequence of fiber formation. Furthermore, all the chaperones are able to protect and recondition the cerebellar granule cells (CGC) from the cytotoxicity produced by the hIAPP20-29 fragment or by a low potassium medium, regardless of their capacity for accelerating or inhibiting in vitro formation of fibers. In vivo animal experiments are required to study the impact of chemical chaperones in cognitive and metabolic syndromes.

Novel ethical dilemmas arising in geriatric clinical practice.

The purpose of this study is to determine empirically the state of the art of the medical care, when healthcare personal is confronted with ethical dilemmas related with the care they give to the geriatric population. An observational, longitudinal, prospective and qualitative study was conducted by analyzing the correlation between healthcare personnel-patient relationship, and ethical judgments regarding dilemmas that arise in daily clinical practice with geriatric patients. Mexican healthcare personnel with current active practices were asked to write up an ethical dilemma that arose frequently or that had impacted their medical practice. From the narrative input, we were able to draw up a database with 421 dilemmas, and those corresponding to patients 60 years and older were selected (n = 54, 12.8 %). The axiological analysis of the narrative dilemmas of geriatric patients was made using dialectical empiricism. The axiological analysis values found most frequently were classified into three groups: the impact of healthcare, the roles of the physician, and refusal of therapy; the healthcare role of educator, caring for the patients' life and the risk of imminent death where the values found more often. The persistence and universality of certain dilemmas in geriatrics calls for awareness and requires a good training in the ethical discernment of these dilemmas. This would help to improve substantially the care and the life quality of this population.

Promoting networks between evidence-based medicine and values-based medicine in continuing medical education.

BACKGROUND: In recent years, medical practice has followed two different paradigms: evidence-based medicine (EBM) and values-based medicine (VBM). There is an urgent need to promote medical education that strengthens the relationship between these two paradigms. This work is designed to establish the foundations for a continuing medical education (CME) program aimed at encouraging the dialogue between EBM and VBM by determining the values relevant to everyday medical activities. METHODS: A quasi-experimental, observational, comparative, prospective and qualitative study was conducted by analyzing through a concurrent triangulation strategy the correlation between healthcare personnel-patient relationship, healthcare personnel's life history, and ethical judgments regarding dilemmas that arise in daily clinical practice.In 2009, healthcare personnel working in Mexico were invited to participate in a free, online clinical ethics course. Each participant responded to a set of online survey instruments before and after the CME program. Face-to-face semi-structured interviews were conducted with healthcare personnel, focusing on their views and representations of clinical practice. RESULTS: The healthcare personnel's core values were honesty and respect. There were significant differences in the clinical practice axiology before and after the course (P <0.001); notably, autonomy climbed from the 10th (order mean (OM) = 8.00) to the 3rd position (OM = 5.86). In ethical discernment, the CME program had an impact on autonomy (P ≤0.0001). Utilitarian autonomy was reinforced in the participants (P ≤0.0001). Regarding work values, significant differences due to the CME intervention were found in openness to change (OC) (P <0.000), self-transcendence (ST) (P <0.001), and self-enhancement (SE) (P <0.019). Predominant values in life history, ethical discernment and healthcare personnel-patient relation were beneficence, respect and compassion, respectively. CONCLUSIONS: The healthcare personnel participating in a CME intervention in clinical ethics improved high-order values: Openness to change (OC) and Self Transcendence (ST), which are essential to fulfilling the healing ends of medicine. The CME intervention strengthened the role of educators and advisors with respect to healthcare personnel. The ethical values developed by healthcare professionals arise from their life history and their professional formation.

Del proteoma humano a la medicina transfuncional personalizada / From human proteome to cross-functional personalized medicine

Actualmente, se ha dado una revolución tecnológica en la medicina personalizada. En esta nueva fase de la proteómica, la prioridad es la apreciación de los valores y virtudes del ser humano. Por esto, no debemos olvidar que las dos razones principales de la medicina personalizada son el reconocimiento de la dignidad de la persona y el diagnóstico y el tratamiento hecho a la medida para cada paciente, se deben tomar en cuenta el trasfondo social y el entorno ambiental a la par de los genes y las proteínas.

Personalized medicine has led the technological revolution in proteomics into a new phase where appreciation of the values and virtues of the human being are paramount. Thus we must not forget that the two main reason for personalized medicine are both acknowledgment of the person's dignity and a tailored diagnosis and treatment of each patient, taking into account not only genes and proteins but also the person's social background and environment.

¿Cómo prepararnos para la deliberación ética en la práctica clínica en pediatría? / Rethinking ethical decision-making in pediatrics

En el siglo XXI, el reto para la medicina es utilizar nuevamente términos, como filantropía y filotecnia, para la práctica clínica contemporánea, ya que estos términos se adaptan a nuestro actual entendimiento de que la medicina basada en valores y la medicina basada en evidencias deben ir siempre de la mano. Nuestro propósito es proponer un método integral de deliberación ética que implique una visión holística de los dilemas éticos en la práctica clínica de la pediatría.

A challenge for 21st century medicine is to rediscover the value of philanthropy and philotechnia in contemporary clinical practice because both are terms that adapt to our more current understanding of how value-based medicine and evidence-based medicine must always go "hand in hand." Our proposal is to offer an integral ethical deliberation method that implies a holistic view of the ethical dilemmas in pediatric clinical practice.