Computational planning of the synthesis of complex natural products.

Training algorithms to computationally plan multistep organic syntheses has been a challenge for more than 50 years1-7. However, the field has progressed greatly since the development of early programs such as LHASA1,7, for which reaction choices at each step were made by human operators. Multiple software platforms6,8-14 are now capable of completely autonomous planning. But these programs 'think' only one step at a time and have so far been limited to relatively simple targets, the syntheses of which could arguably be designed by human chemists within minutes, without the help of a computer. Furthermore, no algorithm has yet been able to design plausible routes to complex natural products, for which much more far-sighted, multistep planning is necessary15,16 and closely related literature precedents cannot be relied on. Here we demonstrate that such computational synthesis planning is possible, provided that the program's knowledge of organic chemistry and data-based artificial intelligence routines are augmented with causal relationships17,18, allowing it to 'strategize' over multiple synthetic steps. Using a Turing-like test administered to synthesis experts, we show that the routes designed by such a program are largely indistinguishable from those designed by humans. We also successfully validated three computer-designed syntheses of natural products in the laboratory. Taken together, these results indicate that expert-level automated synthetic planning is feasible, pending continued improvements to the reaction knowledge base and further code optimization.

Lipids and Lipid-Mediated Signaling in Plant-Pathogen Interactions.

Plant lipids are essential cell constituents with many structural, storage, signaling, and defensive functions. During plant-pathogen interactions, lipids play parts in both the preexisting passive defense mechanisms and the pathogen-induced immune responses at the local and systemic levels. They interact with various components of the plant immune network and can modulate plant defense both positively and negatively. Under biotic stress, lipid signaling is mostly associated with oxygenated natural products derived from unsaturated fatty acids, known as oxylipins; among these, jasmonic acid has been of great interest as a specific mediator of plant defense against necrotrophic pathogens. Although numerous studies have documented the contribution of oxylipins and other lipid-derived species in plant immunity, their specific roles in plant-pathogen interactions and their involvement in the signaling network require further elucidation. This review presents the most relevant and recent studies on lipids and lipid-derived signaling molecules involved in plant-pathogen interactions, with the aim of providing a deeper insight into the mechanisms underpinning lipid-mediated regulation of the plant immune system.

The standardization of the Polish version of the Alberta Infant Motor Scale.

BACKGROUND: The Alberta Infant Motor Scale (AIMS) is a standardized tool for assessing gross motor development from birth through independent walking (0-18 months). The AIMS was developed, validated and standardized in the Canadian population. Results of previous studies on the standardization of the AIMS have discerned differences in some samples in comparison with Canadian norms. This study aimed to establish reference values of the AIMS for the Polish population and compare them to Canadian norms. METHODS: The research involved 431 infants (219 girls, 212 boys, aged 0-<19 months), divided into nineteen age groups. The translated into Polish and validated version of the AIMS was used. The mean AIMS total scores and percentiles for every age group were calculated and compared with the Canadian reference values. Raw total AIMS scores were converted to 5th, 10th, 25th, 50th, 75th, and 90th percentiles. A one sample t-test was used to compare the AIMS total scores between Polish and Canadian infants (p-value < 0.05). A binomial test was performed to compare percentiles (p-value < 0.05). RESULTS: The mean AIMS total scores in the Polish population were significantly lower in the seven age groups: 0-<1, 1-<2, 4-<5, 5-<6, 6-<7, 13-<14, and 15-<16 months of age (with small to large effect size). A few significant differences were found in the comparison of percentile ranks, mostly in the 75th percentile. CONCLUSION: Our study provides the norms for the Polish AIMS version. According to differences in the mean AIMS total scores and percentiles, the original Canadian reference values are not congruent for Polish infants. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT05264064. URL https://clinicaltrials.gov/ct2/show/NCT05264064 . Date of registration: 03/03/2022.

Insulin resistance is associated with impaired olfactory function in adult patients with type 1 diabetes: A cross-sectional study.

AIM: To investigate whether insulin resistance is a predictor for decreased olfactory function in adult type 1 diabetes patients (T1DM). MATERIALS AND METHODS: The following parameters were examined in the group of 113 T1DM participants: body mass index (BMI), waist-hip ratio (WHR), TG/HDL ratio, glycated hemoglobin (HbA1c ), visceral fat (VF) in body bioimpedance, specific calculators (eGDR, VAI). Bilateral olfactory test score (BOTS) was performed using 12-odour-tests from Sniffin' Sticks. Then participants were allocated to one of two groups: normosmia (10-12 odours identified) or hyposmia/anosmia (0-9 odours). The association between BOTS and insulin resistance indicators was analyzed using: Spearman's rank correlation, multivariate linear regression analysis, and receiver operating characteristic (ROC) curve. RESULTS: 49.6% participants were diagnosed with hyposmia/anosmia, median BOTS was 10. BOTS correlated significantly with: WHR, TG, VF index, TG/HDL ratio, VAI, and eGDR. In multivariate linear regression analysis higher WHR turned out to be statistically significant independent predictor of lower BOTS (ß = -0.36; P = .005) after adjustment for age, sex, TG and peripheral neuropathy (R2 = 0.19; P = .0005). The ROC analysis indicated a WHR cut-off of 0.92 [area under the ROC curve (AUC): 0.737; 95% confidence interval (CI): 0.647-0.828, P < .0001] as the best among evaluated factors significantly affecting hyposmia/anosmia occurrence (sensitivity of this cut-off 0.50 and specificity 0.86). CONCLUSIONS: We have provided evidence of an association between lowered insulin sensitivity expressed in bioelectrical impedance analysis, anthropometrical (WHR), laboratory (TG/HDL ratio) measurements, specific calculators (eGDR, VAI) and deteriorated olfactory function.

Synergy Between Expert and Machine-Learning Approaches Allows for Improved Retrosynthetic Planning.

When computers plan multistep syntheses, they can rely either on expert knowledge or information machine-extracted from large reaction repositories. Both approaches suffer from imperfect functions evaluating reaction choices: expert functions are heuristics based on chemical intuition, whereas machine learning (ML) relies on neural networks (NNs) that can make meaningful predictions only about popular reaction types. This paper shows that expert and ML approaches can be synergistic-specifically, when NNs are trained on literature data matched onto high-quality, expert-coded reaction rules, they achieve higher synthetic accuracy than either of the methods alone and, importantly, can also handle rare/specialized reaction types.

Prediction of Major Regio-, Site-, and Diastereoisomers in Diels-Alder Reactions by Using Machine-Learning: The Importance of Physically Meaningful Descriptors.

Machine learning can predict the major regio-, site-, and diastereoselective outcomes of Diels-Alder reactions better than standard quantum-mechanical methods and with accuracies exceeding 90 % provided that i) the diene/dienophile substrates are represented by "physical-organic" descriptors reflecting the electronic and steric characteristics of their substituents and ii) the positions of such substituents relative to the reaction core are encoded ("vectorized") in an informative way.

Propagation of Oscillating Chemical Signals through Reaction Networks.

Akin to electronic systems that can tune to and process signals of select frequencies, systems/networks of chemical reactions also "propagate" time-varying concentration inputs in a frequency-dependent manner. Whereas signals of low frequencies are transmitted, higher frequency inputs are dampened and converted into steady-concentration outputs. Such behavior is observed in both idealized reaction chains as well as realistic signaling cascades, in the latter case explaining the experimentally observed responses of such cascades to input calcium oscillations. These and other results are supported by numerical simulations within the freely available Kinetix web application we developed to study chemical systems of arbitrary architectures, reaction kinetics, and boundary conditions.

Computer-Assisted Synthetic Planning: The End of the Beginning.

Exactly half a century has passed since the launch of the first documented research project (1965 Dendral) on computer-assisted organic synthesis. Many more programs were created in the 1970s and 1980s but the enthusiasm of these pioneering days had largely dissipated by the 2000s, and the challenge of teaching the computer how to plan organic syntheses earned itself the reputation of a "mission impossible". This is quite curious given that, in the meantime, computers have "learned" many other skills that had been considered exclusive domains of human intellect and creativity-for example, machines can nowadays play chess better than human world champions and they can compose classical music pleasant to the human ear. Although there have been no similar feats in organic synthesis, this Review argues that to concede defeat would be premature. Indeed, bringing together the combination of modern computational power and algorithms from graph/network theory, chemical rules (with full stereo- and regiochemistry) coded in appropriate formats, and the elements of quantum mechanics, the machine can finally be "taught" how to plan syntheses of non-trivial organic molecules in a matter of seconds to minutes. The Review begins with an overview of some basic theoretical concepts essential for the big-data analysis of chemical syntheses. It progresses to the problem of optimizing pathways involving known reactions. It culminates with discussion of algorithms that allow for a completely de novo and fully automated design of syntheses leading to relatively complex targets, including those that have not been made before. Of course, there are still things to be improved, but computers are finally becoming relevant and helpful to the practice of organic-synthetic planning. Paraphrasing Churchill's famous words after the Allies' first major victory over the Axis forces in Africa, it is not the end, it is not even the beginning of the end, but it is the end of the beginning for the computer-assisted synthesis planning. The machine is here to stay.

Nickel-induced oxidative stress and phospholipid remodeling in cucumber leaves.

Nickel phytotoxicity has been attributed, among others, to oxidative stress. However, little is known about Ni-induced phospholipid modifications, including the oxidative ones. Accumulation of reactive oxygen species (ROS), antioxidative enzyme activities, malondialdehyde and the early lipid oxidation products contents, membrane permeability, phospholipid profile as well as phospholipid unsaturation degree were studied in the 1st and the 2nd leaves of hydroponically grown cucumber seedlings subjected to Ni stress. Compared to the 2nd leaf the 1st one showed stronger visual Ni toxicity symptoms, higher Ni, O2.- and H2O2 accumulation as well as greater enhancement in membrane permeability. Enzyme activities were differently influenced by Ni stress, however most pronounced changes were generally found in the 1st leaf. Ni treatment resulted in oxidation of leaf lipids, which was evidenced by appearance of increased contents of MDA and the early produced oxylipins. Among the latter 9-hydroxyoctadecatrienoic acid (9-HOTrE) and 13-hydroxyoctadecatrienoic acid (13-HOTrE) contents showed the most pronounced increase in response to Ni treatment. Exposure to the metal led to the changes in the leaf phospholipid profile and increased degree of phospholipid unsaturation. The obtained results have been discussed in relation to the difference in Ni stress severity between the 1st and the 2nd leaves.

Functional and Structural Changes in Patients with Spinal Muscular Atrophy Treated in Poland during 12-Month Follow-Up: A Prospective Cohort Study.

Background: In recent years, rapid advances in diagnosis and treatment have been observed in spinal muscular atrophy (SMA) patients. The introduction of modern therapies and screening tests has significantly changed the clinical picture of the disease. The previous classification has, therefore, been replaced by new phenotypes: non-sitters, sitters, and walkers, defined by the patient's functional level. However, despite the change in the clinical picture of the disease, patients still suffer from accompanying structural disorders such as scoliosis or joint contractures. Their presence also significantly affects the acquisition of subsequent motor skills. Due to this, monitoring structural changes and ensuring therapists are aware of improvements or declines in patient functionality are essential components of clinical practice. This study aims to compare the assessment of structural and functional changes after a 12-month follow-up in SMA patients who have already experienced the effects of the disease and are now receiving modern therapy. Methods: We present a study of 34 SMA patients being treated with modern therapies and tested twice 12 months apart. The participants were tested using structural measurements and validated scales such as The Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) and Hammersmith Functional Motor Scale-Expanded (HFMSE). Results: During the 12-month follow-up, patients showed deteriorating, non-statistically significant structural changes. We also proved that patients showed a trend toward functional improvement. Analyzing the individual scale items, we distinguished which participants obtained the maximum score for a given parameter and no longer had an opportunity to improve during the second examination. Conclusions: Our study proved that most patients improved overall motor function. The examination of structural measurements should become a standard in the evaluation of SMA patients.

The impact of inertial exercises performed in the workplace on shoulder muscles' strength and muscles' fatigue resistance in women with disabilities.

BACKGROUND: Workers who do monotonous and repetitive work in a static position often complain about fatigue and decreased work efficiency. Some studies indicate that to improve muscle fatigue, resistance strength training can be used. MATERIAL AND METHODS: To investigate the effect of 4-week inertial training on shoulder muscles' strength and muscles' fatigue resistance 44 female workers with disabilities were examined. The participants were randomized into the training group (T) (N = 32) and the control group (C) (N = 12). Before the training and after that shoulder muscles' strength were tested at the start and at the end of the workday (Monday and Friday). The participants were asked to complete questionnaire concerning their fatigue at work (T and C), inertial training and work efficiency (T). RESULTS: The work performed during the last day of the workweek, i.e., Friday (before training) resulted in a significant decrease in shoulder muscles' strength in T and C. Muscle strength achieved at the end of the workweek (Friday afternoon) was significantly lower than achieved at the start of the workweek (Monday morning) in both tested groups (before training). Moreover, inertial training resulted in a significant increase in shoulder muscles' strength in T; 34-74% for different muscles. No changes in muscles' strength were noted in C. Increased muscle strength in T following inertial training effectively prevented muscle fatigue. After training the differences in shoulder muscles' strength noted in T during different times of the workday and workweek were insignificant. Moreover, 4-week inertial training increased significantly the work efficiency of women from T by 4%; no changes were noted in C. Inertial training was well tolerated by the participants. CONCLUSIONS: Using inertial training in women with disabilities to prevent shoulder muscles' fatigue during the workday and workweek is recommended. Med Pr Work Health Saf. 2024;75(2):113-122.

Obesity, physical fitness, and inflammatory markers in Polish children.

BACKGROUND: The relationship between obesity, physical fitness, and inflammation was analyzed in a Polish population aged 12 to 18 years. MATERIAL/METHODS: Body mass index measurements and Eurofit physical fitness tests were undertaken to assess the adiposity and physical fitness status, respectively, of subjects. Serum samples were collected to measure standard inflammatory markers, including interleukin 6; and the acute-phase proteins alpha1-acid glycoprotein and alpha1-antichymotrypsin. In addition, the glycosylation profiles of alpha1-acid glycoprotein and alpha1-antichymotrypsin were analyzed to further evaluate immune statuses. RESULTS: The physical fitness of individuals was negatively influenced by obesity. Obese subjects were characterized by an abnormal immune balance, including increased levels of alpha1-acid glycoprotein, as well as alpha1-antichymotrypsin, and altered glycosylation profiles indicative of an underlying inflammatory condition. Older age, male sex, and a large body mass index appeared to correlate with poor physical fitness scores and a disturbed immune status. CONCLUSIONS: Impaired physical fitness is indicative for non-compensated overweight and affects mainly males aged 15 to 18 years. Female subjects seemed to cope better with increased body mass.

Achieving motor development milestones at the age of three months may determine, but does not guarantee, proper further development.

Proper motor performance at 3rd month is necessary for further motor development. The paper aims to demonstrate the reliability, sensitivity, and predictive value of an original motor performance assessment tool in comparison with the neurological assessment at 3, 6, and 9 months. Children (n = 123), born at term without pre- or perinatal complications, born at term with pre- or perinatal complications, or born preterm, were assessed at the age of 3, 6, and 9 months, by a neurologist and a physiotherapist. The physiotherapist evaluated 15 qualitative features typical for the age of 3 months in the prone and supine positions. The final neurological assessment determined the degree of developmental disorder. Neurological and global physiotherapeutic assessments showed a statistically significant correlation. Qualitative assessment results were very good in healthy children and decreased with worsening neurological diagnoses. Children diagnosed with cerebral palsy did not show proper qualitative features of 3 months when analyzed at 3, 6, and 9 months. Children with delayed motor development revealed minor qualitative performance impairments as early as 3 months but improved with age. Qualitative assessment at 3 months not only facilitates diagnosis of major developmental disorders but is also a good predictor of delayed motor development in children.

Influence of age on the outcome of rehabilitation after total hip replacement.

BACKGROUND: This publication compares the results of physiotherapy after total hip replacement in two groups, each consisting of 50 subjects, differing in age by 10 years. MATERIAL AND METHODS: A group of 100 patients after total hip replacement was divided into two subgroups consisting of 50 subjects each, with mean age difference of 10 years. The first group included patients aged 47-60 years, the other 61-69 years. Patients were assessed at 6 weeks and reevaluated at 10 weeks after surgery during a 4-week in-hospital rehabilitation program. The study was based on a questionnaire, physical examination, 6-minute walking test and a test on stabilometric platform. RESULTS: In the younger group we observed easier and faster resolution of pain in the operated joint. In group II, which included patients aged 61 to 69 years, improvement in hip joint mobility was less pronounced than in the younger group. Six-minute walking test showed less improvement in walking distance in group II than group I. Among group II patients we noted less pronounced increase in weight bearing on the operated limb (by 2%, while 4% improvement was noted in group I), while final degree of weight-bearing was greater in group II than in group I and amounted to 48%. CONCLUSIONS: Younger patients recover faster, hip pain subsides easier, hip function returns more readily and to a greater extent. During a 4-week course of in-hospital rehabilitation older patients may regain hip function in a manner that brings them closer to the younger group.

Qualitative assessment in the third month of life allows for a better prognosis of the achievement of motor milestones versus assessment of pathological reflexes- prospective studies on Polish children.

Introduction: The characteristic feature of primitive reflexes is that they occur early in development and must expire at a well-defined age. The study was conducted prospectively on a group of 107 children (74 boys). The study population included 83 infants born on time (weight 3,465 ± 395 g) and 24 born prematurely (weight 2,225 ± 793 g). Methods: An analysis of motor development at 3 months of age consisting of a qualitative assessment (motor performance) and a check of reflexes was performed; at 9 months, the child was checked for crawling and sitting down, and at 16 months for walking. Results: The more abnormal reflexes, the less likely it was to achieve the assessed milestones in time. It is possible to notice that the qualitative assessment is, in each case, a better predictor of the milestones than any of the reflexes, except for walking, where the Babkin reflex was strongly predictive. However, the qualitative assessment sum still occupies the second and third positions in prone and supine positions. Discussion: The occurrence of Babkin's reflex at 3 months of age impacts the achievement of sitting down and walking functions. An abnormal Galant reflex was strongly associated with the lack of occurrence of crawling on time. At the same time, a high-quality score at 3 months of age guarantees the development of crawling on time, sitting down, and walking.

Examination of Upper Limb Function and the Relationship with Gross Motor Functional and Structural Parameters in Patients with Spinal Muscular Atrophy.

Spinal muscular atrophy (SMA) is an autosomal recessive disorder caused by the deletion or/and mutation in the survival motor neuron 1 (SMN1) gene on chromosome 5. Until now, only a few articles investigating the relationship between upper limb function and the gross motor function in untreated SMA patients have been published. However, there is still a lack of publications including the relationship between structural changes such as cervical rotation, trunk rotation and side trunk shortening, and upper limb function. The aim of the study was to examine the upper limb function in patients with spinal muscular atrophy and the relationship between the upper limb function, gross motor function, and structural parameters. We present an analysis of 25 SMA patients, divided into sitter and walker groups, undergoing pharmacological treatment (nusinersen or risdiplam), examined twice between the initial examination and evaluation after a 12-month period. The participants were tested using validated scales such as the Revised Upper Limb Module (RULM), the Hammersmith Functional Motor Scale-Extended (HFMSE), and the structural parameters. Our results showed that patients demonstrated greater improvement on the RULM scale than on the HFMSE scale. Moreover, persistent structural changes negatively affected both the upper limb function and gross motor skills.

Impact of selected risk factors on motor performance in the third month of life and motor development in the ninth month.

Background: Proper motor development can be influenced by a range of risk factors. The resulting motor performance can be assessed through quantitative and qualitative analysis of posture and movement patterns. Methods: This study was designed as the cohort follow-up of the motor assessment and aimed to demonstrate, in a mathematical way, the impact of particular risk factors on elements of motor performance in the 3rd month and the final motor performance in the 9th month of life. Four hundred nineteen children were assessed (236 male and 183 female), including 129 born preterm. Each child aged 3 month underwent a physiotherapeutic assessment of the quantitative and qualitative development, in the prone and supine positions. The neurologist examined each child aged 9 month, referring to the Denver Development Screening Test II and assessing reflexes, muscle tone and symmetry. The following risk factors were analyzed after the neurological consultation: condition at birth (5th min Apgar score), week of gestation at birth, intraventricular hemorrhage, respiratory distress syndrome, and the incidence of intrauterine hypotrophy and hyperbilirubinemia determined based on medical records. Results: A combination of several risk factors affected motor development stronger than any one of them solely, with Apgar score, hyperbilirubinemia, and intraventricular hemorrhage exhibiting the most significant impact. Conclusions: Premature birth on its own did not cause a substantial delay in motor development. Nonetheless, its co-occurrence with other risk factors, namely intraventricular hemorrhage, respiratory distress syndrome, and hyperbilirubinemia, notably worsened motor development prognosis. Moreover, improper position of the vertebral column, scapulae, shoulders, and pelvis in the third month of life may predict disturbances in further motor development.

The Alberta Infant Motor Scale: A tool for the assessment of motor aspects of neurodevelopment in infancy and early childhood.

According to the recommendations of the American Academy of Pediatrics, the surveillance of motor development should accompany systematic appointments with medical professionals in infancy and early childhood. One of the standardized tools for evaluating motor development is the Alberta Infant Motor Scale (AIMS). This paper aims to present assumptions and psychometric properties of the AIMS, the methodology of assessment of an infant's performance with the AIMS, and research on the validation and standardization of the AIMS as well as the use of the scale as an outcome measure. We conducted a non-systematic literature review using three electronic databases: PubMed, Scopus, and Embase (from June 1992 to February 2022). We included original research with a full-text manuscript in English. No geographical restrictions were applied. The search terms "alberta infant motor scale" AND "reliability" OR "validity" and "alberta infant motor scale" AND "norms" OR "reference" OR "standardization" were used for literature review on the validation and standardization of the AIMS in other non-Canadian populations. This narrative review also focuses on how the AIMS is applied as an outcome measure in research by presenting studies on the AIMS conducted over the last decade. Our review found that the AIMS is widely used for both research and clinical purposes. The AIMS has been used as an outcome measure in both interventional and observational studies conducted on both neurotypical infants and those with conditions affecting motor development. The advantages of the scale are its infant-friendliness, time duration of the examination, and relative ease of application for an examiner. The scale has been validated and standardized in many countries.

Running versus cardiorespiratory endurance: not the same issue?

BACKGROUND: Obesity is considered as one of the main chronic, non-communicable diseases, which has become a global epidemic according to the World Health Organization. The present study was a detailed analysis of the endurance and physical fitness of boys at the age of 10-11-12 years depending on their body weight. METHODS: The study group included the total of 71 boys aged 10-12 years, who were divided according to the BMI value. All the boys were subject to the cardiorespiratory endurance assessment using the test by Ruffier and the Cooper's endurance run. RESULTS: The Cooper and Ruffier Test results in the study group according to BMI showed that endurance and physical fitness in obese boys was the poorest. Physical fitness was equally poor in the other subjects, although the level of endurance assessed with the Cooper Test was good. CONCLUSIONS: Regardless of age, the results of physical fitness were much worse than those of endurance in all boys. Even most boys with normal body weight showed average results in the endurance test, and bad ones in the physical fitness test. Obese subjects showed worse results in case of both parameters.

Prospective Analysis of Functional and Structural Changes in Patients with Spinal Muscular Atrophy-A Pilot Study.

Spinal muscular atrophy (SMA) is a rare, autosomal recessive neuromuscular disease. Recent years have seen a significant development of therapeutic options for SMA patients. With the development of treatment methods, it has become necessary to adapt a physiotherapeutic approach to the evolving clinical picture of SMA patients. We presented an analysis of 40 SMA patients undergoing pharmacological treatment, examined twice in an average interval of 5 months. Twelve patients (non-sitters) were evaluated using CHOP-INTEND, while 28 (sitters) were tested using the Hammersmith scale. The research protocol consisted of measurements of upper and lower limb ranges of motion, and four tests for early detection of musculoskeletal changes. Both non-sitters and sitters patients showed motor improvement between the first and second examinations. Favorable changes in range of motion parameters were noted in most children, except for hip extension (HE) range, which deteriorated. An association was also observed between scale scores and the presence of contractures in the hip and knee joints depending on the group studied. Our findings showed that the presence of contractures at the hip and knee joint negatively affected functional improvement as measured by the scale scores.