Miracle-dz/UniFAR-FTUs huggingface dataset:
Control of the heat stress‐induced alternative splicing of a subset of genes by hnRNP K

Pre‐mRNA splicing is widely repressed upon heat shock in eukaryotic cells. However, it has been shown that HSP105 pre‐mRNA is alternatively spliced in response to heat stress. Using RNAi screening in HeLa cells, we found that RNA‐binding proteins hnRNP K and PSF/SFPQ are necessary for the exon 12 exclusion of HSP105 during heat stress. Moreover, exon array analyses showed that a group of genes is alternatively spliced during heat stress in an hnRNP K‐dependent manner, whereas hnRNP K is not necessary for the stress‐induced alternative splicing of the remaining genes. Among the latter group, we found that SRp38/SRSF10 and SC35/SRSF2 are necessary for the inclusion of exon 13 of TNRC6A during heat stress. Thus, our study clearly showed that several RNA‐binding proteins are involved in the splicing regulation in response to heat stress in mammalian cells.
Perturbing low dimensional activity manifolds in spiking neuronal networks

Several recent studies have shown that neural activity in vivo tends to be constrained to a low-dimensional manifold. Such activity does not arise in simulated neural networks with homogeneous connectivity and it has been suggested that it is indicative of some other connectivity pattern in neuronal networks. In particular, this connectivity pattern appears to be constraining learning so that only neural activity patterns falling within the intrinsic manifold can be learned and elicited. Here, we use three different models of spiking neural networks (echo-state networks, the Neural Engineering Framework and Efficient Coding) to demonstrate how the intrinsic manifold can be made a direct consequence of the circuit connectivity. Using this relationship between the circuit connectivity and the intrinsic manifold, we show that learning of patterns outside the intrinsic manifold corresponds to much larger changes in synaptic weights than learning of patterns within the intrinsic manifold. Assuming larger changes to synaptic weights requires extensive learning, this observation provides an explanation of why learning is easier when it does not require the neural activity to leave its intrinsic manifold.
Diverse spinal commissural neuron populations revealed by fate mapping and molecular profiling using a novel Robo3Cre mouse

The two sides of the nervous system coordinate and integrate information via commissural neurons, which project axons across the midline. Commissural neurons in the spinal cord are a highly heterogeneous population of cells with respect to their birthplace, final cell body position, axonal trajectory, and neurotransmitter phenotype. Although commissural axon guidance during development has been studied in great detail, neither the developmental origins nor the mature phenotypes of commissural neurons have been characterized comprehensively, largely due to lack of selective genetic access to these neurons. Here, we generated mice expressing Cre recombinase from the Robo3 locus specifically in commissural neurons. We used Robo3 Cre mice to characterize the transcriptome and various origins of developing commissural neurons, revealing new details about their extensive heterogeneity in molecular makeup and developmental lineage. Further, we followed the fate of commissural neurons into adulthood, thereby elucidating their settling positions and molecular diversity and providing evidence for possible functions in various spinal cord circuits. Our studies establish an important genetic entry point for further analyses of commissural neuron development, connectivity, and function.
The pig transport network in Switzerland: Structure, patterns, and implications for the transmission of infectious diseases between animal holdings

The topology of animal transport networks contributes substantially to how fast and to what extent a disease can transmit between animal holdings. Therefore, public authorities in many countries mandate livestock holdings to report all movements of animals. However, the reported data often does not contain information about the exact sequence of transports, making it impossible to assess the effect of truck sharing and truck contamination on disease transmission. The aim of this study was to analyze the topology of the Swiss pig transport network by means of social network analysis and to assess the implications for disease transmission between animal holdings. In particular, we studied how additional information about transport sequences changes the topology of the contact network. The study is based on the official animal movement database in Switzerland and a sample of transport data from one transport company. The results show that the Swiss pig transport network is highly fragmented, which mitigates the risk of a large-scale disease outbreak. By considering the time sequence of transports, we found that even in the worst case, only 0.34% of all farm-pairs were connected within one month. However, both network connectivity and individual connectedness of farms increased if truck sharing and especially truck contamination were considered. Therefore, the extent to which a disease may be transmitted between animal holdings may be underestimated if we only consider data from the official animal movement database. Our results highlight the need for a comprehensive analysis of contacts between farms that includes indirect contacts due to truck sharing and contamination. As the nature of animal transport networks is inherently temporal, we strongly suggest the use of temporal network measures in order to evaluate individual and overall risk of disease transmission through animal transportation.
Individual Differences in Women During Walking Affect Tibial Response to Load Carriage: The Importance of Individualized Musculoskeletal Finite-Element Models

Subject-specific features can contribute to the susceptibility of an individual to stress fracture. Here, we incorporated tibial morphology and material properties into a standard musculoskeletal finite-element (M/FE) model and investigated how load carriage influences joint kinetics and tibial mechanics in women. We obtained the morphology and material properties of the tibia from computed tomography images for women of three distinctly different heights, 1.51 m (short), 1.63 m (medium), and 1.75 m (tall), and developed individualized M/FE models for each. Then, we calculated joint and muscle forces, and subsequently, tibial stress/strain for each woman walking at 1.3 m/s under various load conditions (0, 11.3, or 22.7 kg). Among the subjects investigated, using individualized and standard M/FE models, the joint reaction forces (JRFs) differed by up to 4 (hip), 22 (knee), and 26% (ankle), and the 90th percentile von Mises stress by up to 30% (tall woman). Load carriage evoked distinct biomechanical responses, with a 22.7-kg load decreasing the peak hip JRF during late stance by ∼18% in the short woman, while increasing it by ∼39% in the other two women. It also increased peak knee and ankle JRFs by up to ∼48 (tall woman) and ∼36% (short woman). The same load increased the 90th percentile von Mises stress (and corresponding cumulative stress) by 31 (28), 22 (30), and 27% (32%) in the short, medium, and tall woman, respectively. Our findings highlight the critical role of individualized M/FE models to assess mechanical loading in different individuals performing the same physical activity.
Time to Reflect on the Role of Motor Control in Low Back Pain.

The articles in this special issue on low back pain are the outcome of work undertaken by a series of working parties established during the meeting, "State-of-the-Art in Motor Control and Low Back Pain: International Clinical and Research Expert Forum," held in Chicago in October 2015. This multidisciplinary meeting provided an opportunity for discussion of key issues that interconnect motor control, pain, and the spine. What started as a relatively straightforward objective to summarize the field subsequently developed into an extensive process of literature review and discussion that culminated in the commentaries and articles presented in this special issue. We hope that the up-to-date information and in-depth insights into pain, motor control, and rehabilitation provide novel insights and a clear trajectory for future work and form the foundation for ongoing lively discussion. J Orthop Sports Phys Ther 2019;49(6):367-369. doi:10.2519/jospt.2019. 0104.
Severe Acute Malnutrition Results in Lower Lumefantrine Exposure in Children Treated With Artemether‐Lumefantrine for Uncomplicated Malaria

Severe acute malnutrition (SAM) has been reported to be associated with increased malaria morbidity in Sub‐Saharan African children and may affect the pharmacology of antimalarial drugs. This population pharmacokinetic (PK)‐pharmacodynamic study included 131 SAM and 266 non‐SAM children administered artemether‐lumefantrine twice daily for 3 days. Lumefantrine capillary plasma concentrations were adequately described by two transit‐absorption compartments followed by two distribution compartments. Allometrically scaled body weight and an enzymatic maturation effect were included in the PK model. Mid‐upper arm circumference was associated with decreased absorption of lumefantrine (25.4% decreased absorption per 1 cm reduction). Risk of recurrent malaria episodes (i.e., reinfection) were characterized by an interval‐censored time‐to‐event model with a sigmoid maximum‐effect model describing the effect of lumefantrine. SAM children were at risk of underexposure to lumefantrine and an increased risk of malaria reinfection compared with well‐nourished children. Research on optimized regimens should be considered for malaria treatment in malnourished children.
Plant Desiccation and Protein Synthesis : V. Stability of Poly (A) and Poly (A) RNA during Desiccation and Their Synthesis upon Rehydration in the Desiccation-Tolerant Moss Tortula ruralis and the Intolerant Moss Cratoneuron filicinum.

Upon desiccation of gametophytes of the desiccation-tolerant moss Tortula ruralis preexisting pools of poly(A)(-) RNA (rRNA) remain inact, regardless of the speed at which desiccation is achieved. Preexisting poly(A)(+) RNA pools (mRNA) are unaffected by slow desiccation but are substantially reduced during rapid desiccation. Poly(A)(-) RNA involved in protein synthesis is also unaffected by desiccation, whereas the levels of polysomal poly(A)(+) RNA in rapid- and slow-dried moss closely reflect the state of the protein synthetic complex in these dried samples.Poly(A)(-) RNA pools, both total and polysomal, are also stable during the rehydration of both rapid- and slow-dried moss. The total poly(A)(+) RNA pool decreases upon rehydration, but this reduction is simply an expression of the normal turnover of poly(A)(+) RNA in this moss. Analysis of polysomal fractions during rehydration reveals the continued use of conserved poly(A)(+) RNA for protein synthesis. The rate of synthesis of poly(A)(+) RNA upon rehydration appears to depend upon the speed at which prior desiccation is administered. Rapidly dried moss synthesizes poly(A)(+) RNA at a faster rate, 60 to 120 minutes after the addition of water, than does rehydrated slowly dried moss. Recruitment of this RNA into the protein synthetic complex also follows this pattern. Comparative studies involving the aquatic moss Cratoneuron filicinum are used to gain an insight into the relevance of these findings with respect to the cellular mechanisms associated with desiccation tolerance.
Climate change has likely already affected global food production

Crop yields are projected to decrease under future climate conditions, and recent research suggests that yields have already been impacted. However, current impacts on a diversity of crops subnationally and implications for food security remains unclear. Here, we constructed linear regression relationships using weather and reported crop data to assess the potential impact of observed climate change on the yields of the top ten global crops–barley, cassava, maize, oil palm, rapeseed, rice, sorghum, soybean, sugarcane and wheat at ~20,000 political units. We find that the impact of global climate change on yields of different crops from climate trends ranged from -13.4% (oil palm) to 3.5% (soybean). Our results show that impacts are mostly negative in Europe, Southern Africa and Australia but generally positive in Latin America. Impacts in Asia and Northern and Central America are mixed. This has likely led to ~1% average reduction (-3.5 X 1013 kcal/year) in consumable food calories in these ten crops. In nearly half of food insecure countries, estimated caloric availability decreased. Our results suggest that climate change has already affected global food production.
Multiple rare and common variants in APOB gene locus associated with oxidatively modified low-density lipoprotein levels

Oxidatively modified low-density lipoproteins (oxLDL) play an important role in the occurrence and progression of atherosclerosis. To identify the genetic factors influencing the oxLDL levels, we have genotyped 776 DNA samples of Russian individuals for 196,725 single-nucleotide polymorphisms (SNPs) using the Cardio-MetaboChip (Illumina, USA) and conducted genome-wide association study (GWAS). Fourteen common variants in the locus including APOB gene were significantly associated with the oxLDL levels (P < 2.18 × 10−7). These variants explained only 6% of the variation in the oxLDL levels. Then, we assessed the contribution of rare coding variants of APOB gene to the oxLDL levels. Individuals with the extreme oxLDL levels (48 with the lowest and 48 with the highest values) were selected for targeted sequencing of the region including APOB gene. To evaluate the contribution of the SNPs to the oxLDL levels we used various statistical methods for the association analysis of rare variants: WST, SKAT, and SKAT-O. We revealed that both synonymous and nonsynonymous SNPs affected the oxLDL levels. For the joint analysis of the rare and common variants, we conducted the SKAT-C testing and found a group of 15 SNPs significantly associated with the oxLDL levels (P = 2.14 × 10−9). Our results indicate that the oxLDL levels depend on both common and rare variants of the APOB gene.
Physical activity and risk of instant and 28-day case-fatality in myocardial infarction

Background While physical activity reduces risk of developing myocardial infarction (MI), it is unknown whether a history of physical activity is also protective of fatal arrhythmia and case-fatality in patients who have suffered an acute MI. Methods 104,801 individuals included in 2003–2014 in the Copenhagen General Population Study (CGPS), a prospective population-based study with self-reported leisure time physical activity (LTPA) in three categories measured at baseline, were followed until 2014 through national registries. The 1,517 individuals who suffered a first time MI during follow-up constituted the study population. Outcomes were fatal MI, defined as date of death same as date of MI (including out-of-hospital deaths) and 28-day fatality. Through multivariable analyses the association between baseline LTPA and outcomes were assessed adjusted for CVD risk factors. Results Of 1,517 MI events, 117 (7.7%) were fatal and another 79 (5.6%) lead to death within 28 days. Median time from baseline to MI was 3.6 years (IQR 1.7–5.8). LTPA was associated with lower risk of fatal MI with odds ratios of 0.40 (95% CI: 0.22–0.73) for light and 0.41 (0.22–0.76) for moderate/high LTPA after multivariable adjustment with sedentary LTPA as reference. Age, alcohol-intake, education and smoking were identified as other predictors for fatal MI. We found no association between LTPA and 28-day case fatality. Conclusions Among individuals with MI, those that have engaged in any light or moderate physical activity were more likely to survive their MI. Results are consistent with effect of exercise preconditioning on risk of fatal arrhythmia.
Counting Low-Period Cycles for Flows

In this paper we describe a rigorous method to find for a continuous system all low-period cycles enclosed in a certain region of the state space. As an example of the application of this technique we present the complete analysis of the Rossler attractor in terms of short periodic orbits. We construct the trapping region for the associated Poincare map. The trapping region encloses the numerically observed attractor. We find all periodic orbits of the Poincare map up to period 20. We prove that these periodic orbits correspond to all cycles of the flow with period shorter than 120. Using the number of short periodic orbits we compute estimates for topological entropy of the Poincare map and the flow.
Citric Acid Tunes the Formation of Antimicrobial Melanin-Like Nanostructures

Nature has provided a valuable source of inspiration for developing high performance multifunctional materials. Particularly, catechol-containing amino acid l-3,4-dihydroxyphenylalanine (l-DOPA) has aroused the interest to design hybrid multifunctional materials with superior adhesive ability. DOPA oxidative polymerization mediated by either melanogenic enzymes or an alkaline environment involving catechol intermolecular cross-linking, ultimately leads to melanin oligomers. Recently, relevant studies disclosed the ability of Ti-based nanostructures to tune melanin’s supramolecular structure during its formation, starting from melanogenic precursors, thus improving both antioxidant and antimicrobial properties. In this work, we propose a novel biomimetic approach to design hybrid DOPA melanin-like nanostructures through a hydrothermal synthesis opportunely modified by using citric acid to control hydrolysis and condensation reactions of titanium alkoxide precursors. UV-Vis and Electron paramagnetic resonance (EPR) spectroscopic evidences highlighted the key role of citrate–Ti(IV) and DOPA–Ti(IV) complexes in controlling DOPA polymerization, which specifically occurred during the hydrothermal step, mediating and tuning its conversion to melanin-like oligomers. Trasmission electron microscopy (TEM) images proved the efficacy of the proposed synthesis approach in tuning the formation of nanosized globular nanostructures, with high biocide performances. The obtained findings could provide strategic guidelines to set up biomimetic processes, exploiting the catechol-metal complex to obtain hybrid melanin-like nanosystems with optimized multifunctional behavior.
Development of the Inhibitors That Target the PD-1/PD-L1 Interaction—A Brief Look at Progress on Small Molecules, Peptides and Macrocycles

Cancer immunotherapy based on antibodies targeting the immune checkpoint PD-1/PD-L1 pathway has seen unprecedented clinical responses and constitutes the new paradigm in cancer therapy. The antibody-based immunotherapies have several limitations such as high production cost of the antibodies or their long half-life. Small-molecule inhibitors of the PD-1/PD-L1 interaction have been highly anticipated as a promising alternative or complementary therapeutic to the monoclonal antibodies (mAbs). Currently, the field of developing anti-PD-1/PD-L1 small-molecule inhibitors is intensively explored. In this paper, we review anti-PD-1/PD-L1 small-molecule and peptide-based inhibitors and discuss recent structural and preclinical/clinical aspects of their development. Discovery of the therapeutics based on small-molecule inhibitors of the PD-1/PD-L1 interaction represents a promising but challenging perspective in cancer treatment.
Changes in Structure and Function of the Back Muscles in Low Back Pain: Different Time Points, Observations, and Mechanisms.

SYNOPSIS Spinal health depends on optimal back muscle performance, and this is determined by muscle structure and function. There has been substantial research evaluating the differences in structure and function of many back muscles, including the multifidus and erector spinae, but with considerable variation in results. Many studies have shown atrophy, fat infiltration, and connective tissue accumulation in back muscles, particularly deep fibers of the multifidus, but the results are not uniform. In terms of function, results are also somewhat inconsistent, often reporting lower multifidus activation and augmented recruitment of more superficial components of the multifidus and erector spinae, but, again, with variation between studies. A major recent observation has been the identification of time-dependent differences in features of back muscle adaptation, from acute to subacute/recurrent to chronic states of the condition. Further, these adaptations have been shown to be explained by different time-dependent mechanisms. This has substantial impact on the rationale for rehabilitation approaches. The aim of this commentary was to review and consolidate the breadth of research investigating adaptation in back muscle structure and function, to consider explanations for some of the variation between studies, and to propose how this model can be used to guide rehabilitation in a manner that is tailored to individual patients and to underlying mechanisms. J Orthop Sports Phys Ther 2019;49(6):464-476. doi:10.2519/jospt.2019. 8827.
Mechanisms by which cells of the osteoblast lineage control osteoclast formation and activity

The cells of bone are of two lineages, the osteoblasts arising from pluripotential mesenchymal cells and osteoclasts from hemopoietic precursors of the monocyte‐macrophage series. Resorption of bone by the multinucleate osteoclast requires the generation of new osteoclastsw and their activation. Many hormones and cytokines are able to promote bone resorption by influencing these processes, but they achieve this without acting directly on osteoclastws. Most evidence indicates that their actions are mediated by cells of the osteoblast lineage. Evidence for hormone‐and cytokine‐induced activation of osteoclasts requiring the mediation of osteoblasts comes from studies of rsorption by isolated osteoclasts. However, consistent evidence for a spiceific “activating factor” is lacking, and the argument is presented that the isolated osteoclast resorption assays have not been shown convincingly to be assays of osteoclast activation. The view is presented that osteoblast‐mediated osteoclast activation is the result of several events in the microenvironment without necessarily requiring the existence of a spicific, essential osteoclast activator. On the other hand, a specific promoter of osteoclast differentiation does seem likely to be a product of cells of the stromal/osteoblast series. Evidence in facour of this comes from studies of osteoclast generation in co‐cultures of osteoblast/stromal cells with hemopoietic cells. Conflicting view, maintaining that osteoclasts can develop from hemooietic cells without stromal intervention, might be explaind by varying criteria used in identification of osteoclasts. Osteoblastic and osteoclastic renewal, and the interactions of these lineages, are central to the process of bone remodeling.