Miracle-dz/UniFAR-FTUs huggingface dataset:
Structural Aspects of DNA Repair and Recombination in Crop Improvement

The adverse effects of global climate change combined with an exponentially increasing human population have put substantial constraints on agriculture, accelerating efforts towards ensuring food security for a sustainable future. Conventional plant breeding and modern technologies have led to the creation of plants with better traits and higher productivity. Most crop improvement approaches (conventional breeding, genome modification, and gene editing) primarily rely on DNA repair and recombination (DRR). Studying plant DRR can provide insights into designing new strategies or improvising the present techniques for crop improvement. Even though plants have evolved specialized DRR mechanisms compared to other eukaryotes, most of our insights about plant-DRRs remain rooted in studies conducted in animals. DRR mechanisms in plants include direct repair, nucleotide excision repair (NER), base excision repair (BER), mismatch repair (MMR), non-homologous end joining (NHEJ) and homologous recombination (HR). Although each DRR pathway acts on specific DNA damage, there is crosstalk between these. Considering the importance of DRR pathways as a tool in crop improvement, this review focuses on a general description of each DRR pathway, emphasizing on the structural aspects of key DRR proteins. The review highlights the gaps in our understanding and the importance of studying plant DRR in the context of crop improvement.
Learning a force field from small-molecule crystal lattice predictions enables consistent sub-Angstrom protein-ligand docking

Accurate and rapid calculation of protein-small molecule interaction energies is critical for computational drug discovery. Because of the large chemical space spanned by drug-like molecules, classical force fields contain thousands of parameters describing atom-pair distance and torsional preferences; each parameter is typically optimized independently on simple representative molecules. Here we describe a new approach in which small-molecule force field parameters are jointly optimized guided by the rich source of information contained within thousands of available small molecule crystal structures. We optimize parameters by requiring that the experimentally determined molecular lattice arrangements have lower energy than all alternative lattice arrangements. Thousands of independent crystal lattice-prediction simulations were run on each of 1,386 small molecule crystal structures, and energy function parameters of an implicit solvent energy model were optimized so native crystal lattice arrangements had lowest energy. The resulting energy model was implemented in Rosetta, together with a rapid genetic algorithm docking method employing grid based scoring and receptor flexibility. The success rate of bound structure recapitulation in cross-docking on 1,112 complexes was improved by more than 10% over previously published methods, with solutions within <1 Å in over half of the cases. Our results demonstrate that small molecule crystal structures are a rich source of information for systematically improving computational drug discovery.
Individual Responses to Heat Stress: Implications for Hyperthermia and Physical Work Capacity

Background Extreme heat events are increasing in frequency, severity, and duration. It is well known that heat stress can have a negative impact on occupational health and productivity, particularly during physical work. However, there are no up-to-date reviews on how vulnerability to heat changes as a function of individual characteristics in relation to the risk of hyperthermia and work capacity loss. The objective of this narrative review is to examine the role of individual characteristics on the human heat stress response, specifically in relation to hyperthermia risk and productivity loss in hot workplaces. Finally, we aim to generate practical guidance for industrial hygienists considering our findings. Factors included in the analysis were body mass, body surface area to mass ratio, body fat, aerobic fitness and training, heat adaptation, aging, sex, and chronic health conditions. Findings We found the relevance of any factor to be dynamic, based on the work-type (fixed pace or relative to fitness level), work intensity (low, moderate, or heavy work), climate type (humidity, clothing vapor resistance), and variable of interest (risk of hyperthermia or likelihood of productivity loss). Heat adaptation, high aerobic fitness, and having a large body mass are the most protective factors during heat exposure. Primary detrimental factors include low fitness, low body mass, and lack of heat adaptation. Aging beyond 50 years, being female, and diabetes are less impactful negative factors, since their independent effect is quite small in well matched participants. Skin surface area to mass ratio, body composition, hypertension, and cardiovascular disease are not strong independent predictors of the heat stress response. Conclusion Understanding how individual factors impact responses to heat stress is necessary for the prediction of heat wave impacts on occupational health and work capacity. The recommendations provided in this report could be utilized to help curtail hyperthermia risk and productivity losses induced by heat.
Reproductive Health Literacy and Fertility Awareness Among Polish Female Students

The falling fertility indicators and high prevalence of infertility in Poland make it important for people of reproductive age to have good knowledge of their own fertility in order to be able to take care of their reproductive health. This paper examines reproductive health literacy and fertility awareness among Polish female students. It can help identify gaps in reproductive health education in Poland. The study group included 456 women aged 18–29, who were students of 6 public universities located in Poznan, Poland. The method used was a survey using a self-developed questionnaire assessing the students' knowledge of female and male fertility-related physiology and fertility patterns. The respondents' knowledge was assessed on the basis of the percentage of correct answers. Regression analysis and univariate analysis of variance were used to explore relationships between the students' knowledge and their age, year of study, university and source(s) of information. The average score of correct answers was 55.8%. Older students and medical university students were the most knowledgeable. 93.4% of the respondents correctly identified the optimum age for a woman to have the first child from the point of view of achieving pregnancy fast. Over 90% of the respondents knew such fertility-compromising risks as smoking, diseases and psychological distress. There was much poorer awareness of the adverse effect of unbalanced diet, irregular sleep, and long-lasting physical effort. 47.1% of the students reported gaining information from a number of sources, but as many as 28.3% said their only source was primary or middle school classes. Reproductive health knowledge among the young female students is incomplete, especially as regards lifestyle-related risks. They should be encouraged to supplement it by consulting reliable sources such as health professionals. It is advisable to ensure that the curricula of medical university students provide thorough knowledge in this area, and to arrange suitable electives for students from other universities. As primary and secondary school classes remain an important source of information, quality teaching at these levels should be offered with a focus on making the knowledge as practical and operational as possible. Relevant graduate, postgraduate and in-service courses should be available to professionals responsible for spreading reproductive health knowledge.
Rv3091, An Extracellular Patatin-Like Phospholipase in Mycobacterium tuberculosis, Prolongs Intracellular Survival of Recombinant Mycolicibacterium smegmatis by Mediating Phagosomal Escape

Patatin-like phospholipases (PLPs) are important virulence factors of many pathogens. However, there are no prevailing studies regarding PLPs as a virulence factor of Mycobacterium tuberculosis (Mtb). Analysis of Rv3091, a putative protein of Mtb, shows that it belongs to the PLPs family. Here, we cloned and expressed the rv3091 gene in Mycobacterium smegmatis and, subsequently, conducted protein purification and characterization. We show that it possesses phospholipase A1, phospholipase A2, and lipase activity. We confirm the putative active site residues, namely, Ser214 and Asp407, using site directed mutagenesis. The Rv3091 is an extracellular protein that alters the colony morphology of M. smegmatis. The presence of Rv3091 enhances the intracellular survival capability of M. smegmatis in murine peritoneal macrophages. Additionally, it promotes M. smegmatis phagosomal escape from macrophages. Moreover, Rv3091 significantly increased the survival of M. smegmatis and aggravated lesions in C57BL/6 J murine lungs in vivo. Taken together, our results indicate that Rv3091 as an extracellular PLP that is critical to the pathogenicity of mycobacterium as it allows mycobacterium to utilize phospholipids for its growth and provides resistance to phagosome killing, resulting in its enhanced intracellular survival.
Control of β-glucan exposure by the endo-1,3-glucanase Eng1 in Candida albicans modulates virulence

Candida albicans is a major cause of invasive candidiasis, which has a high mortality rate. The hyphal form of C. albicans is virulent and activates the host innate immune response, while the yeast form is hypovirulent and less immunogenic. The innate immune response is critical for host defense, but overactivation can cause tissue damage and sepsis. The innate immune response can be triggered when the C-type lectin receptor Dectin-1 recognizes β-glucans, which is protected by the outer mannan layer of the cell wall on C. albicans. Here, we demonstrate that there is low level of Dectin-1 binding at the septum of yeast cells, but high level of Dectin-1 binding over the entire surface of hyphae. We find that β-glucan masking in yeast is controlled by two highly expressed yeast proteins, the endo-1,3-β-glucanase Eng1 and the Yeast Wall Protein Ywp1. An eng1 deletion mutant shows enhanced Dectin-1 binding at the septa, while an eng1 ywp1 double mutant, but not an ywp1 single mutant, shows strong overall Dectin-1 binding. Thus, Eng1-mediated β-glucan trimming and Ywp1-mediated β-glucan masking are two parallel mechanisms utilized by C. albicans yeast to minimize recognition by Dectin-1. In the model of disseminated candidiasis, mice infected with the eng1 deletion mutant showed delayed mortality with an increased renal immune response in males compared to mice infected with the wild-type strain, but earlier mortality with a higher renal immune response in females. Using the eng1 mutant that is specifically defective in β-glucan masking in yeast, this study demonstrates that the level of β-glucan exposure is important for modulating the balance between immune protection and immunopathogenesis. Abstract Importance Candida albicans is a major opportunistic fungal pathogen of humans. Systemic Candidiasis has high mortality rates. C. albicans is also a constituent of the human microbiome and found in gastrointestinal and genitourinary tracts of most healthy individuals. C. albicans is able to switch reversibly between yeast and hyphae in response to environmental cues. The hyphal form is virulent, while the yeast form is hypovirulent and less immunogenic. This study demonstrates that β-glucan exposure in yeast is protected by two highly expressed yeast proteins, the endo-1,3-β-glucanase Eng1 and the Yeast Wall Protein Ywp1. Eng1-mediated β-glucan trimming and Ywp1-mediated β-glucan masking are two parallel mechanisms utilized by C. albicans yeast to minimize recognition by the host C-type lectin receptor Dectin-1. The eng1 mutant triggers a higher immune response and leads to earlier mortality compared to the wild-type strain. Thus, β-glucan masking in yeast keeps yeast cells less immunogenic and hypovirulent.
Phase precession in the human hippocampus and entorhinal cortex

Knowing where we are, where we have been, and where we are going is critical to many behaviors, including navigation and memory. One potential neuronal mechanism underlying this ability is phase precession, in which spatially tuned neurons represent sequences of positions by activating at progressively earlier phases of local network theta (~5–10 Hz) oscillations. Phase precession may be a general neural pattern for representing sequential events for learning and memory. However, phase precession has never been observed in humans. By recording human single-neuron activity during spatial navigation, we show that spatially tuned neurons in the human hippocampus and entorhinal cortex exhibit phase precession. Furthermore, beyond the neural representation of locations, we show evidence for phase precession related to specific goal-states. Our findings thus extend theta phase precession to humans and suggest that this phenomenon has a broad functional role for the neural representation of both spatial and non-spatial information.
Joint actions of diverse transcription factor families ensure enhancer selectivity and robust neuron terminal differentiation

Identifying general principles for neuron-type specification programs remains a major challenge. Here we performed RNA interference (RNAi) screen against all 875 transcription factors (TFs) encoded in Caenorhabditis elegans genome to systematically investigate the complexity of neuron-specification regulatory networks. Using this library, we screened for defects in nine different neuron types of the monoaminergic (MA) superclass and two cholinergic motorneurons to search for common themes underlying neuron specification.We identified more than 90 TF candidates to be involved in neuron specification, of which 28 were also confirmed by mutant analysis. Correct specification of each individual neuron type requires at least nine different TFs. Individual neuron types do not usually share TFs involved in their specification but share a common pattern of involved TF families, composed mainly by five out of more than fifty in C. elegans: Homeodomain (HD), basic Helix Loop Helix (bHLH), Zinc Finger (ZF), Basic Leucine Zipper Domain (bZIP) and Nuclear Hormone Receptors (NHR). In addition, we studied terminal differentiation complexity focusing on the dopaminergic terminal regulatory program. We found three TFs (UNC-62, VAB-3 and MEF-2) that work together with the three known dopaminergic terminal selectors (AST-1, CEH-43, CEH-20). This complex combination of TFs provides genetic robustness and imposes a specific gene regulatory signature enriched in the regulatory regions of dopamine effector genes. Our results provide new insights on neuron-type regulatory programs in C. elegans that could help better understand neuron specification and the evolution of neuron types.
Intensity coded octopaminergic modulation of aversive crawling behavior in Drosophila melanogaster larvae

Activation and modulation of sensory-guided behaviors by biogenic amines assure appropriate adaptations to changes in an insect’s environment. Given its genetic tool kit Drosophila melanogaster represents an excellent model organism to study larger networks of neurons by optophysiological methods. Here, we studied stationary crawling movements of 3rd instar larvae and revealed how the octopaminergic VUM neuron system reacts during crawling behavior and tactile stimulations. We conducted calcium imaging experiments on dissections of the isolated nervous system (missing all sensory input) and found spontaneous rhythmic wave pattern of neuronal activity in VUM neuron clusters over the range of thoracic and abdominal neuromeres in the VNC. In contrast, in vivo preparations (semi-intact animals, receiving sensory input) did not reveal such spontaneous rhythmic pattern. However, tactile stimulations activated different clusters of the VUM neuron system simultaneously in these preparations. The activation intensity of VUM neurons in the VNC was correlated with the location and degree of body wall stimulation. While VUM neuron cluster near the respective location of body wall stimulation were less activated more distant cluster showed stronger activation. Repeated gentle touch stimulations led to decreased response intensities, repeated harsh stimulations resulted in increasing intensities over trials. Optophysiological signals correlated highly with crawling behavior in freely moving larvae stimulated similarly. We conclude that the octopaminergic system is strongly coupled to the neuronal pattern generator of crawling movements and that it is simultaneously activated by physical stimulation, rather intensity than sequential coded. We hope that our work raises the interest in whole biogenic network activity and shows that octopamine release does not only underlie “the more the better” principle but instead has a more complex function in control and modulation of insect’s locomotion.
A Highly Selective Perylenediimide-Based Chemosensor: “Naked-Eye” Colorimetric and Fluorescent Turn-On Recognition for Al3+

A novel “turn-on” fluorescent probe (PCN) was designed, synthesized, and characterized with perylene tetracarboxylic disimide as the fluorophore and Schiff base subunit as the metal ion receptor. The probe demonstrated a considerable fluorescence enhancement in the presence of Al3+ in DMF with high selectivity and sensitivity. Furthermore, the considerably “off–on” fluorescence response simultaneously led to the apparent color change from colorless to brilliant yellow, which could also be identified by naked eye easily. The sensing capability of PCN to Al3+ was evaluated by the changes in ultraviolet–visible, fluorescence, Fourier transform–infrared, proton nuclear magnetic resonance, and high-resolution mass spectrometry spectroscopies. The linear concentration range for Al3+ was 0–63 μM with a detection limit of 0.16 μM, which allowed for the quantitative determination of Al3+.
Cell-to-cell spread inhibiting antibodies constitute a correlate of protection against Herpes Simplex Virus Type 1 reactivations

Herpes simplex viruses (HSV) cause ubiquitous human infections. For vaccine development, knowledge concerning correlates of protection against HSV is essential. Therefore, we investigated if humans principally can produce highly protective cell-to-cell spread inhibiting antibodies upon natural infection and whether such antibody responses correlate with protection from HSV reactivation. We established a high-throughput HSV-1 GFP reporter virus-based assay and screened 2496 human plasma samples for HSV-1 cell-to-cell spread inhibiting antibodies. We conducted a survey among the blood donors to analyze the correlation between the presence of cell-to-cell spread inhibiting antibodies in plasma and the frequency of HSV reactivations. In total, 128 of 2496 blood donors (5.1 %) exhibited high levels of HSV-1 cell-to-cell spread inhibiting antibodies in the plasma. Such individuals showed a significantly lower frequency of HSV reactivations compared to subjects without sufficient levels of HSV-1 cell-to-cell spread inhibiting antibodies. This study provides two important findings: (I) a fraction of humans produce HSV cell-to-cell spread inhibiting antibodies upon natural infection and (II) such antibodies correlate with protection against recurrent HSV. Moreover, these elite neutralizers can provide promising material for hyperimmunoglobulin, the isolation of superior antiviral antibodies and information for the design of a vaccine against HSV. Importance Herpes simplex virus 1 infections can cause painful mucosal lesions at the oral or genital tract and severe, life threatening disease in immunosuppressed patients or neonates. There is no approved vaccine available, and the emergence of drug resistances especially in long time treated patients makes the treatment increasingly difficult. We tested 2496 people for HSV-1 cell-to-cell spread inhibiting antibodies. Five percent exhibited functional titers such antibodies and showed significantly lower risk of reactivations, uncovering cell-to-cell spread inhibiting antibodies as a correlate of protection against Herpes simplex virus reactivations. Isolation of the cell-to-cell spread inhibiting antibodies from B-cells of these donors may contribute to develop novel antibody-based interventions for prophylactic and therapeutic use and provide starting material for vaccine development.
A negative feedback loop of the TOR signaling moderates growth and enables rapid sensing of stress signals in plants

TOR kinase is a central coordinator of nutrient-dependent growth in eukaryotes. Maintaining optimal TOR signaling is critical for the normal development of organisms. However, the mechanisms involved in the maintenance of optimal TOR signaling are currently unknown in plants. In this study, we describe a negative feedback loop of TOR signaling helping in the adaptability of plants in changing environmental conditions. Using an interdisciplinary approach, we identified a plant-specific zinc finger protein FLZ8, as a regulator of TOR signaling in Arabidopsis. In sugar sufficiency, FLZ8 is upregulated by TOR-dependent and –independent histone modifications. FLZ8 negatively regulates TOR signaling by promoting antagonistic SnRK1α1 signaling and bridging the interaction of SnRK1α1 with RAPTOR, a crucial accessory protein of TOR. This negative feedback loop moderates the TOR-growth signaling axis in the favorable condition and helps in the rapid activation of stress signaling in unfavorable conditions establishing its importance in the adaptability of plants.
RNA polymerases in strict endosymbiont bacteria with extreme genome reduction show distinct erosions that could result in limited and differential promoters’ recognition

Strict endosymbiont bacteria with high degree of genome reduction retain smaller proteins and, in certain cases, lack complete functional domains compared to their free-living counterparts. Until now, the mechanisms underlying these genetic reductions are not well understood. However, it is thought that, in order to compensate for gene reduction, somehow hosts take over those vital functions that endosymbionts cannot perform. In the present study, the conservation of RNA polymerases, the essential machinery for gene expression, is analysed in bacteria with extreme genome reductions. For this purpose, comparative genomics, phylogenetic analysis and three-dimensional models of RNA polymerase subunits were done over four lineages of endosymbiotic proteobacteria with the smallest genomes known to date. Amino acids under positive selection in the α subunit and loss of motifs in other subunits of RNA polymerase were observed. According to three-dimensional models, sites under positive selection might compensate the loss of motifs in α subunit. In addition, variations in the σ subunit were identified, some of them already studied in E. coli as a result of random mutagenesis. Amino acid changes in RNA polymerase suggest a possible modification in the binding specificity of the canonical −10 box (TATAAT) in some of these organisms. Furthermore, the β-flap helix domain is absent in some Hodgkinia strains, as observed in RNA pol II of Archaea, thus lacking the capacity to bind to the −35 box. Here, we propose several RNA polymerases models for endosymbiont bacteria with extremely reduced genomes. Evidence suggests that RNA polymerases of each endosymbiont bacteria follow a unique evolutionary path, without necessarily following the same path as a lineage, this is probably influenced by the intimate interactions sustained with other endosymbionts and its hosts.