Miracle-dz/UniFAR-FTUs huggingface dataset:
Where is the right path heading from the centromere to spindle microtubules?

ABSTRACT The kinetochore is a large protein complex that ensures accurate chromosome segregation during mitosis by connecting the centromere and spindle microtubules. One of the kinetochore sub-complexes, the constitutive centromere-associated network (CCAN), associates with the centromere and recruits another sub-complex, the KMN (KNL1, Mis12, and Ndc80 complexes) network (KMN), which binds to spindle microtubules. The CCAN-KMN interaction is mediated by two parallel pathways (CENP-C- and CENP-T-pathways) in the kinetochore, which bridge the centromere and microtubules. Here, we discuss dynamic protein-interaction changes in the two pathways that couple the centromere with spindle microtubules during mitotic progression.
Dietary Polyphenols—Important Non-Nutrients in the Prevention of Chronic Noncommunicable Diseases. A Systematic Review

The improvement of the social and economic conditions of society has eliminated the threat of death from the majority of infectious diseases. However, the rapid progress of civilization has created new possibilities for the appearance of factors with adverse effects for the health of society. This has led to increased morbidity from certain diseases, the presence of which had not been observed several centuries ago. Chronic noncommunicable diseases (e.g., cancers, cardio-vascular disorders, diabetes, obesity, neurodegenerative diseases) result from an inappropriate relationship between people and their environment. The common characteristic for all chronic diseases is a “new” form of inflammation, very often called metaflammation, which is considered as a subclinical, permanent inflammation. As a result, metabolic cascade, including cellular oxidative stress, atherosclerotic process, and insulin resistance, occurs, which slowly generates significant deterioration in the organism. Polyphenols are the major group of non-nutrients, considering their diversity, food occurrence, and biological properties. The current review aims to present a wide spectrum of literature data, including the molecular mechanism of their activity and experimental model used, and summarize the recent findings on the multitude of physiological effects of dietary polyphenols towards the prevention of several chronic diseases. However, despite several studies, the estimation of their dietary intake is troublesome and inconclusive, which will be also discussed.
Towards a semantic analysis of argument/oblique alternations in HPSG

I examine the semantic contrasts exhibited by argument/oblique alternations (argument realization alternations where one or more participants may be realized either as a direct argument or an oblique). Previous HPSG accounts of these have proposed that alternating verbs are ambiguous, where each variant has a structured semantics that makes different participants more or less structurally prominent in the semantic representation. I argue that such accounts fail to capture the full richness of the contrasts exhibited by such alternations, and propose instead a model that derives alternations from the lexical entailments each verb associates with the alternating participant.
Pupil phase apodization for achromatic imaging of extra-solar planets

Direct imaging of extra-solar planets in the visible and infrared region has generated great interest among scientists and the general public as well. However, this is a challenging problem. Difficulties of detecting a planet (faint source) are caused, mostly, by two factors: sidelobes caused by starlight diffraction from the edge of the pupil and the randomly scattered starlight caused by the phase errors from the imperfections in the optical system. While the latter difficulty can be corrected by high density active deformable mirrors with advanced phase sensing and control technology, the optimized strategy for suppressing the diffraction sidelobes is still an open question. In this thesis, I present a new approach to the sidelobe reduction problem: pupil phase apodization. It is based on a discovery that an anti-symmetric spatial phase modulation pattern imposed over a pupil or a relay plane causes diffracted starlight suppression sufficient for imaging of extra-solar planets. Numerical simulations with specific square pupil (side D) phase functions, such as φ(x, y) = a[ln( (1 + e) + 2x/D (1 + e)− 2x/D · (1 + e) + 2y/D (1 + e)− 2y/D )] demonstrate annulling in at least one quadrant of the diffraction plane to the contrast level of better than 10−12 with an inner working angle down to 3. 5λ/D (with a = 3 and e = 10−3). Furthermore, our computer experiments show that phase apodization remains effective throughout a broad spectrum (60% of the central wavelength) covering the entire visible light range. In addition to the specific phase functions that can yield deep sidelobe reduction on one quadrant, we also found that a modified Gerchberg-Saxton algorithm can help to find small sized (101 × 101 element) discrete phase functions if regional sidelobe reduction is desired. Our simulation shows that a 101× 101 segmented but gapless active mirror can also generate a dark region with Inner Working Distance about 2. 8λ/D in one quadrant. Phase-only modulation has the additional appeal of potential implementation via active segmented or deformable mirrors, thereby combining compensation of random phase aberrations and diffraction halo removal in a single optical element.
Peroxisomes control mitochondrial dynamics and the mitochondrion-dependent apoptosis pathway

ABSTRACT Peroxisomes cooperate with mitochondria in the performance of cellular metabolic functions, such as fatty acid oxidation and the maintenance of redox homeostasis. However, whether peroxisomes also regulate mitochondrial fission–fusion dynamics or mitochondrion-dependent apoptosis remained unclear. We now show that genetic ablation of the peroxins Pex3 or Pex5, which are essential for peroxisome biogenesis, results in mitochondrial fragmentation in mouse embryonic fibroblasts (MEFs) in a manner dependent on Drp1 (also known as DNM1L). Conversely, treatment with 4-PBA, which results in peroxisome proliferation, resulted in mitochondrial elongation in wild-type MEFs, but not in Pex3-knockout MEFs. We further found that peroxisome deficiency increased the levels of cytosolic cytochrome c and caspase activity under basal conditions without inducing apoptosis. It also greatly enhanced etoposide-induced caspase activation and apoptosis, which is indicative of an enhanced cellular sensitivity to death signals. Taken together, our data unveil a previously unrecognized role for peroxisomes in the regulation of mitochondrial dynamics and mitochondrion-dependent apoptosis. Effects of peroxin gene mutations on mitochondrion-dependent apoptosis may contribute to pathogenesis of peroxisome biogenesis disorders. This article has an associated First Person interview with the first author of the paper. Summary: Peroxisomes regulate mitochondrial morphology through a Drp1-dependent mechanism and suppress the execution of stress-induced mitochondrion-dependent apoptosis.
Kinematic state estimation and motion planning for stochastic nonholonomic systems using the exponential map

SUMMARY A nonholonomic system subjected to external noise from the environment, or internal noise in its own actuators, will evolve in a stochastic manner described by an ensemble of trajectories. This ensemble of trajectories is equivalent to the solution of a Fokker–Planck equation that typically evolves on a Lie group. If the most likely state of such a system is to be estimated, and plans for subsequent motions from the current state are to be made so as to move the system to a desired state with high probability, then modeling how the probability density of the system evolves is critical. Methods for solving Fokker-Planck equations that evolve on Lie groups then become important. Such equations can be solved using the operational properties of group Fourier transforms in which irreducible unitary representation (IUR) matrices play a critical role. Therefore, we develop a simple approach for the numerical approximation of all the IUR matrices for two of the groups of most interest in robotics: the rotation group in three-dimensional space, SO(3), and the Euclidean motion group of the plane, SE(2). This approach uses the exponential mapping from the Lie algebras of these groups, and takes advantage of the sparse nature of the Lie algebra representation matrices. Other techniques for density estimation on groups are also explored. The computed densities are applied in the context of probabilistic path planning for kinematic cart in the plane and flexible needle steering in three-dimensional space. In these examples the injection of artificial noise into the computational models (rather than noise in the actual physical systems) serves as a tool to search the configuration spaces and plan paths. Finally, we illustrate how density estimation problems arise in the characterization of physical noise in orientational sensors such as gyroscopes.
Gating in plant plasma membrane aquaporins: the involvement of leucine in the formation of a pore constriction in the closed state

The control of water permeability in plant PIP2 aquaporins has become a paradigmatic case study of the capping mechanism for pore closure in water channels. From structural data, it has been postulated that the gating process in PIP2 involves a conformational rearrangement in cytosolic loopD that generates an obstruction to the transport of water molecules inside the aquaporin pore. BvPIP2;2 is a PIP2 aquaporin from Beta vulgaris whose pH response has been thoroughly characterized. In this work, we study the participation of Leu206 in BvPIP2;2 gating triggered by cytosolic acidification and show that this residue acts as a plug that blocks water transport. Based on data obtained from in silico and in vitro studies, we demonstrate that Leu206, one of the residues lining the pore, is responsible for ~ 60% of water blockage. Cell osmotic swelling experiments and atomistic molecular dynamics simulations indicate that the replacement of Leu206 by an Ala residue maintains high water permeability under conditions where the pore is expected to be closed. The present work demonstrates that Leu206, located at the cytoplasmic entry of the channel, constitutes a crucial pH‐sensitive steric gate regulating water transport in PIP aquaporins.
Bacillus cereus cshA Is Expressed during the Lag Phase of Growth and Serves as a Potential Marker of Early Adaptation to Low Temperature and pH

The spore-forming bacterium B. cereus is a major cause of foodborne outbreaks in Europe. Some B. cereus strains can grow at low temperatures and low pH in many processed foods. Modeling of the bacterial lag time is hampered by a lack of knowledge of the timing of events occurring during this phase. In this context, the identification of lag phase markers, not currently available, could be a real advance for the better prediction of lag time duration. Currently, no molecular markers of this phase are available. By determining that cshA was always expressed early during the lag phase, we provide a molecular marker of the early adaptation process of B. cereus cells when exposed to low temperature and pH. ABSTRACT Bacterial adaptation is characterized by a lag phase during which cells do not multiply or modify their physiology to cope with the constraints of their environment. Our aim was to determine a sequence of events during the lag phase of growth at low temperature and pH for three Bacillus cereus strains. The onsets of expression of two genes, one of which is essential for stress adaptation (cshA, coding for a RNA helicase) and one of which is involved in the transition between lag phase and exponential phase (abrB, coding for a transition regulator), were determined using fluorescent transcriptional reporter systems. Regardless of the stressing conditions and the tested strains, the cshA promoter was active very early, while the biomass increased and always did so before the first cell division. At 12°C and pH 7.0, the onset of cshA promoter activity occurred at between 3 h and 7 h, while the bacterial counts started to increase at between 12 h and 13 h. At pH 5.0 and at 20°C or 30°C, the onset of cshA promoter activity occurred before 1 h and earlier than at pH 7.0. In contrast, the onset of abrB promoter activity depended on the strain and the stressing conditions. In the ATCC 14579 strain, the onset of abrB promoter activity always started at between 30 min and 3 h, before biomass increased and cell division occurred. For the other strains, it took place along with the first cell division at 12°C but did so much later during growth under the other tested conditions. IMPORTANCE The spore-forming bacterium B. cereus is a major cause of foodborne outbreaks in Europe. Some B. cereus strains can grow at low temperatures and low pH in many processed foods. Modeling of the bacterial lag time is hampered by a lack of knowledge of the timing of events occurring during this phase. In this context, the identification of lag phase markers, not currently available, could be a real advance for the better prediction of lag time duration. Currently, no molecular markers of this phase are available. By determining that cshA was always expressed early during the lag phase, we provide a molecular marker of the early adaptation process of B. cereus cells when exposed to low temperature and pH.
Spatio-temporal prediction in video coding by spatially refined motion compensation

The purpose of this contribution is to introduce a new method of signal prediction in video coding. Unlike most existent prediction methods that either use temporal or use spatial correlations to generate the prediction signal, the proposed method uses spatial and temporal correlations at the same time. The spatio-temporal prediction is obtained by first performing motion compensation for a macroblock, followed by a refinement step that pays attention to the correlations between the macroblock and its surroundings. At the decoder, the refinement step can be performed in the same manner, thus no additional side information has to be transmitted. Implementation of the spatial refinement step into the H.264/AVC video codec leads to reduction in data rate of up to nearly 15% and increase in PSNR of up to 0.75 dB, compared to pure motion compensated prediction.
Addressing Ambiguity In Object Instance Detection

In this thesis, we study the topic of ambiguity when detecting object instances in scenes with severe clutter and occlusions. Our work focuses on the three key areas: (1) objects that have ambiguous features, (2) objects where discriminative point-based features cannot be reliably extracted, and (3) occlusions. Current approaches for object instance detection rely heavily on matching discriminative point-based features such as SIFT. While one-to-one correspondences between an image and an object can often be generated, these correspondences cannot be obtained when objects have ambiguous features due to similar and repeated patterns. We present the Discriminative Hierarchical Matching (DHM) method which preserves feature ambiguity at the matching stage until hypothesis testing by vector quantization. We demonstrate that combining our quantization framework with Simulated Affine features can significantly improve the performance of 3D point-based recognition systems. While discriminative point-based features work well for many objects, they cannot be stably extracted on smooth objects which have large uniform regions. To represent these feature-poor objects, we first present Gradient Networks, a framework for robust shape matching without extracting edges. Our approach incorporates connectivity directly on low-level gradients and significantly outperforms approaches which use only local information or coarse gradient statistics. Next, we present the Boundary and Region Template (BaRT) framework which incorporates an explicit boundary representation with the interior appearance of the object. We show that the lack of texture in the object interior is actually informative and that an explicit representation of the boundary performs better than a coarse representation. While many approaches work well when objects are entirely visible, their performance decrease rapidly with occlusions. We introduce two methods for increasing the robustness of object detection in these challenging scenarios. First, we present a framework for capturing the occlusion structure under arbitrary object viewpoint by modeling the Occlusion Conditional Likelihood that a point on the object is visible given the visibility labelings of all other points. Second, we propose a method to predict the occluding region and score a probabilistic matching pattern by searching for a set of valid occluders. We demonstrate significant increase in detection performance under severe occlusions.
Mutational and Combinatorial Control of Self-Assembling and Disassembling of Human Proteasome α Subunits

Eukaryotic proteasomes harbor heteroheptameric α-rings, each composed of seven different but homologous subunits α1–α7, which are correctly assembled via interactions with assembly chaperones. The human proteasome α7 subunit is reportedly spontaneously assembled into a homotetradecameric double ring, which can be disassembled into single rings via interaction with monomeric α6. We comprehensively characterized the oligomeric state of human proteasome α subunits and demonstrated that only the α7 subunit exhibits this unique, self-assembling property and that not only α6 but also α4 can disrupt the α7 double ring. We also demonstrated that mutationally monomerized α7 subunits can interact with the intrinsically monomeric α4 and α6 subunits, thereby forming heterotetradecameric complexes with a double-ring structure. The results of this study provide additional insights into the mechanisms underlying the assembly and disassembly of proteasomal subunits, thereby offering clues for the design and creation of circularly assembled hetero-oligomers based on homo-oligomeric structural frameworks.
Biallelic mutations in the LPAR6 gene causing autosomal recessive wooly hair/hypotrichosis phenotype in five Pakistani families

Autosomal recessive wooly hair/hypotrichosis is an inherited disorder of hair characterized by less dense, short, and tightly curled hair on the scalp and sometimes less dense to complete absence of eyebrows and eyelashes. Autosomal recessive wooly hair/hypotrichosis phenotypes are mostly associated with pathogenic sequence variants in LIPH and LPAR6 genes.
TLR1/2 ligand enhances antitumor efficacy of CTLA-4 blockade by increasing intratumoral Treg depletion

Significance To overcome the challenge of nonresponsiveness or low effectiveness to current checkpoint blockade drugs, various combination therapies are under investigation for cancer treatment. In this study, we investigated a combination of Toll-like receptor 1/2 (TLR1/2) ligand and anti–CTLA-4 antibody in a mouse model of melanoma. TLR1/2 ligand enhanced the antitumor efficacy of anti–CTLA-4 by increasing Fcγ receptor IV expression, which in turn increased the depletion of tumor-infiltrating regulatory T cells. Whether ipilimumab causes Treg depletion in human patients is debatable; therefore, combining ipilimumab with Pam3CSK4 could lead to greater antitumor efficacy by introducing this modality. These findings are likely extensible to other checkpoint antibodies in cancer patients. Immune checkpoint inhibitors such as anti–CTLA-4 antibody are widely accepted therapeutic options for many cancers, but there is still a considerable gap in achieving their full potential. We explored the potential of activating the innate and adaptive immune pathways together to improve tumor reduction and survival outcomes. We treated a mouse model of melanoma with intratumoral injections of Toll-like receptor 1/2 (TLR1/2) ligand Pam3CSK4 plus i.p. injections of anti–CTLA-4 antibody. This combination treatment enhanced antitumor immune responses both qualitatively and quantitatively over anti–CTLA-4 alone, and its efficacy depended on CD4 T cells, CD8 T cells, Fcγ receptor IV, and macrophages. Interestingly, our results suggest a unique mechanism by which TLR1/2 ligand increased Fcγ receptor IV expression on macrophages, leading to antibody-dependent macrophage-mediated depletion of regulatory T cells in the tumor microenvironment and increasing efficacy of anti–CTLA-4 antibody in the combination treatment. This mechanism could be harnessed to modulate the clinical outcome of anti–CTLA-4 antibodies and possibly other antibody-based immunotherapies.
A comprehensive UHPLC ion mobility QTOF method for profiling and quantification of eicosanoids, other oxylipins and fatty acids.

Analysis of oxylipins by liquid chromatography mass spectrometry (LC/MS) is challenging because of the small mass range occupied by this diverse lipid class, the presence of numerous structural isomers, and their low abundance in biological samples. Although highly sensitive LC/MS/MS methods are commonly used, further separation is achievable by using drift tube ion mobility coupled with high-resolution mass spectrometry (DTIM-MS). Herein, we present a combined analytical and computational method for the identification of oxylipins and fatty acids. We use a reversed-phase LC/DTIM-MS workflow able to profile and quantify the oxylipin and fatty acid content of biological samples while simultaneously acquiring full scan and product ion spectra. The information regarding accurate mass, collision-cross section values in nitrogen (DTCCSN2) and retention times of the species found are compared to an internal library of lipid standards as well as the LIPID MAPS Structure Database by using specifically developed processing tools. Features detected within the DTCCSN2 and m/z ranges of the analyzed standards are flagged as oxylipin-like species, which can be further characterized using drift time alignment of product and precursor ions distinctive of DTIM-MS. This not only helps identification by reducing the number of annotations from LIPID MAPS, but also guides discovery studies of potentially novel species. Testing the methodology on Salmonella enterica serovar Typhimurium infected murine bone-marrow derived macrophages and thrombin activated human platelets yields results in agreement with literature. This workflow has also annotated features as potentially novel oxylipins, confirming its ability in providing further insights into lipid analysis of biological samples.
Synthetic Physical Interactions with the Yeast Centrosome

The yeast centrosome or Spindle Pole Body (SPB) is an organelle situated in the nuclear membrane, where it nucleates spindle microtubules and acts as a signaling hub. Various studies have explored the effects of forcing individual proteins to interact with the yeast SPB, however no systematic study has been performed. We used synthetic physical interactions to detect proteins that inhibit growth when forced to associate with the SPB. We found the SPB to be especially sensitive to relocalization, necessitating a novel data analysis approach. This novel analysis of SPI screening data shows that regions of the cell are locally more sensitive to forced relocalization than previously thought. Furthermore, we found a set of associations that result in elevated SPB number and, in some cases, multi-polar spindles. Since hyper-proliferation of centrosomes is a hallmark of cancer cells, these associations point the way for the use of yeast models in the study of spindle formation and chromosome segregation in cancer.