Miracle-dz/UniFAR-FTUs huggingface dataset:
Sequence-, structure-, and dynamics-based comparisons of structurally homologous CheY-like proteins

Significance We study a set of proteins that exhibit low sequence identity, but high structural homology and functional similarity. It is demonstrated that a physics-based sequence comparison tool, the property factor method, is able to detect differences between the sequences of these proteins that correlate with differences in their structures and dynamics. It is shown that these sequence differences are not detected in this challenging system by conventional alignment methods. This result suggests that a significant amount of the information encoded in protein sequences is not captured by evolutionarily motivated comparison methods. We recently introduced a physically based approach to sequence comparison, the property factor method (PFM). In the present work, we apply the PFM approach to the study of a challenging set of sequences—the bacterial chemotaxis protein CheY, the N-terminal receiver domain of the nitrogen regulation protein NT-NtrC, and the sporulation response regulator Spo0F. These are all response regulators involved in signal transduction. Despite functional similarity and structural homology, they exhibit low sequence identity. PFM sequence comparison demonstrates a statistically significant qualitative difference between the sequence of CheY and those of the other two proteins that is not found using conventional alignment methods. This difference is shown to be consonant with structural characteristics, using distance matrix comparisons. We also demonstrate that residues participating strongly in native contacts during unfolding are distributed differently in CheY than in the other two proteins. The PFM result is also in accord with dynamic simulation results of several types. Molecular dynamics simulations of all three proteins were carried out at several temperatures, and it is shown that the dynamics of CheY are predicted to differ from those of NT-NtrC and Spo0F. The predicted dynamic properties of the three proteins are in good agreement with experimentally determined B factors and with fluctuations predicted by the Gaussian network model. We pinpoint the differences between the PFM and traditional sequence comparisons and discuss the informatic basis for the ability of the PFM approach to detect physical differences between these sequences that are not apparent from traditional alignment-based comparison.
Maximal aerobic capacity in African-American and Caucasian prepubertal children.

The purpose of this study was to examine differences in resting, submaximal, and maximal (V˙o 2 max) oxygen consumption (V˙o 2) in African-American ( n = 44) and Caucasian ( n = 31) prepubertal children aged 5-10 yr. RestingV˙o 2 was measured via indirect calorimetry in the fasted state. SubmaximalV˙o 2 andV˙o 2 max were determined during an all out, progressive treadmill exercise test appropriate for children. Dual-energy X-ray absorptiometry was used to determine total fat mass (FM), soft lean tissue mass (LTM), and leg soft LTM. Doubly labeled water was used to determine total energy expenditure (TEE) and activity energy expenditure (AEE). A significant effect of ethnicity ( P < 0.01) was found for V˙o 2 max but not resting or submaximalV˙o 2, with African-American children having absoluteV˙o 2 max ∼15% lower than Caucasian children (1.21 ± 0.032 vs. 1.43 ± 0.031 l/min, respectively). The lowerV˙o 2 max persisted in African-American children after adjustment for soft LTM (1.23 ± 0.025 vs. 1.39 ± 0.031 l/min; P< 0.01), leg soft LTM (1.20 ± 0.031 vs. 1.43 ± 0.042 l/min; P < 0.01), and soft LTM and FM (1.23 ± 0.025 vs. 1.39 ± 0.031 l/min; P < 0.01). The lowerV˙o 2 max persisted also after adjustment for TEE (1.20 ± 0.02 vs. 1.38 ± 0.0028 l/min P < 0.001) and AEE (1.20 ± 0.024 vs. 1.38 ± 0.028 l/min; P < 0.001). In conclusion, our data indicate that African-American and Caucasian children have similar rates of V˙o 2 at rest and during submaximal exercise, butV˙o 2 max is ∼15% lower in African-American children, independent of soft LTM, FM, leg LTM, TEE, and AEE.
Reexamining cancer metabolism: lactate production for carcinogenesis could be the purpose and explanation of the Warburg Effect

Summary By reversing emphasis from precursor uptake to product accumulation and release, we posit that lactate production (‘lactagenesis’) supports carcinogenesis and it is the explanation and purpose of the Warburg effect. We posit that in carcinogenesis, aberrant cell signaling due to exaggerated and continually high lactate levels yields an inappropriate positive feedback loop that increases glucose uptake, glycolysis, lactate production and release, decreases mitochondrial function and clearance and upregulates glycolytic enzyme and monocarboxylate transporter expression thereby supporting angiogenesis, immune escape, cell migration, metastasis and self-sufficient metabolism, all of which encourage progression to cancer.
Minimal influence of blood flow on interstitial glucose and lactate-normal and insulin-resistant muscle.

To study the regulation of the interstitial glucose concentration in skeletal muscle, nine control subjects and nine older and overweight non-insulin-dependent diabetes mellitus (NIDDM) subjects with extreme insulin resistance were investigated with microdialysis in the medial femoral muscle before and during a euglycemic insulin clamp. After an overnight fast, arterial plasma glucose concentration was 4.9 ± 0.1 and 8.5 ± 0.6 mmol/l ( P < 0.001), respectively. The arterial-interstitial concentration ([a-i]) differences of glucose and lactate were 0.43 ± 0.16 ( P < 0.05) and -0.13 ± 0.05 mmol/l, respectively, in normal subjects. In NIDDM subjects, [a-i] differences for glucose and lactate were nonsignificant. Muscle blood flow was similar in controls and NIDDM subjects. During the glucose clamp, the glucose [a-i] differences increased and the lactate [a-i] differences decreased significantly in both groups. The glucose 170 infusion rate was 8.0 ± 0.77 vs. 3.2 ± 0.51 mg ⋅ kg-1 ⋅ min-1( P < 0.001), and blood flow was 9.9 ± 1.6 vs. 6.7 ± 0.9 ml ⋅ 100 g-1 ⋅ min-1( P < 0.05) in controls and NIDDM subjects, respectively. These results show that 1) the capillary wall is rate limiting for muscle glucose uptake and lactate release in control subjects but not in postabsorptive hyperglycemic insulin-resistant subjects, 2) vasodilation during insulin infusion does not prevent the increase in [a-i] difference of glucose in normal subjects, and 3) in severely insulin-resistant muscle, the [a-i] difference of glucose is not extended despite lack of vasodilation.
Glycosaminoglycan Interactions Fine-Tune Chemokine-Mediated Neutrophil Trafficking: Structural Insights and Molecular Mechanisms

Circulating neutrophils, rapidly recruited in response to microbial infection, form the first line in host defense. Humans express ~50 chemokines, of which a subset of seven chemokines, characterized by the conserved “Glu-Leu-Arg” motif, mediate neutrophil recruitment. Neutrophil-activating chemokines (NACs) share similar structures, exist as monomers and dimers, activate the CXCR2 receptor on neutrophils, and interact with tissue glycosaminoglycans (GAGs). Considering cellular assays have shown that NACs have similar CXCR2 activity, the question has been and remains, why do humans express so many NACs? In this review, we make the case that NACs are not redundant and that distinct GAG interactions determine chemokine-specific in vivo functions. Structural studies have shown that the GAG-binding interactions of NACs are distinctly different, and that conserved and specific residues in the context of structure determine geometries that could not have been predicted from sequences alone. Animal studies indicate recruitment profiles of monomers and dimers are distinctly different, monomer–dimer equilibrium regulates recruitment, and that recruitment profiles vary between chemokines and between tissues, providing evidence that GAG interactions orchestrate neutrophil recruitment. We propose in vivo GAG interactions impact several chemokine properties including gradients and lifetime, and that these interactions fine-tune and define the functional response of each chemokine that can vary between different cell and tissue types for successful resolution of inflammation.
The Relative Importance of Competition and Predation Varies with Productivity in a Model Community

Recent theory predicts that productivity can influence the relative importance of predation and competition in determining patterns in abundance, diversity, and community structure. In low‐productivity systems, competition is predicted to be the major influence on community patterns, while at high productivity, the major influence is predicted to be predation. We directly tested this theory using a laboratory model community. Our model community consisted of the bacteriophage T2 (a virus that feeds on Escherichia coli) and two populations of E. coli, in glucose‐limited chemostats. One E. coli population consisted of individuals that were sensitive to predation by T2 (“vulnerable” E. coli), and the other population consisted of individuals that were partially resistant to predation by T2 (“less vulnerable” E. coli). We manipulated productivity in this experiment by running replicate chemostats with different input concentrations of glucose. Our observations were consistent with theoretical predictions. We observed the decline of the more vulnerable prey population at higher productivity but not at lower productivity, and the decline of the less vulnerable prey population at lower productivity but not at higher productivity. However, the rate of decline in some replicates was slower than predicted, and extinctions were not observed during the experiments, contrary to theoretical predictions. We present some testable hypotheses that might explain the slow rate of decline observed.
Recent Advances in Polymer-based Wound Dressings for the Treatment of Diabetic Foot Ulcer: An Overview of State-of-the-art.

BACKGROUND Diabetic foot ulcers (DFUs) are the chronic, non-healing complications of diabetic mellitus which compels a significant burden to the patients and the healthcare system. Peripheral vascular disease, diabetic neuropathy, and abnormal cellular and cytokine/chemokine activity are among the prime players which exacerbate the severity and prevent wound repair. Unlike acute wounds, DFUs impose a substantial challenge to the conventional wound dressings and demand the development of novel and advanced wound healing modalities. In general, an ideal wound dressing should provide a moist wound environment, offer protection from secondary infections, eliminate wound exudate and stimulate tissue regeneration. OBJECTIVE To date, numerous conventional wound dressings are employed for the management of DFUs but there is a lack of absolute and versatile choice. The current review was therefore aimed to summarize and critically discuss the available evidences related to pharmaceutical and therapeutic viability of polymer-based dressings for the treatment of DFUs. RESULTS A versatile range of naturally-originated polymers including chitosan (CS), hyaluronic acid (HA), cellulose, alginate, dextran, collagen, gelatin, elastin, fibrin and silk fibroin have been utilized for the treatment of DFUs. These polymers have been used in the form of hydrogels, films, hydrocolloids, foams, membranes, scaffolds, microparticles, and nanoparticles. Moreover, the wound healing viability and clinical applicability of various mutually modified, semi-synthetic or synthetic polymers have also been critically discussed. CONCLUSION In summary, this review enlightens the most recent developments in polymer-based wound dressings with special emphasis on advanced polymeric biomaterials, innovative therapeutic strategies and delivery approaches for the treatment of DFUs.
Nitric oxide-independent activation of soluble guanylyl cyclase contributes to endotoxin shock in rats.

We investigated whether a complete inhibition of nitric oxide (NO) formation caused by bacterial endotoxin (lipopolysaccharide, LPS) in vivo prevents the hypotension and restores the vascular hyporeactivity to normal in vivo and ex vivo. The combination of dexamethasone (Dex; 3 mg/kg at 30 min before LPS) plus aminoguanidine (AG; 15 mg/kg at 2 h after LPS) inhibited the overproduction of nitrate (an indicator of NO) in the plasma and aortic smooth muscle and also prevented the development of the delayed hypotension in rats treated with LPS for 6 h. However, the vascular hyporeactivity to norepinephrine (NE) was only partially improved either in vivo or ex vivo in endotoxemic rats treated with Dex plus AG. Pretreatment of aortic rings with N ω-nitro-l-arginine methyl ester (l-NAME) or 1 H-[1,2,4]oxidazolo[4,3-a]quinoxalin-1-one (ODQ) enhanced the contraction to NE in rings obtained from LPS-treated rats, but not in those from Dex plus AG-treated endotoxemic rats. Methylene blue, an inhibitor of soluble guanylyl cyclase (GC), completely restored contractions to NE and aortic cGMP levels to normal either in LPS-treated rats or in Dex plus AG-treated endotoxemic rats, whereas the cGMP level was partially inhibited by ODQ in LPS-treated rats only. These results suggest that non-NO mediator(s) also activates soluble GC during endotoxemia. Interestingly, we found that in the presence of tetraethylammonium (an inhibitor of K+ channels) plusl-NAME or charybdotoxin [a specific inhibitor of large-conductance Ca2+-activated K+(KCa) channels] plus ODQ, the vascular hyporeactivity to NE in the LPS-treated group was also completely restored to normal. In addition, in the presence ofl-NAME or ODQ, the vascular hyporeactivity to high K+ was abolished in rings from the LPS-treated group. These results suggest that LPS causes the production of other mediator(s), in addition to NO, which also stimulates soluble GC (i.e., increases the formation of cGMP) and then activates the large-conductance KCa channels in the vascular smooth muscle causing vascular hyporeactivity.
The heritability and patterns of DNA methylation in normal human colorectum

DNA methylation (DNAm) has been linked to changes in chromatin structure, gene expression and disease. The DNAm level can be affected by genetic variation; although, how this differs by CpG dinucleotide density and genic location of the DNAm site is not well understood. Moreover, the effect of disease causing variants on the DNAm level in a tissue relevant to disease has yet to be fully elucidated. To this end, we investigated the phenotypic profiles, genetic effects and regional genomic heritability for 196080 DNAm sites in healthy colorectum tissue from 132 unrelated Colombian individuals. DNAm sites in regions of low-CpG density were more variable, on average more methylated and were more likely to be significantly heritable when compared with DNAm sites in regions of high-CpG density. DNAm sites located in intergenic regions had a higher mean DNAm level and were more likely to be heritable when compared with DNAm sites in the transcription start site (TSS) of a gene expressed in colon tissue. Within CpG-dense regions, the propensity of the DNAm level to be heritable was lower in the TSS of genes expressed in colon tissue than in the TSS of genes not expressed in colon tissue. In addition, regional genetic variation was associated with variation in local DNAm level no more frequently for DNAm sites within colorectal cancer risk regions than it was for DNAm sites outside such regions. Overall, DNAm sites located in different genomic contexts exhibited distinguishable profiles and may have a different biological function.
Bradykinin induces tubulin phosphorylation and nuclear translocation of MAP kinase in mesangial cells.

Glomerular hypertension and glomerular hypertrophy act early and synergistically to promote glomerular injury in diabetes. We have previously shown that increased renal kinin production contributes to the glomerular hemodynamic abnormalities associated with diabetes. Glomerulosclerosis, characterized by mesangial cell proliferation and matrix expansion, is the final pathway leading to renal failure. The signal(s) initiating mesangial cell proliferation is ill defined. In the present study, we utilized immunofluorescence, immunoprecipitation, and immunoblotting techniques to identify substrates that are tyrosine phosphorylated in response to bradykinin action in mesangial cells. Immunofluorescence microscopy of mesangial cells stained with anti-phosphotyrosine (anti-PY) antibodies following bradykinin treatment (10-9-10-6M) revealed a dose-dependent increase in the labeling of cytoplasmic and nuclear proteins. Immunoprecipitation with anti-PY, followed by immunoblot revealed bradykinin-induced tyrosyl phosphorylation of tubulin and mitogen-activated protein kinase (MAPK). Confocal microscopy of mesangial cells stained for MAPK indicated that bradykinin stimulation resulted in translocation of MAPK from the cytoplasm to the nucleus by 2 h. These data demonstrate that bradykinin action results in the tyrosine phosphorylation of cellular proteins in mesangial cells and suggest a role for tubulin and MAPK in the signaling cascade of bradykinin leading to altered mesangial function.
LIQUID: an‐open source software for identifying lipids in LC‐MS/MS‐based lipidomics data

Summary: We introduce an open‐source software, LIQUID, for semi‐automated processing and visualization of LC‐MS/MS‐based lipidomics data. LIQUID provides users with the capability to process high throughput data and contains a customizable target library and scoring model per project needs. The graphical user interface provides visualization of multiple lines of spectral evidence for each lipid identification, allowing rapid examination of data for making confident identifications of lipid molecular species. LIQUID was compared to other freely available software commonly used to identify lipids and other small molecules (e.g. CFM‐ID, MetFrag, GNPS, LipidBlast and MS‐DIAL), and was found to have a faster processing time to arrive at a higher number of validated lipid identifications. Availability and Implementation: LIQUID is available at http://github.com/PNNL‐Comp‐Mass‐Spec/LIQUID. Contact: jennifer.kyle@pnnl.gov or thomas.metz@pnnl.gov Supplementary information: Supplementary data are available at Bioinformatics online.
Effects of production systems on the carcass and meat quality characteristics of spent laying hens

ABSTRACT This study evaluated the carcass characteristics and meat quality attributes of spent laying hens raised under conventional battery cage and free‐range systems. Thirty free‐range and 30 conventional battery‐caged Lohmann Brown‐Elite spent laying hens of 53 and 40 wk of age, respectively were obtained from a commercial egg producer. Carcass, portion, and organ weights and percentages were determined. Physicochemical analyses were performed on thigh and breast meat samples. Caged hens had heavier (P ≤ 0.05) warm and cold carcasses, thighs, wings, and feet. The percentages of the breast (26.1 ± 0.51 vs. 28.3 ± 0.28), drum, breast bones, breast thaw and cooking loss, and thigh cooking loss were higher (P ≤ 0.05) for free‐range than for caged hens. Free‐range hens had heavy (P ≤ 0.05) gizzards (33.9 ± 1.04 vs. 30.5 ± 0.73) and bones and a lower (P ≤ 0.05) breast meat percentage (47.3 ± 0.94 vs. 51.7 ± 1.35). Meat redness (a*) (0.54 ± 0.222 vs. 1.40 ± 0.135) and hue angle, skin redness (a*), breast (12.37 ± 0.411 vs. 17.10 ± 0.751), and thigh (29.68 ± 0.306 vs. 39.75 ± 0.826) Warner‐Bratzler shear force values (N), breast moisture, and thigh ash content were higher (P ≤ 0.05) for free‐range hens. Caged hens had a higher (P ≤ 0.05) thigh thaw loss percentage and breast ash content. Production system significantly influenced the carcass characteristics and meat quality of spent laying hens. The results of this study supply baseline information for the utilization of spent laying hens by the poultry industry and consumers.
AL Amyloidosis (Amyloidosis Antibody Light). Part 1. Definition, Classification, Amyloid Structure, Development and Etiopathogenesis of AL Amyloidosis

Amyloidosis is an inherited or acquired systemic storage disease in which a pathologic, amorphous substance pro- duced as a result of abnormal protein metabolism and resistant to proteolysis is deposited in the extracellular space of various tissues (intracellular deposits occur rarely). This leads to the destruction of normal tissue architecture and disturbs its function. The development of amyloidosis is associated with the transformation of the α-spiral con- formation of fibrous protein into a stratified, parallel, folded spatial β-conformation. The transition of the fibrous proteins conformation and their tissue localization causes resistance of the fibers to proteolytic processes as a result of a limited access of the protein converting enzymes. In this paper we show the actual classification of amyloidosis and up-to-date knowledge about the amyloid structure, development and etiopathogenesis of AL amyloidosis (Adv Clin Exp Med 2011, 20, 5, 647-652).
Lymph Node Dissection

Gastric cancer remains as one of the leading causes of death worldwide (Yoshida et al., 2004). Middle third and distal cancers tend to decline worldwide. However, in the western populations proximal gastric cancers tend to increase even though the incidence of those cancers stays the same in Japan. Today, the incidence of early gastric cancer has reached above 50% in Japan while in the west two thirds of gastric cancers are at an advanced stage at the time of diagnosis (Biondi, 2010). This problem is complicated further by a recurrence rate of 40% to 65% in patients resected with curative intent (Dicken, 2005). Currently, the only potentially curative option for gastric cancer is surgery which may promise complete resection, although the extent of regional lymphadenectomy (LND) has been a matter of considerable debate.
Epigenetic Control of Human Endogenous Retrovirus Expression: Focus on Regulation of Long-Terminal Repeats (LTRs)

Transposable elements, including endogenous retroviruses (ERVs), comprise almost 45% of the human genome. This could represent a significant pathogenic burden but it is becoming more evident that many of these elements have a positive contribution to make to normal human physiology. In particular, the contributions of human ERVs (HERVs) to gene regulation and the expression of noncoding RNAs has been revealed with the help of new and emerging genomic technologies. HERVs have the common provirus structure of coding open reading frames (ORFs) flanked by two long-terminal repeats (LTRs). However, over the course of evolution and as a consequence of host defence mechanisms, most of the sequences contain INDELs, mutations or have been reduced to single LTRs by recombination. These INDELs and mutations reduce HERV activity. However, there is a trade-off for the host cells in that HERVs can provide beneficial sources of genetic variation but with this benefit comes the risk of pathogenic activity and spread within the genome. For example, the LTRs are of critical importance as they contain promoter sequences and can regulate not only HERV expression but that of human genes. This is true even when the LTRs are located in intergenic regions or are in antisense orientation to the rest of the gene. Uncontrolled, this promoter activity could disrupt normal gene expression or transcript processing (e.g., splicing). Thus, control of HERVs and particularly their LTRs is essential for the cell to manage these elements and this control is achieved at multiple levels, including epigenetic regulations that permit HERV expression in the germline but silence it in most somatic tissues. We will discuss some of the common epigenetic mechanisms and how they affect HERV expression, providing detailed discussions of HERVs in stem cell, placenta and cancer biology.