gebhart/patrepeval huggingface dataset:
Disease-Related Misassembly of Membrane Proteins (2004)

Medical genetics so far has identified approximately 16,000 missense mutations leading to single amino acid changes in protein sequences that are linked to human disease. A majority of these mutations affect folding or trafficking, rather than specifically affecting protein function. Many disease-linked mutations occur in integral membrane proteins, a class of proteins about whose folding we know very little. We examine the phenomenon of disease-linked misassembly of membrane proteins and describe model systems currently being used to study the delicate balance between proper folding and misassembly. We review a mechanism by which cells recognize membrane proteins with a high potential to misfold before they actually do, and which targets these culprits for degradation. Serious disease phenotypes can result from loss of protein function and from misfolded proteins that the cells cannot degrade, leading to accumulation of toxic aggregates. Misassembly may be averted by small-molecule drugs that bind and stabilize the native state.
Cloning of the psbK gene from Synechocystis sp. PCC 6803 and characterization of photosystem II in mutants lacking PSII-K (1991)

We cloned and sequenced the psbK gene, coding for a small photosystem II component (PSII-K), from the transformable cyanobacterium, Synechocystis sp. PCC 6803, and determined the N-terminal sequence of mature PSII-K. The psbK gene product is processed by cleaving off eight amino acid residues from the N terminus. A mutant lacking psbK was constructed; this mutant grew photoautotrophically, but its growth rate was reduced. The number of photosystem II reaction centers on a chlorophyll basis was decreased by less than a factor of 2 in the psbK-deletion mutant. In Synechocystis sp. PCC 6803, the psbK gene is transcribed as a single gene and is not part of an operon. Single-site mutations were introduced into psbK leading to early termination or deletion of the presequence. The phenotype of these mutants strongly resembles that of the psbK deletion mutant, indicating that indeed the change in phenotype in the deletion mutant is directly correlated with PSII-K. PSII-K is not essential for photosystem II assembly or activity but is needed for optimal photosystem II function.
Immunocytochemical detection of prostate-specific antigen (PSA) in skin adnexal and breast tissues and tumors. (1989)

Prostate Specific Antigen (PSA) is regarded as a specific marker of prostatic epithelium and has never been detected by immunocytochemistry in extra-prostatic tissues. The casual finding of a strong positivity for polyclonal antisera to PSA in a sweat gland carcinoma prompted a study on a series of skin adnexial and breast specimens (normal and neoplastic). Normal axillary and perineal apocrine sweat glands, some apocrine foci in fibrocystic breast disease and two sweat gland and two breast apocrine carcinomas were stained by several PSA antisera; a recently introduced monoclonal to PSA, however, was unreactive. These observations cast doubt on the specificity of PSA for prostatic epithelium, especially when polyclonal antisera are employed. Immunocytochemical reactions obtained with PSA, in the investigation of skin, lesions must be interpreted with caution and confirmed if necessary with monoclonals to PSA and with PAP.
Structure of Microsomal Cytochrome P450 2B4 Complexed with the Antifungal Drug Bifonazole (2005)

To better understand ligand-induced structural transitions in cytochrome P450 2B4, protein-ligand interactions were investigated using a bulky inhibitor. Bifonazole, a broad spectrum antifungal agent, inhibits monooxygenase activity and induces a type II binding spectrum in 2B4dH(H226Y), a modified enzyme previously crystallized in the presence of 4-(4-chlorophenyl)imidazole (CPI). Isothermal titration calorimetry and tryptophan fluorescence quenching indicate no significant burial of protein apolar surface nor altered accessibility of Trp-121 upon bifonazole binding, in contrast to recent results with CPI. A 2.3 A crystal structure of 2B4-bifonazole reveals a novel open conformation with ligand bound in the active site, which is significantly different from either the U-shaped cleft of ligand-free 2B4 or the small active site pocket of 2B4-CPI. The O-shaped active site cleft of 2B4-bifonazole is widely open in the middle but narrow at the top. A bifonazole molecule occupies the bottom of the active site cleft, where helix I is bent approximately 15 degrees to accommodate the bulky ligand. The structure also defines unanticipated interactions between helix C residues and bifonazole, suggesting an important role of helix C in azole recognition by mammalian P450s. Comparison of the ligand-free 2B4 structure, the 2B4-CPI structure, and the 2B4-bifonazole structure identifies structurally plastic regions that undergo correlated conformational changes in response to ligand binding. The most plastic regions are putative membrane-binding motifs involved in substrate access or substrate binding. The results allow us to model the membrane-associated state of P450 and provide insight into how lipophilic substrates access the buried active site.
Phosphorylation of the Myofibrillar Proteins (1980)

In muscle, protein phosphorylation takes place in both the sarcoplasm and the myofibrils. This review deals only with those myofibrillar proteins that can be phosphorylated-i.e. myosin light chain and in a few cases the heavy chain, the inhibitory and tropomyosin-binding subunits of troponin, and tropomyosin. Although research on this topic began as recently as 1972, several interesting results have been accumulated (for reviews, see 86-88, 114, 116).
Opening mitoKATPincreases superoxide generation from complex I of the electron transport chain (2006)

Opening the mitochondrial ATP-sensitive K(+) channel (mitoK(ATP)) increases levels of reactive oxygen species (ROS) in cardiomyocytes. This increase in ROS is necessary for cardioprotection against ischemia-reperfusion injury; however, the mechanism of mitoK(ATP)-dependent stimulation of ROS production is unknown. We examined ROS production in suspensions of isolated rat heart and liver mitochondria, using fluorescent probes that are sensitive to hydrogen peroxide. When mitochondria were treated with the K(ATP) channel openers diazoxide or cromakalim, their ROS production increased by 40-50%, and this effect was blocked by 5-hydroxydecanoate. ROS production exhibited a biphasic dependence on valinomycin concentration, with peak production occurring at valinomycin concentrations that catalyze about the same K(+) influx as K(ATP) channel openers. ROS production decreased with higher concentrations of valinomycin and with all concentrations of a classical protonophoretic uncoupler. Our studies show that the increase in ROS is due specifically to K(+) influx into the matrix and is mediated by the attendant matrix alkalinization. Myxothiazol stimulated mitoK(ATP)-dependent ROS production, whereas rotenone had no effect. This indicates that the superoxide originates in complex I (NADH:ubiquinone oxidoreductase) of the electron transport chain.
Physical factors in the stimulation of calonic peristalsis (1970)

The effect of colonic distension and changes in intraluminal pH and osmolality have been investigated in patients with well established colostomies. Small volumes of acidic buffer (pH4) and hypertonic saline (4%) were found to be only a very weak peristaltic stimulus. Strong hypertonic solutions (glycerine BP) induced a poorly sustained peristaltic response in the majority of cases. Distension of the inactive colon did not stimulate peristalsis. Distension of a colon previously stimulated to peristaltic activity caused fresh waves of contraction. This study appears to show that by themselves physical factors play an unimportant role in initiating peristaltic activity in the colon.
Typhoid fever in African and Indian children in Durban. (1969)

Medical literature contains surprisingly few accounts of large series of typhoid fever in children in which such items as severity, response to therapy, complications, and relapse rates are reported in detail.
A yeast protein that binds to vertebrate telomeres and conserved yeast telomeric junctions. (1991)

We have identified three yeast proteins that bind to poly(C.A)/poly(T.G) repeats characteristic of telomeric sequences from yeast to human. TBF alpha binds to the telomeric sequences of yeast, Tetrahymena, and vertebrates. In contrast, TBF beta binds only to yeast telomeric sequences. Also identified was RAP1, the transcriptional silencer protein, which binds to a sequence motif found in upstream activating sequences (UASs) of a number of genes; the sequence motif also occurs frequently in yeast telomeric sequences. Because poly(C.A)/poly(T.G) sequences from a wide range of organisms will serve as the primer for the in vivo extension of telomeres in yeast, TBF alpha is of particular interest. DNase I footprinting analysis indicated that TBF alpha binds to the junction between the subtelomeric X sequence and poly(C1-3A) in a cloned yeast telomere. Examination of the junctions of known X sequences indicated that they all contain one or more repeats of CCCTAA, a sequence that is repeated in vertebrate telomeres. Earlier, Murray et al. (1988) reported that heterologous telomeric sequences positioned as far as several hundred base pairs from the termini of linear molecules can allow the addition of yeast telomeric sequences from nontelomeric termini in vivo. A possible function for TBF alpha might be to serve as an anchoring protein for the yeast telomerase by binding to the conserved junction sequence at a distance from the terminus to allow addition of an irregular repeating sequence at the chromosome end.
Propagation of intense, ultrashort laser pulses through metal vapor: refraction-limited behavior for single pulses (1996)

Propagation of intense, ultrashort laser pulses through self-induced underdense aluminum plasmas is examined at intensity levels of as high as 5 × 1017 W/cm2. Observations of the on-axis transmitted portion of the incident pulse are consistent with optical-field ionization and subsequent plasma refraction. A novel application of frequency-resolved optical gating provides measurement of time-resolved spectra, giving amplitude and phase information of the transmitted laser waveform. At high enough incident intensity the transmitted energy is reduced to the 1% level, the short-wavelength extent of the complex spectra can be downshifted by as much as 19% from the incident wavelength, and the duration of the transmitted laser waveform is noticeably shortened. The usefulness of the frequency-resolved optical gating diagnostic in studying the dynamics of ionization and laser–plasma interactions is demonstrated.
A dose-escalating phase I of imatinib mesylate with fixed dose of metronomic cyclophosphamide in targeted olid tumours (2013)

This combination is feasible and may warrant further exploration in refractory GIST or chordoma patients.
Proxy activation of protein ErbB2 by heterologous ligands implies a heterotetrameric mode of receptor tyrosine kinase interaction (1998)

The oncoprotein ErbB2 is frequently overexpressed in human tumours, but no activating ErbB2-specific ligand has yet been identified. Here we analyse the catalytic and oligomeric behaviour of ErbB2 using phosphorylation-state-specific antibodies which distinguish kinase-active and -inactive ErbB2 receptor subsets. Heregulin-alpha (HRG) activates ErbB2 in G8/DHFR 3T3 cells by selectively inducing hetero-oligomerization with kinase-defective ErbB3, indicating that heterologous transphosphorylation is an unlikely prerequisite for ErbB2 activation. HRG also triggers association of epidermal-growth-factor receptors (EGFR) with a kinase-inactive ErbB2 subset while reducing EGFR association with active ErbB2. Similarly, EGF treatment of A431 cells induces concomitant hetero-oligomerization of active ErbB2 with inactive EGFR, of active EGFR with inactive ErbB2, and of inactive ErbB2 with kinase-defective ErbB3. These combinatorial patterns of ligand-dependent oligomerization suggest a multivalent model of receptor tyrosine kinase interaction in which liganded homodimers provide stable oligomerization interfaces for unliganded ErbB2 or other bystander receptors. We submit that ErbB2 may be physiologically activated via a 'proxy' ligand-inducible heterotetrameric mechanism similar to that already established for transforming-growth-factor-beta type I receptors.
On the Analysis of Short-Pulse Laser Heating of Metals Using the Dual Phase Lag Heat Conduction Model (2009)

Transient heat conduction in a thin metal film exposed to short-pulse laser heating is studied using the dual phase lag heat conduction model. The initial heat flux distribution in the film, resulting from the temporal distribution function of the laser pulse, together with the zero temperature gradients at the boundaries normally used in literature with the presumption that they are equivalent to negligible boundary heat losses is analyzed in detail in this paper. The analysis presented here shows that using zero temperature gradients at the boundaries within the framework of the dual phase lag heat conduction model does not guarantee negligible boundary heat losses unless the initial heat flux distribution is negligibly small. Depending on the value of the initial heat flux distribution, the presumed negligible heat losses from the boundaries can be even way larger than the heat flux at any location within the film during the picosecond laser heating process. Predictions of the reflectivity change of thin gold films due to a laser short heat pulse using the dual phase lag model with constant phase lags are found to deviate considerably from the experimental data. The dual phase lag model is found to overestimate the transient temperature in the thermalization stage of the laser heating process of metal films, although it is still superior to the parabolic and hyperbolic one-step models.
Early development of intractable epilepsy in children (2001)

Approximately 10% of children meet criteria for IE early in the course of their epilepsy. Cryptogenic/symptomatic generalized syndromes carry the highest risk and idiopathic syndromes the lowest. Half of IE occurs in children with nonidiopathic localization-related syndromes. Initial seizure frequency is highly predictive of IE. By contrast, absolute number of seizures and unprovoked or febrile status epilepticus are not.
Complement Component C1q and Anti‐C1q Antibodies in Theory and in Clinical Practice (2008)

The complement system is a major part of the innate immunity. The first component of the classical pathway of complement activation, C1q, plays a crucial role in the clearance of immune complexes and apoptotic bodies from the organism. Autoantibodies against C1q (anti-C1q) have been found in a number of autoimmune and infectious diseases. They have been best described in patients with systemic lupus erythematosus, where they are thought to play a pathogenic role in lupus nephritis (LN). Their high negative predictive value for the occurrence of active proliferative LN, as well as their possible ability to indicate a renal flare as soon as 6 months in advance, have rendered anti-C1q antibodies a novel non-invasive tool in the detection of active LN.
Crystal engineering of the composition of pharmaceutical phases. Do pharmaceutical co-crystals represent a new path to improved medicines? (2004)

The evolution of crystal engineering into a form of supramolecular synthesis is discussed in the context of problems and opportunities in the pharmaceutical industry. Specifically, it has become clear that a wide array of multiple component pharmaceutical phases, so called pharmaceutical co-crystals, can be rationally designed using crystal engineering, and the strategy affords new intellectual property and enhanced properties for pharmaceutical substances.
The role of yeasts other than Candida albicans in oropharyngeal candidiasis (2001)

Candida albicans has been recognized as the predominant infecting organism in oropharyngeal candidiasis. Yeasts other than C. albicans are commonly recognized as colonizing the oral cavity but have not been thought to be a significant cause of disease. This review will describe the emergence of yeasts other than C. albicans as causative pathogens in oropharyngeal candidiasis both as co-infecting organisms with C. albicans and as sole pathogens themselves. Diagnosis and treatment of these emerging infections will also be discussed.
Expression of a Maize Sucrose Phosphate Synthase in Tomato Alters Leaf Carbohydrate Partitioning (1991)

Ann C. Worrell, Jean-Michel Bruneau, Kristin Summerfelt, Mike Boersig, Toni A. Voelker, Expression of a Maize Sucrose Phosphate Synthase in Tomato Alters Leaf Carbohydrate Partitioning, The Plant Cell, Vol. 3, No. 10 (Oct., 1991), pp. 1121-1130
Lack of Tyrosylprotein Sulfotransferase-2 Activity Results in Altered Sperm-Egg Interactions and Loss of ADAM3 and ADAM6 in Epididymal Sperm (2011)

Tyrosine O-sulfation is a post-translational modification catalyzed by two tyrosylprotein sulfotransferases (TPST-1 and TPST-2) in the trans-Golgi network. Tpst2-deficient mice have male infertility, sperm motility defects, and possible abnormalities in sperm-egg membrane interactions. Studies here show that compared with wild-type sperm, fewer Tpst2-null sperm bind to the egg membrane, but more of these bound sperm progress to membrane fusion. Similar outcomes were observed with wild-type sperm treated with the anti-sulfotyrosine antibody PSG2. The increased extent of sperm-egg fusion is not due to a failure of Tpst2-null sperm to trigger establishment of the egg membrane block to polyspermy. Anti-sulfotyrosine staining of sperm showed localization similar to that of IZUMO1, a sperm protein that is essential for gamete fusion, but we detected little to no tyrosine sulfation of IZUMO1 and found that IZUMO1 expression and localization were normal in Tpst2-null sperm. Turning to a discovery-driven approach, we used mass spectrometry to characterize sperm proteins that associated with PSG2. This identified ADAM6, a member of the A disintegrin and A metalloprotease (ADAM) family; members of this protein family are associated with multiple sperm functions. Subsequent studies revealed that Tpst2-null sperm lack ADAM6 and ADAM3. Loss of ADAM3 is strongly associated with male infertility and is observed in knockouts of male germ line-specific endoplasmic reticulum-resident chaperones, raising the possibility that TPST-2 may function in quality control in the secretory pathway. These data suggest that TPST-2-mediated tyrosine O-sulfation participates in regulating the sperm surface proteome or membrane order, ultimately affecting male fertility.
The Yeast AMPK Homolog SNF1 Regulates Acetyl Coenzyme A Homeostasis and Histone Acetylation (2013)

Acetyl coenzyme A (acetyl-CoA) is a key metabolite at the crossroads of metabolism, signaling, chromatin structure, and transcription. Concentration of acetyl-CoA affects histone acetylation and links intermediary metabolism and transcriptional regulation. Here we show that SNF1, the budding yeast ortholog of the mammalian AMP-activated protein kinase (AMPK), plays a role in the regulation of acetyl-CoA homeostasis and global histone acetylation. SNF1 phosphorylates and inhibits acetyl-CoA carboxylase, which catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the first and rate-limiting reaction in the de novo synthesis of fatty acids. Inactivation of SNF1 results in a reduced pool of cellular acetyl-CoA, globally decreased histone acetylation, and reduced fitness and stress resistance. The histone acetylation and transcriptional defects can be partially suppressed and the overall fitness improved in snf1Δ mutant cells by increasing the cellular concentration of acetyl-CoA, indicating that the regulation of acetyl-CoA homeostasis represents another mechanism in the SNF1 regulatory repertoire.
Ursodeoxycholate Alleviates Alcoholic Fatty Liver Damage in Rats (1998)

The hydrophilic bile salt ursodeoxycholate (UDC) improves cholestasis in several liver diseases and is in vitro an efficient membrane stabilizer. However, its action on chronic ethanol-induced liver damage is not established. We thus sought to determine the effect of UDC on chronic ethanol-induced steatosis and on liver plasma membrane fluidity in rats. Male rats were pair-fed liquid diets containing 36% of calories as ethanol (alcohol diet) or an isocaloric maltose-dextrin mixture (control diet). Four groups of 10 animals received, respectively, during 30 days: the control diet, the control diet + UDC (90 mg/kg/day), the alcohol diet, and the alcohol diet + UDC. Bile was collected for assessment of bile flow, biliary lipids, and individual bile salts. Liver lipid contents and lipid peroxidation were determined. Plasma membrane fluidity was assessed by fluorescence polarization of various probes. Alcohol treatment caused a 4-fold increase in liver triacylglycerol and cholesterol ester levels. UDC supplementation significantly reduced these increases by 50% and 40%, respectively. UDC intake was associated with a marked decrease in alcohol-induced lipid peroxidation. Bile flow, bile salt, and phospholipid secretion were slightly increased by alcohol intake. The addition of UDC-enriched bile with tauroursodeoxycholate (38%) without significantly affecting the biliary parameters. Lastly, UDC treatment almost totally prevented the 20% increase in liver plasma membrane fluidity due to chronic alcohol intake. This study shows that UDC intake, concomitant with alcohol diet, exerts a clear-cut membrane protective effect that might alleviate ethanol-induced lipid disorders.
Islet Cell Antibody Seroconversion in Children Is Temporally Associated with Enterovirus Infections (1997)

Exposure to Coxsackie B virus or other enteroviruses prenatally or in childhood increases the risk for later manifestation of insulin-dependent diabetes mellitus (IDDM). The occurrence of enterovirus infections was analyzed in 23 initially nondiabetic and islet cell antibody (ICA)-negative siblings of IDDM patients who converted to ICA positivity during a prospective follow-up study. Increases in enterovirus antibody levels, documented by heavy chain-capture RIA and EIA techniques, were significantly more frequent in sample intervals in which ICA first appeared (18/23, 78%) than in other sample intervals in these siblings (30/92, 33%; P < .001) or all sample intervals in 97 ICA-negative control siblings (117/403, 29%; P < .001). The children who converted to ICA positivity during an enterovirus infection more often had the high-risk HLA-DQB1 genotype than did children who were constantly ICA-negative (P < .01). The results suggest that enteroviruses may be important in the induction of a beta cell damaging process long before the clinical manifestation of IDDM.