Channel assisted noise propagation in a two-step cascade.

Signal propagation in biochemical networks is characterized by the inherent randomness in gene expression and fluctuations of the environmental components, commonly known as intrinsic and extrinsic noise, respectively. We present a theoretical framework for noise propagation in a generic two-step cascade (S→X→Y) regarding intrinsic and extrinsic noise. We identify different channels of noise transmission that regulate the individual and the overall noise properties of each component. Our analysis shows that the intrinsic noise of S alleviates the general noise and information transmission capacity along the cascade. On the other hand, the intrinsic noise of X and Y acts as a bottleneck of information transmission. We also show a hierarchical relationship among the intrinsic noise levels of S, X, and Y, with S exhibiting the highest level of intrinsic noise, followed by X and then Y. This hierarchy is preserved within the two-step cascade, facilitating the highest information transmission from S to Y via X.

Bi-stability of the master gene regulatory network of the common dendritic precursor cell: Implications for cell differentiation.

In cell lineage commitment decisions, a gene regulatory network (GRN) consisting of a limited number of transcription factors forms the regulatory pivot. Myeloid lineage dendritic cells or DCs are specialized cells having the antigen-presenting ability and are of immense importance in immune surveillance. In this report, we analyze the GRN that governs the lineage commitment of Common DC Progenitor (CDP) cells to conventional dendritic cells (cDC) and plasmacytoid dendritic cells (pDC). We have analyzed the quantitative behavior of the master regulatory circuit of CDP that governs the lineage commitment. Simulations showed that the GRN displays a bi-stable behavior within a range of parameter values. Several transcription factors, PU.1, IRF8, Flt3, and Stat3, whose concentrations vary significantly in the two steady states, appear to be the key players. We hypothesize that the two stable steady states are precursors of cDC and pDC, and the variation of concentration of these key transcription factors in the two states may be responsible for early events in lineage commitment.

Emergence of dynamic cooperativity in the stochastic kinetics of fluctuating enzymes.

Dynamic co-operativity in monomeric enzymes is characterized in terms of a non-Michaelis-Menten kinetic behaviour. The latter is believed to be associated with mechanisms that include multiple reaction pathways due to enzymatic conformational fluctuations. Recent advances in single-molecule fluorescence spectroscopy have provided new fundamental insights on the possible mechanisms underlying reactions catalyzed by fluctuating enzymes. Here, we present a bottom-up approach to understand enzyme turnover kinetics at physiologically relevant mesoscopic concentrations informed by mechanisms extracted from single-molecule stochastic trajectories. The stochastic approach, presented here, shows the emergence of dynamic co-operativity in terms of a slowing down of the Michaelis-Menten (MM) kinetics resulting in negative co-operativity. For fewer enzymes, dynamic co-operativity emerges due to the combined effects of enzymatic conformational fluctuations and molecular discreteness. The increase in the number of enzymes, however, suppresses the effect of enzymatic conformational fluctuations such that dynamic co-operativity emerges solely due to the discrete changes in the number of reacting species. These results confirm that the turnover kinetics of fluctuating enzyme based on the parallel-pathway MM mechanism switches over to the single-pathway MM mechanism with the increase in the number of enzymes. For large enzyme numbers, convergence to the exact MM equation occurs in the limit of very high substrate concentration as the stochastic kinetics approaches the deterministic behaviour.

Wilkie's syndrome: review of eight cases.

BACKGROUND: The superior mesenteric artery (SMA) syndrome is a rare entity presenting with upper gastrointestinal tract obstruction and abrupt weight loss. Usually seen in tall individual with low bod mass index (BMI), the weight loss may be primary or secondary to a systemic disease or to the syndrome itself Compression of the duodenum between the abdominal aorta and the superior mesenteric artery due to loss of the duodenal pad of fat causes the obstruction. Early recognition prevent complications. Imaging and endoscopy is diagnostic. Aorto-mesenteric angle and SMA aorta distance is lower than 22 degree and eight millimeter respectively. If nutritional support fails, surgery is required (e.g. guodeno-jejunostomy). Studies to determine the optimal methods of diagnosis and treatment, especially in a suburban hospitals with limited expertise are essential. CASE REPORT: We retrospectively evaluated 8 cases presented over three years. Six (75%) patients were males, age ranged from 19 to 70 years and weight from 40 to 55 kg. The mean BMI was 18.7 kg/ m2 (range 16.42 to 25.11 kg/m2). Mean weight loss before diagnosis was 9.88 kg (range 6 to 12 kg). Symptoms developed between 8 to 180 days (median 12 days). Commonest presentation was epigastric pain, vomiting and nausea. Four patients had pre-morbid conditions and the syndrome was idiopathic in the other 4. Median aorto-mesentric angle was 16.5 degree and SMA-aorta distance was 5.15 mm. Four patients required operation. The rest improved on conservative treatment. CONCLUSION: Early recognition, institution of the appropriate conservative measures and timely selection of a definite surgical method are critical to prevent severe complications and death.

Role of integrated noise in pathway-specific signal propagation in feed-forward loops.

Cells impose optimal noise control mechanism in diverse situations to cope with distinct environmental cues. Sometimes, it is desirable for the cell to utilize fluctuations for noise-driven processes. In other cases, noise can be harmful to the cell to show optimal fitness. It is, therefore, important to unravel the noise propagation mechanism inside the cell. Such noise controlling mechanism is accomplished by using gene transcription regulatory networks. One such gene regulatory network is feed-forward loop, having three regulatory nodes S, X and Y. Here, we consider the most abundant type 1 of coherent and incoherent feed-forward loops with both OR and AND logic functions, forming four different architectures. In OR logic function, the functions representing S and X act additively for the regulation of Y, while in AND logic function, the same functions (S and X) act multiplicatively for the regulation of Y. Measurement of susceptibility of the signal at output Y is done using elasticity of each regulation in FFLs. Using susceptibility, we demonstrate the nature of pathway integration by which one-step and two-step pathways get overlapped. The integration type is competitive for motifs having OR gate, while it is noncompetitive for the same with AND gate. The pathway integration property explains the output noise behavior of the motifs properly but cannot infer about the mechanism by which the upstream noise propagates to output. To account this, the total output noise is decomposed, which results in integrated noise as an additional noise source along with pathway-specific noise components. The integrated noise is found to appear as a consequence of integration between the pathways and has different functional characteristics explaining noise amplification and noise attenuation property of coherent and incoherent feed-forward loops, respectively. The noise decomposition also quantifies the contribution of different noise sources toward total noise. Finally, the noise propagation is being tuned as a function of input signal noise and its time scale of fluctuations, which shows considerable intrinsic noise strength and relatively slow relaxation time scale causes a higher degree of noise propagation in FFLs.

Information transmission in a two-step cascade: interplay of activation and repression.

We present an information-theoretic formalism to study signal transduction in four architectural variants of a model two-step cascade with increasing input population. Our results categorize these four types into two classes depending upon the effect of activation and repression on mutual information, net synergy, and signal-to-noise ratio. Using the Gaussian framework and linear noise approximation, we derive the analytic expressions for these metrics to establish their underlying relationships in terms of the biochemical parameters. We also verify our approximations through stochastic simulations.

Restricted information in a two-step cascade.

A cell must sense extracellular and intracellular fluctuations and respond appropriately to survive for optimal cellular functioning. Accordingly, a cell builds up biochemical networks which can transduce information of extracellular and intracellular fluctuations accurately. We consider a generic two-step cascade as a model gene regulatory network containing three regulatory proteins S, X, and Y connected as S→X→Y. The intermediate node X is a stochastic variable, acts as an obstacle, and impedes the information flow from S to Y. We quantify the information that is restricted by X using the tools of information theory and term this as restricted information. In this context, we further propose two measurable quantities, restricted efficiency and information transfer efficiency. The former determines how efficiently X restricts the upstream information coming from S, while the latter computes the efficiency of X to pass the upstream information toward Y. We also quantify the information that is being uniquely transferred from X to Y, which determines the extent of the ability of X to act as a source of information. Our analysis shows that when the signal strength (or mean population of S, 〈s〉) is low, the intermediate X can carry forward the upstream information reliably as well, as it acts as a better source of information, thereby increasing the fidelity of the network. But at the high signal strength, X restricts most of the upstream information, and its ability to act as a source of information gets reduced. This leads to a loss of fidelity of the network.

Giant neck swelling.

The most common benign salivary gland tumor is pleomorphic adenoma. They can attain giant proportions and weigh several kilograms. They can cause facial disfigurement and, if untreated, could lead malignant transformation. This image depicts a 7.5 kg pleomorphic adenoma of right submandibular gland with malignant change in a 55-year-old male.

Wilkie’s syndrome: review of eight cases / Wilkie’s syndrome: review of eight cases.

BACKGROUND: The superior mesenteric artery (SMA) syndrome is a rare entity presenting with upper gastrointestinal tract obstruction and abrupt weight loss. Usually seen in tall individual with low bod mass index (BMI), the weight loss may be primary or secondary to a systemic disease or to the syndrome itself Compression of the duodenum between the abdominal aorta and the superior mesenteric artery due to loss of the duodenal pad of fat causes the obstruction. Early recognition prevent complications. Imaging and endoscopy is diagnostic. Aorto-mesenteric angle and SMA aorta distance is lower than 22 degree and eight millimeter respectively. If nutritional support fails, surgery is required (e.g. guodeno-jejunostomy). Studies to determine the optimal methods of diagnosis and treatment, especially in a suburban hospitals with limited expertise are essential. CASE REPORT: We retrospectively evaluated 8 cases presented over three years. Six (75

) patients were males, age ranged from 19 to 70 years and weight from 40 to 55 kg. The mean BMI was 18.7 kg/ m2 (range 16.42 to 25.11 kg/m2). Mean weight loss before diagnosis was 9.88 kg (range 6 to 12 kg). Symptoms developed between 8 to 180 days (median 12 days). Commonest presentation was epigastric pain, vomiting and nausea. Four patients had pre-morbid conditions and the syndrome was idiopathic in the other 4. Median aorto-mesentric angle was 16.5 degree and SMA-aorta distance was 5.15 mm. Four patients required operation. The rest improved on conservative treatment. CONCLUSION: Early recognition, institution of the appropriate conservative measures and timely selection of a definite surgical method are critical to prevent severe complications and death.

Wilkies syndrome: review of eight cases. / Wilkies syndrome: review of eight cases.

BACKGROUND: The superior mesenteric artery (SMA) syndrome is a rare entity presenting with upper gastrointestinal tract obstruction and abrupt weight loss. Usually seen in tall individual with low bod mass index (BMI), the weight loss may be primary or secondary to a systemic disease or to the syndrome itself Compression of the duodenum between the abdominal aorta and the superior mesenteric artery due to loss of the duodenal pad of fat causes the obstruction. Early recognition prevent complications. Imaging and endoscopy is diagnostic. Aorto-mesenteric angle and SMA aorta distance is lower than 22 degree and eight millimeter respectively. If nutritional support fails, surgery is required (e.g. guodeno-jejunostomy). Studies to determine the optimal methods of diagnosis and treatment, especially in a suburban hospitals with limited expertise are essential. CASE REPORT: We retrospectively evaluated 8 cases presented over three years. Six (75

) patients were males, age ranged from 19 to 70 years and weight from 40 to 55 kg. The mean BMI was 18.7 kg/ m2 (range 16.42 to 25.11 kg/m2). Mean weight loss before diagnosis was 9.88 kg (range 6 to 12 kg). Symptoms developed between 8 to 180 days (median 12 days). Commonest presentation was epigastric pain, vomiting and nausea. Four patients had pre-morbid conditions and the syndrome was idiopathic in the other 4. Median aorto-mesentric angle was 16.5 degree and SMA-aorta distance was 5.15 mm. Four patients required operation. The rest improved on conservative treatment. CONCLUSION: Early recognition, institution of the appropriate conservative measures and timely selection of a definite surgical method are critical to prevent severe complications and death.