Pathways Across the Valley of Death: Novel Intellectual Property Strategies for Accelerated Drug Discovery

Drug discovery is stagnating. Government agencies, industry analysts, and industry scientists have all noted that, despite significant increases in pharmaceutical R&D funding, the production of fundamentally new drugs - particularly drugs that work on new biological pathways and proteins - remains disappointingly low. To some extent, pharmaceutical firms are already embracing the prescription of new, more collaborative R&D organizational models suggested by industry analysts. In this Article, we build on collaborative strategies that firms are already employing by proposing a novel public-private collaboration that would help move upstream academic research across the valley of death that separates upstream research from downstream drug candidates. By exchanging trade secrecy for contract-based collaboration, our proposal would both protect intellectual property rights and enable many more researchers to search for potential drug candidates

A Case Report on Metformin-Associated Lactic Acidosis.

Metformin is the first-line therapy for patients with type 2 diabetes, and its most common adverse effects are gastrointestinal. Lactic acidosis associated with metformin use is rare. Here, we report the case of a 77-year-old man with a medical history of diabetes (treated with metformin), hypertension, chronic alcohol abuse, and prostate and bladder cancer, who presented with abdominal pain, nausea, vomiting, and diarrhea for five days. He was admitted with severe metabolic acidosis due to metformin toxicity (metformin-associated lactic acidosis) with metformin level 23 mcg/mL (therapeutic range approximately 1-2 mcg/mL) in the setting of acute kidney failure due to acute pancreatitis and sepsis secondary to aspiration pneumonia. He was intubated, required pressor support, and received daily hemodialysis. Despite aggressive management, his hospital course became complicated with acute respiratory distress syndrome, myocardial infarction, acute hepatic failure, and ischemic and metabolic encephalopathy. In the end, the family decided to withdraw care and the patient was terminally extubated

Atypical Presentation of Panhypopituitarism.

Hypopituitarism is a rare disorder. Hypopituitarism can present as a deficiency of individual anterior pituitary hormones (e.g., adrenocorticotropic hormone, thyroid-stimulating hormone, luteinizing hormone, follicle-stimulating hormone, prolactin, growth hormone) or posterior pituitary hormones (e.g., oxytocin, vasopressin) or as the deficiency of all these pituitary hormones, also known as panhypopituitarism. Here, we discuss a 59-year-old man who presented with two episodes of unwitnessed syncope after an episode of vomiting. On admission, the patient was hypotensive to 88/54 mmHg, afebrile, and with a leukocyte count of 21.43 K/µL (reference range: 3.80 to 10.50 K/µL). CT scan of the head revealed a hyperdensity in the left intracranial internal carotid artery just proximal to the bifurcation, suggesting an artifact or presence of an embolus. Additional findings included a sellar mass with calcifications and suprasellar extensions. The patient was admitted for further workup of syncope. Other differential diagnoses included sepsis, stroke, cardiac arrhythmias, and pulmonary embolism. Sepsis, stroke, and cardiac workup were negative for significant findings. The patient remained persistently hypotensive despite aggressive intravenous hydration, raising suspicion for an underlying endocrine disorder. MRI of the brain was negative for stroke but again was significant for a sellar mass. Additional workup showed a deficiency of all the anterior pituitary hormones likely secondary to mass effect. The patient was diagnosed with panhypopituitarism due to pituitary macroadenoma

Dissociative Autoionization in (1+2)-photon Above Threshold Excitation of H2 Molecules

We have theoretically studied the effect of dissociative autoionization on the photoelectron energy spectrum in (1+2)-photon above threshold ionization(ATI) of H2 molecules. We have considered excitation from the ground state X-singlet-Sigma-g+(v=0,j) to the doubly excited autoionizing states of singlet-Sigma-u+ and singlet-Pi-u+ symmetry, via the intermediate resonant B-singlet-Sigma-u+(v=5,j) states. We have shown that the photoelectron energy spectrum is oscillatory in nature and shows three distinct peaks above the photoelectron energy 0.7 eV. This feature has been observed in a recent experiment by Rottke et al, J. Phys. B, Vol. 30, p-4049 (1997).Comment: 11 pages and 4 figure

Predicting solar cycle 24 with a solar dynamo model

Whether the upcoming cycle 24 of solar activity will be strong or not is being hotly debated. The solar cycle is produced by a complex dynamo mechanism. We model the last few solar cycles by `feeding' observational data of the Sun's polar magnetic field into our solar dynamo model. Our results fit the observed sunspot numbers of cycles 21-23 extremely well and predict that cycle~24 will be about 35% weaker than cycle~23.Comment: 10 pages 1 table 3 figure

Chromatic adaptation and photoreversal in blue-green alga Calothrix clavata West

Complementary chromatic adaptation, a well-established phenomenon in some blue-green algae, has been observed inCalothrix clavata, a heterocystous blue-green alga of the family Rivulariaceae. The chromatic adaptation has been observed for fluorescent and incandescent light by measuring the absorption spectra. The material grown in fluorescent light forms more of phycoerythrin whereas more of phycocyanin tends to be formed in incandescent light. Besides this, photoreversal was observed by transferring the incandescent light grown alga to fluorescent light conditions and vice-versa. Effect of photoreversal and chromatic adaptation has also been discussed for this alga under different monochromatic light conditions. The influence of different light conditions on morphological changes, heterocysts and hormogonia formation has also been investigated. Both chromatic adaptation and photomorphogentic phenolmena in this alga show the involvement of some photoreversible (red:green) pigment

Scaling Law for Criticality Conditions in Heterogeneous Energetic Materials under Shock Loading

Initiation in heterogeneous energetic material (HEM) subjected to shock loading occurs due to the formation of hot spots. The criticality of the hot spots governs the initiation and sensitivity of HEMs. In porous energetic materials, collapse of pores under impact leads to the formation of hot spots. Depending on the size and strength of the hot spots chemical reaction can initiate. The criticality of the hot spots is dependent on the imposed shock load, void morphology and the type of energetic material. This work evaluates the relative importance of material constitutive and reactive properties on the criticality condition of spots. Using a scaling-based approach, the criticality criterion for cylindrical voids as a function of shock pressure, Ps and void diameter, Dvoid is obtained for two different energetic material HMX and TATB. It is shown that the criticality of different energetic materials is significantly dependent on their reactive properties