Foraging in a non-foraging task: Fitness maximization explains human risk preference dynamics under changing environment.

Changes in risk preference have been reported when making a series of independent risky choices or non-foraging economic decisions. Behavioral economics has put forward various explanations for specific changes in risk preference in non-foraging tasks, but a consensus regarding the general principle underlying these effects has not been reached. In contrast, recent studies have investigated human economic risky choices using tasks adapted from foraging theory, which require consideration of past choices and future opportunities to make optimal decisions. In these foraging tasks, human economic risky choices are explained by the ethological principle of fitness maximization, which naturally leads to dynamic risk preference. Here, we conducted two online experiments to investigate whether the principle of fitness maximization can explain risk preference dynamics in a non-foraging task. Participants were asked to make a series of independent risky economic decisions while the environmental richness changed. We found that participants' risk preferences were influenced by the current and past environments, making them more risk-averse during and after the rich environment compared to the poor environment. These changes in risk preference align with fitness maximization. Our findings suggest that the ethological principle of fitness maximization might serve as a generalizable principle for explaining dynamic preferences, including risk preference, in human economic decision-making.

Movies, stigma and choice: Evidence from the pharmaceutical industry.

Do movies reduce stigma, increasing healthcare product choices offered by firms? We provide causal evidence on this question in the context of Indian pharmaceutical markets. For unpacking these effects, we use an exogenous shock to the market due to the release of a Bollywood blockbuster movie - My Name is Khan (MNIK) where the protagonist, superstar Shahrukh Khan, suffers from Asperger's Syndrome (AS). Using a difference-in-differences design, we find a positive and statistically significant effect of MNIK (between 14% and 22% increase in variety sold and prescribed) on product differentiation and choices in the market for antipsychotic medicines used to clinically treat AS. Results are consistent using alternative controls, a placebo treatment-based test and with a variety of other robustness checks. Our findings document likely for the first-time, supply side responses to edutainment and suggests potential associated welfare effects in healthcare markets characterized by sticky demand. Implications for global health and public policy given worldwide concerns around a mental wellness epidemic with Covid-19 are discussed.

Conditioned approach behavior of SHR and SD rats during Pavlovian conditioning.

Individual differences in reward-related learning are relevant to many behavioral disorders. Sensory cues that predict reward can become incentive stimuli that adaptively support behavior, or alternatively, cause maladaptive behaviors. The spontaneously hypertensive rat (SHR) expresses a genetically determined elevated sensitivity to delay of reward, and has been extensively studied as a behavioral model for attention deficit hyperactivity disorder (ADHD). We investigated reward-related learning in the SHR, comparing them to Sprague-Dawley (SD) rats as a reference strain. A standard Pavlovian conditioned approach task was used, in which a lever cue was followed by reward. Lever presses could occur while the lever was extended, but had no effect on reward delivery. The behavior of both the SHRs and the SD rats showed that they learnt that the lever cue predicted reward. However, the pattern of behavior differed between the strains. During lever cue presentation, SD rats pressed the lever more often and made fewer magazine entries than SHRs. When lever contacts that did not result in lever presses were analyzed, there was no significant difference between SHRs and SDs. These results suggest that the SHRs attributed less incentive value to the conditioned stimulus than the SD rats. During the presentation of the conditioned cue, cue directed responses are called sign tracking responses, whereas responses directed towards the food magazine are called goal tracking responses. Analysis of behavior using a standard Pavlovian conditioned approach index to quantify sign and goal tracking tendencies showed that both strains had a tendency towards goal tracking in this task. However, the SHRs showed a significantly greater goal tracking tendency than the SD rats. Taken together, these findings suggest that attribution of incentive value to reward predicting cues is attenuated in SHRs, which might explain their elevated sensitivity to delay of reward.

Abdominal Wall Reconstruction Using Pedicled Antero Lateral Thigh Flap.

Background: Reconstructing abdominal wall defects has been a difficult task for surgeons. The abdominal wall defects range from defects of only soft tissue to full thickness defects including all the three layers of the abdomen. Only soft tissue defects are commonly caused by peritonitis and laparotomies, and full thickness defects can occur from en bloc resection of tumours as well as trauma. Treatment options available include component separation, partition technique, flap coverage, and more recently acellular dermal matrix. Methods: This retrospective study done between 2016 and 2020 where 20 patients were operated for abdominal wall defect using Pedicled ALT flap in the Department of Plastic and Reconstructive Surgery, Sawai Man Singh Hospital, Jaipur, Rajasthan, India. Results: The study consisted of total 20 patients, 14 males and 6 females. Eight patients were post electric burn, 5 patients had suffered trauma, 4 patients underwent resection of abdominal wall tumour and 3 patients were post laparotomy for peritonitis. Mean age of patients was 48 years (range from 36 to 62 years). Mean fascia defect size was 14.2 cm (range 12.2 to 16.4 cm). Mean operative time was 170 minutes (range from 140 minutes to 220 minutes). Postoperative hospital stay ranged from 8 days to 24 days (mean- 12 days). Conclusion: Pedicled ALT flap has expanded the armamentarium of plastic surgeons for reconstruction of abdominal wall defects.

Behavioral determinants in the expression of the Kamin blocking effect: Implications for associative learning theory.

Associative learning makes important contributions to our behavior and decisions. The Kamin blocking effect is an associative learning phenomenon that plays a central role in understanding of the psychological principles underlying associative learning. However, several recent failures to replicate the blocking effect suggest that the conditions necessary for blocking are poorly understood. To understand the conditions necessary for blocking, here we review studies into the expression of blocking in subjects that either approach and interact with the conditioned cue (sign trackers) or approach and interact with the reward location (goal trackers) during appetitive classical conditioning. Psychological theory and the neurophysiological correlates of appetitive classical conditioning make opposing predictions regarding the expression of blocking in sign and goal trackers. We reconcile these opposing predictions in a qualitative model using two parallel learning processes. Such models offer a better framework for understanding the psychological associative structures acquired during learning, their interactions contributing to the conditioned response, and how they affect subsequent learning and the expression of the Kamin blocking effect.

Demographic and clinicopathological profile of patients of gastrointestinal stromal tumor from a tertiary care center of North India: An observational study.

BACKGROUND: Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal system. This study was aimed to analyze the demographic and clinicopathological data of the patient with a primary diagnosis of GIST, who were treated at our center. MATERIALS AND METHODOLOGY: Patients of GIST registered at our center from September 1, 2008, to August 31, 2016, were enrolled for this study. Patient's demographic and clinicopathological data were collected from clinical records. The data were represented as absolute number, percentage, and median (range: minimum to maximum), whichever applicable. RESULTS AND OBSERVATIONS: The analysis of 27 patients revealed that pain was the most common clinical feature. The stomach was the most common primary site. Most of the patients underwent upfront radical surgery (92.6%) followed by adjuvant imatinib. Histopathological data revealed that most tumors were >10 cm in size, 51.8% of patients had low mitotic index, and all these patients were either immunohistochemical positive for cluster differentiation 117 or KIT. The median duration of tyrosine kinase inhibitors therapy (imatinib) in our study individual was 2.5 years with a range of 4.8 months-3 years. Response assessment revealed 74.1% complete remission, 11.1% stable disease, and 3.7% progressive disease. Median overall survival in study individuals was 2.63 years (range: 0.1-8.6 years). Patient- and tumor-related factors were analyzed for prognostic significance using univariate survival analysis; however, none was found to have a significant prognostic correlation. CONCLUSIONS: Patients who underwent upfront surgery followed by adjuvant imatinib has shown good response to the treatment. However, the limitation of the small sample size and short follow-up in this study may not be a true data representation of the entire population.

The nucleus accumbens and inhibition in the ventral tegmental area play a causal role in the Kamin blocking effect.

The discovery of Kamin blocking led to the idea that associative learning occurs only when there is a mismatch between actual and predicted outcomes, or prediction error. The neural substrates involved in regulating this prediction error during behavioral learning are still not fully elucidated. We investigated in rats the role of the ventral tegmental area and the nucleus accumbens in Kamin blocking. Our blocking paradigm involved three phases: appetitive classical conditioning of a lever cue, conditioning of a compound of the lever cue plus an auditory cue, and testing response to the auditory cue in extinction. We found that disruption of inhibition in the ventral tegmental area by bicuculline, or designer receptor mediated inactivation of the nucleus accumbens, during compound cue conditioning, attenuated Kamin blocking. These results suggest that inhibition in the ventral tegmental area and inhibitory output from the nucleus accumbens are necessary for blocking and make behaviorally significant contributions to the computation of reward prediction error. In addition, we found that inactivating the neurons in the nucleus accumbens during classical conditioning of the lever cue also attenuated blocking, without affecting classical conditioning of the lever. This indicates that learning in the nucleus accumbens is necessary for blocking and reward estimation. Our results reveal a causal role for nucleus accumbens modulated inhibitory inputs to the ventral tegmental area in the blocking effect and suggest that they contribute to computation of reward prediction error during associative learning.

Structural Mapping of Anion Inhibitors to ß-Carbonic Anhydrase psCA3 from Pseudomonas aeruginosa.

Pseudomonas aeruginosa is a Gram-negative facultative anaerobe belonging to the Pseudomonadaceae family. It is a multidrug-resistant opportunistic human pathogen, a common cause of life-threatening nosocomial infections, and a key bacterial agent in cystic fibrosis and endocarditis. The bacterium exhibits intrinsic resistance to most antibacterial agents, including aminoglycosides and quinolones. Hence, the identification of new drug targets for P. aeruginosa is ongoing. PsCA3 is a ß-class carbonic anhydrase (ß-CA) that catalyzes the reversible hydration of carbon dioxide to bicarbonate and represents a new class of antimicrobial target. Previously, inhibitor screening studies of psCA3 have shown that a series of small anions including sulfamide (SFN), imidazole (IMD), and 4-methylimidazole (4MI), and thiocyanate (SCN) inhibit the enzyme with efficiencies in the micro- to millimolar range. Herein the X-ray crystal structures of these inhibitors in complex with psCA3 are presented and compared with human CA II. This structural survey into the binding modes of small anions forms the foundation for the development of inhibitors against ß-CAs and more selective inhibitors against P. aeruginosa.

"To Be or Not to Be" Protonated: Atomic Details of Human Carbonic Anhydrase-Clinical Drug Complexes by Neutron Crystallography and Simulation.

Human carbonic anhydrases (hCAs) play various roles in cells, and have been drug targets for decades. Sequence similarities of hCA isoforms necessitate designing specific inhibitors, which requires detailed structural information for hCA-inhibitor complexes. We present room temperature neutron structures of hCA II in complex with three clinical drugs that provide in-depth analysis of drug binding, including protonation states of the inhibitors, hydration water structure, and direct visualization of hydrogen-bonding networks in the enzyme's active site. All sulfonamide inhibitors studied bind to the Zn metal center in the deprotonated, anionic, form. Other chemical groups of the drugs can remain neutral or be protonated when bound to hCA II. MD simulations have shown that flexible functional groups of the inhibitors may alter their conformations at room temperature and occupy different sub-sites. This study offers insights into the design of specific drugs to target cancer-related hCA isoform IX.

Modulatory Effects of Chemoradiation on Angiogenic Factors and Laminin in Cervical Cancer: Link with Treatment Response

Objective: Carcinoma of the uterine cervix is either the first or second most common malignancy in Indian women, depending on the registry. Tumor growth and metastasis primarily are determined by angiogenesis and parameters of the molecular environment including extracellular matrix elements, growth factors and cytokines. Effects of chemo-irradiation on biomarkers like vascular endothelial growth factor (VEGF), angiopoietin-2 (Ang-2) and laminin in patients with carcinoma cervix therefore need to be explored. Methods: Circulatory and mRNA levels of VEGF, Ang-2 and laminin in patients with stage III carcinoma cervix (n=40) were compared with those of normal healthy women (n=20). Measurement was prior to treatment, and after chemotherapy and teleradiation, using high sensitivity ELISA kits and Q-PCR. Clinical response was evaluated as per WHO criteria and was assessed for correlation with the biochemical markers. Results: Levels of all the studied molecules were significantly (p<0.001) higher in patients than in controls. After treatment significant decline (p<0.001) was noted. Out of 40 patients, 33 were complete responders and 7 were non-responders on clinical assessment. On comparison of before and after treatment levels of these molecules complete responders showed significant decline whereas non-responders showed non-significant decrease. Follow-up of the responders for 3 years, revealed 28 of 33 patients to still be disease free, the other 5 demonstrating recurrence. Conclusions: Higher levels of angiogenic factors along with laminin indicate roles played in disease progression aiding angiogenesis. These markers may serve as useful tools in post treatment disease mapping, for which available imaging methods may not provide a true picture.

Cryoannealing-induced space-group transition of crystals of the carbonic anhydrase psCA3.

Cryoannealing has been demonstrated to improve the diffraction quality and resolution of crystals of the ß-carbonic anhydrase psCA3 concomitant with a change in space group. After initial flash-cooling in a liquid-nitrogen cryostream an X-ray diffraction data set from a psCA3 crystal was indexed in space group P21212 and was scaled to 2.6 Šresolution, but subsequent cryoannealing studies revealed induced protein rearrangements in the crystal contacts, which transformed the space group to I222, with a corresponding improvement of 0.7 Šin resolution. Although the change in diffraction resolution was significant, only minor changes in the psCA3 structure, which retained its catalytic `open' conformation, were observed. These findings demonstrate that cryoannealing can be successfully utilized to induce higher diffraction-quality crystals while maintaining enzymatically relevant conformations and may be useful as an experimental tool for structural studies of other enzymes where the initial diffraction quality is poor.

Broncho-biliary fistula secondary to biliary obstruction and lung abscess in a patient with pancreatic neuro-endocrine tumor.

We present a case report of broncho-biliary fistula that developed due to the blockage of biliary stent placed during the management of pancreatic neuroendocrine tumor (pNET); diagnosed on high clinical suspicion, percutaneous cholangiogram and contrast enhanced computed tomography (CECT); and successfully treated with percutaneous transhepatic biliary drainage (PTBD).

Neutron structure of human carbonic anhydrase II in complex with methazolamide: mapping the solvent and hydrogen-bonding patterns of an effective clinical drug.

Carbonic anhydrases (CAs; EC 4.2.1.1) catalyze the interconversion of CO2 and HCO3-, and their inhibitors have long been used as diuretics and as a therapeutic treatment for many disorders such as glaucoma and epilepsy. Acetazolamide (AZM) and methazolamide (MZM, a methyl derivative of AZM) are two of the classical CA inhibitory drugs that have been used clinically for decades. The jointly refined X-ray/neutron structure of MZM in complex with human CA isoform II (hCA II) has been determined to a resolution of 2.2 Šwith an Rcryst of ∼16.0%. Presented in this article, along with only the second neutron structure of a clinical drug-bound hCA, is an in-depth structural comparison and analyses of differences in hydrogen-bonding network, water-molecule orientation and solvent displacement that take place upon the binding of AZM and MZM in the active site of hCA II. Even though MZM is slightly more hydrophobic and displaces more waters than AZM, the overall binding affinity (Ki) for both of the drugs against hCA II is similar (∼10 nM). The plausible reasons behind this finding have also been discussed using molecular dynamics and X-ray crystal structures of hCA II-MZM determined at cryotemperature and room temperature. This study not only allows a direct comparison of the hydrogen bonding, protonation states and solvent orientation/displacement of AZM and MZM, but also shows the significant effect that the methyl derivative has on the solvent organization in the hCA II active site.

A sucrose-binding site provides a lead towards an isoform-specific inhibitor of the cancer-associated enzyme carbonic anhydrase IX.

Human carbonic anhydrase (CA; EC 4.2.1.1) isoform IX (CA IX) is an extracellular zinc metalloenzyme that catalyzes the reversible hydration of CO2 to HCO3(-), thereby playing a role in pH regulation. The majority of normal functioning cells exhibit low-level expression of CA IX. However, in cancer cells CA IX is upregulated as a consequence of a metabolic transition known as the Warburg effect. The upregulation of CA IX for cancer progression has drawn interest in it being a potential therapeutic target. CA IX is a transmembrane protein, and its purification, yield and crystallization have proven challenging to structure-based drug design, whereas the closely related cytosolic soluble isoform CA II can be expressed and crystallized with ease. Therefore, we have utilized structural alignments and site-directed mutagenesis to engineer a CA II that mimics the active site of CA IX. In this paper, the X-ray crystal structure of this CA IX mimic in complex with sucrose is presented and has been refined to a resolution of 1.5 Å, an Rcryst of 18.0% and an Rfree of 21.2%. The binding of sucrose at the entrance to the active site of the CA IX mimic, and not CA II, in a non-inhibitory mechanism provides a novel carbohydrate moiety binding site that could be further exploited to design isoform-specific inhibitors of CA IX.

Carbon Dioxide "Trapped" in a ß-Carbonic Anhydrase.

Carbonic anhydrases (CAs) are enzymes that catalyze the hydration/dehydration of CO2/HCO3(-) with rates approaching diffusion-controlled limits (kcat/KM ∼ 10(8) M(-1) s(-1)). This family of enzymes has evolved disparate protein folds that all perform the same reaction at near catalytic perfection. Presented here is a structural study of a ß-CA (psCA3) expressed in Pseudomonas aeruginosa, in complex with CO2, using pressurized cryo-cooled crystallography. The structure has been refined to 1.6 Å resolution with R(cryst) and R(free) values of 17.3 and 19.9%, respectively, and is compared with the α-CA, human CA isoform II (hCA II), the only other CA to have CO2 captured in its active site. Despite the lack of structural similarity between psCA3 and hCA II, the CO2 binding orientation relative to the zinc-bound solvent is identical. In addition, a second CO2 binding site was located at the dimer interface of psCA3. Interestingly, all ß-CAs function as dimers or higher-order oligomeric states, and the CO2 bound at the interface may contribute to the allosteric nature of this family of enzymes or may be a convenient alternative binding site as this pocket has been previously shown to be a promiscuous site for a variety of ligands, including bicarbonate, sulfate, and phosphate ions.

Carbonic Anhydrase Inhibition with Benzenesulfonamides and Tetrafluorobenzenesulfonamides Obtained via Click Chemistry.

A series of novel benzene- and 2,3,5,6-tetrafluorobenzenesulfonamide was synthesized by using a click chemistry approach starting from azido-substituted sulfonamides and alkynes, incorporating aryl, alkyl, cycloalkyl, and amino-/hydroxy-/halogenoalkyl moieties. The new compounds were medium potency inhibitors of the cytosolic carbonic anhydrase (CA, EC 4.2.1.1) isoforms I and II and low nanomolar/subnanomolar inhibitors of the tumor-associated hCA IX and XII isoforms. The X-ray crystal structure of two such sulfonamides in adduct with hCA II allowed us to understand the factors governing inhibitory power.

Structural insight into activity enhancement and inhibition of H64A carbonic anhydrase II by imidazoles.

Human carbonic anhydrases (CAs) are zinc metalloenzymes that catalyze the hydration and dehydration of CO2 and HCO3 (-), respectively. The reaction follows a ping-pong mechanism, in which the rate-limiting step is the transfer of a proton from the zinc-bound solvent (OH(-)/H2O) in/out of the active site via His64, which is widely believed to be the proton-shuttling residue. The decreased catalytic activity (∼20-fold lower with respect to the wild type) of a variant of CA II in which His64 is replaced with Ala (H64A CA II) can be enhanced by exogenous proton donors/acceptors, usually derivatives of imidazoles and pyridines, to almost the wild-type level. X-ray crystal structures of H64A CA II in complex with four imidazole derivatives (imidazole, 1--methylimidazole, 2--methylimidazole and 4-methylimidazole) have been determined and reveal multiple binding sites. Two of these imidazole binding sites have been identified that mimic the positions of the 'in' and 'out' rotamers of His64 in wild-type CA II, while another directly inhibits catalysis by displacing the zinc-bound solvent. The data presented here not only corroborate the importance of the imidazole side chain of His64 in proton transfer during CA catalysis, but also provide a complete structural understanding of the mechanism by which imidazoles enhance (and inhibit when used at higher concentrations) the activity of H64A CA II.

Mesenchymal chondrosarcoma of kidney.

Mesenchymal chondrosarcoma of the kidney is a very rare entity with no definite treatment protocol. Herein, we describe one such case with discussion of its diagnosis and management. The patient had a well circumscribed mass in right kidney extending into the inferior vena cava and metastasis to both the lungs. Right nephrectomy was performed and the histopathological examination confirmed the diagnosis to be renal mesenchymal chondrosarcoma. After surgical removal of the tumor, the patient was given chemotherapy with Cisplatin and Epirubicin, following which there was significant regression of lung nodules.