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.

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.

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.

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.

Water networks in fast proton transfer during catalysis by human carbonic anhydrase II.

Variants of human carbonic anhydrase II (HCA II) with amino acid replacements at residues in contact with water molecules in the active-site cavity have provided insights into the proton transfer rates in this protein environment. X-ray crystallography and (18)O exchange measured by membrane inlet mass spectrometry have been used to investigate structural and catalytic properties of variants of HCA II containing replacements of Tyr7 with Phe (Y7F) and Asn67 with Gln (N67Q). The rate constants for transfer of a proton from His64 to the zinc-bound hydroxide during catalysis were 4 and 9 µs(-1) for Y7F and Y7F/N67Q, respectively, compared with a value of 0.8 µs(-1) for wild-type HCA II. These higher values observed for Y7F and Y7F/N67Q HCA II could not be explained by differences in the values of the pK(a) of the proton donor (His64) and acceptor (zinc-bound hydroxide) or by the orientation of the side chain of the proton shuttle residue His64. They appeared to be associated with a reduced level of branching in the networks of hydrogen-bonded water molecules between proton shuttle residue His64 and the zinc-bound solvent molecule as observed in crystal structures at 1.5-1.6 Å resolution. Moreover, Y7F/N67Q HCA II is unique among the variants studied in having a direct, hydrogen-bonded chain of water molecules between the zinc-bound solvent and N(ε) of His64. This study provides the clearest example to date of the relevance of ordered water structure to rate constants for proton transfer in catalysis by carbonic anhydrase.

Effects of cryoprotectants on the structure and thermostability of the human carbonic anhydrase II-acetazolamide complex.

Protein X-ray crystallography has seen a progressive shift from data collection at cool/room temperature (277-298 K) to data collection at cryotemperature (100 K) because of its ease of crystal preparation and the lessening of the detrimental effects of radiation-induced crystal damage, with 20-25%(v/v) glycerol (GOL) being the preferred choice of cryoprotectant. Here, a case study of the effects of cryoprotectants on the kinetics of carbonic anhydrase II (CA II) and its inhibition by the clinically used inhibitor acetazolamide (AZM) is presented. Comparative studies of crystal structure, kinetics, inhibition and thermostability were performed on CA II and its complex with AZM in the presence of either GOL or sucrose. These results suggest that even though the cryoprotectant GOL was previously shown to be directly bound in the active site and to interact with AZM, it affects neither the thermostability of CA II nor the binding of AZM in the crystal structure or in solution. However, addition of GOL does affect the kinetics of CA II, presumably as it displaces the water proton-transfer network in the active site.

Insights towards sulfonamide drug specificity in α-carbonic anhydrases.

Carbonic anhydrases (CAs, EC 4.2.1.1) are a group of metalloenzymes that play important roles in carbon metabolism, pH regulation, CO2 fixation in plants, ion transport etc., and are found in all eukaryotic and many microbial organisms. This family of enzymes catalyzes the interconversion of CO2 and HCO3(-). There are at least 16 different CA isoforms in the alpha structural class (α-CAs) that have been isolated in higher vertebrates, with CA isoform II (CA II) being ubiquitously abundant in all human cell types. CA inhibition has been exploited clinically for decades for various classes of diuretics and anti-glaucoma treatment. The characterization of the overexpression of CA isoform IX (CA IX) in certain tumors has raised interest in CA IX as a diagnostic marker and drug target for aggressive cancers and therefore the development of CA IX specific inhibitors. An important goal in the field of CA is to identify, rationalize, and design potential compounds that will preferentially inhibit CA IX over all other isoforms of CA. The variations in the active sites between isoforms of CA are subtle and this causes non-specific CA inhibition which leads to various side effects. In the case of CA IX inhibition, CA II along with other isoforms of CA provide off-target binding sites which is undesirable for cancer treatment. The focus of this article is on CA IX inhibition and two different structural approaches to CA isoform specific drug designing: tail approach and fragment addition approach.

Structural annotation of human carbonic anhydrases.

Carbonic anhydrases (CAs, EC 4.2.1.1) are a family of metalloenzymes that catalyze the reversible interconversion of CO(2) and HCO(3)(-). Of the 15 isoforms of human (h) α-CA, 12 are catalytic (hCAs I-IV, VA, VB, VI, VII, IX, XII-XIV). The remaining three acatalytic isoforms (hCAs VIII, X and XI) lack the active site Zn(2+) and are referred to as CA-related proteins (CA-RPs); however, their function remains elusive. Overall these isoforms are very similar to each other in structure but they differ in their expression and distribution. The favourable properties of hCA II such as fast kinetics, easy expression and purification, high solubility and intermediate heat resistance have made it an attractive candidate for numerous industrial applications. This review highlights the structural similarity and stability comparison among hCAs.

Comparison of low-dose ketamine to midazolam for sedation during pediatric urodynamic study.

INTRODUCTION: Aim of sedation during pediatric urodynamic studies (UDS) is a calm and cooperative child while not affecting measurements. We compared the effectiveness of midazolam to low-dose ketamine infusion for sedation and their impact on urodynamics. MATERIALS AND METHODS: ASA-I children undergoing UDS were randomly assigned to group K (ketamine) loading dose (0.25 mg·kg(-1)) followed by infusion of 10-20 µg·kg(-1) ·min(-1) or group M (midazolam) loading dose of (0.02 mg·kg(-1)) followed by 1-2 µg·kg(-1) ·min(-1). The sedation scores and reactivity to catheterization were monitored by Children Hospital of Wisconsin Sedation Scale and Frankl Behavior Rating Scale, respectively. The UDS included two-channel filling cystometry in supine position followed by a free uroflowmetry in sitting position. The UDS was performed and interpreted in accordance with good urodynamic practice guidelines of International Continence Society (2002). RESULTS: A total of 34 children were enrolled. Group K children (n = 17) attained sedation earlier 6.80 (±3.36) min vs. 9.40 (±2.82) min; (P = 0.03) than group M (n = 17) and also recovered earlier 11.60 (±3.13) min vs. 19.67 (±5.49) min (P = 0.01). Reactivity scores during urinary and rectal catheterization were lower in group K (P = 0.03 and 0.01), respectively. Historical UDS data of 21 participants were available for comparison with effect of medication. None of the study drugs affected UDS parameters significantly. CONCLUSIONS: Midazolam or low-dose ketamine provide satisfactory sedation during pediatric UDS without impacting urodynamic values.

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.

Lactate flux in astrocytes is enhanced by a non-catalytic action of carbonic anhydrase II.

Rapid exchange of metabolites between different cell types is crucial for energy homeostasis of the brain. Besides glucose, lactate is a major metabolite in the brain and is primarily produced in astrocytes. In the present study, we report that carbonic anhydrase 2 (CAII) enhances both influx and efflux of lactate in mouse cerebellar astrocytes. The augmentation of lactate transport is independent of the enzyme's catalytic activity, but requires direct binding of CAII to the C-terminal of the monocarboxylate transporter MCT1, one of the major lactate/proton cotransporters in astrocytes and most tissues. By employing its intramolecular proton shuttle, CAII, bound to MCT1, can act as a 'proton collecting antenna' for the transporter, suppressing the formation of proton microdomains at the transporter-pore and thereby enhancing lactate flux. By this mechanism CAII could enhance transfer of lactate between astrocytes and neurons and thus provide the neurons with an increased supply of energy substrate.

Neutron diffraction of acetazolamide-bound human carbonic anhydrase II reveals atomic details of drug binding.

Carbonic anhydrases (CAs) catalyze the hydration of CO(2) forming HCO(3)(-) and a proton, an important reaction for many physiological processes including respiration, fluid secretion, and pH regulation. As such, CA isoforms are prominent clinical targets for treating various diseases. The clinically used acetazolamide (AZM) is a sulfonamide that binds with high affinity to human CA isoform II (HCA II). There are several X-ray structures available of AZM bound to various CA isoforms, but these complexes do not show the charged state of AZM or the hydrogen atom positions of the protein and solvent. Neutron diffraction is a useful technique for directly observing H atoms and the mapping of H-bonding networks that can greatly contribute to rational drug design. To this end, the neutron structure of H/D exchanged HCA II crystals in complex with AZM was determined. The structure reveals the molecular details of AZM binding and the charged state of the bound drug. This represents the first determined neutron structure of a clinically used drug bound to its target.

Neural control of dopamine neurotransmission: implications for reinforcement learning.

In the past few decades there has been remarkable convergence of machine learning with neurobiological understanding of reinforcement learning mechanisms, exemplified by temporal difference (TD) learning models. The anatomy of the basal ganglia provides a number of potential substrates for instantiation of the TD mechanism. In contrast to the traditional concept of direct and indirect pathway outputs from the striatum, we emphasize that projection neurons of the striatum are branched and individual striatofugal neurons innervate both globus pallidus externa and globus pallidus interna/substantia nigra (GPi/SNr). This suggests that the GPi/SNr has the necessary inputs to operate as the source of a TD signal. We also discuss the mechanism for the timing processes necessary for learning in the TD framework. The TD framework has been particularly successful in analysing electrophysiogical recordings from dopamine (DA) neurons during learning, in terms of reward prediction error. However, present understanding of the neural control of DA release is limited, and hence the neural mechanisms involved are incompletely understood. Inhibition is very conspicuously present among the inputs to the DA neurons, with inhibitory synapses accounting for the majority of synapses on DA neurons. Furthermore, synchronous firing of the DA neuron population requires disinhibition and excitation to occur together in a coordinated manner. We conclude that the inhibitory circuits impinging directly or indirectly on the DA neurons play a central role in the control of DA neuron activity and further investigation of these circuits may provide important insight into the biological mechanisms of reinforcement learning.

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.

Conformational variability of different sulfonamide inhibitors with thienyl-acetamido moieties attributes to differential binding in the active site of cytosolic human carbonic anhydrase isoforms.

The X-ray crystal structures of the adducts of human carbonic anhydrase (hCA, EC 4.2.1.1) II complexed with two aromatic sulfonamides incorporating 2-thienylacetamido moieties are reported here. Although, the two inhibitors only differ by the presence of an additional 3-fluoro substituent on the 4-amino-benzenesulfonamide scaffold, their inhibition profiles against the cytosolic isoforms hCA I, II, III, VII and XIII are quite different. These differences were rationalized based on the obtained X-ray crystal structures, and their comparison with other sulfonamide CA inhibitors with clinical applications, such as acetazolamide, methazolamide and dichlorophenamide. The conformations of the 2-thienylacetamido tails in the hCA II adducts of the two sulfonamides were highly different, although the benzenesulfonamide parts were superimposable. Specific interactions between structurally different inhibitors and amino acid residues present only in some considered isoforms have thus been evidenced. These findings can explain the high affinity of the 2-thienylacetamido benzenesulfonamides for some pharmacologically relevant CAs (i.e., isoforms II and VII) being also useful to design high affinity, more selective sulfonamide inhibitors of various CAs.

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.

A large number of the human microRNAs target lentiviruses, retroviruses, and endogenous retroviruses.

Retroelements (including transposons, retrotransposons, retroviruses, and lentiviruses) make up a significant portion of eukaryotic genomes. Given their ability to mutate genes these mobile elements always present a threat to the integrity of the host genomes. Recent studies have revealed complex molecular mechanisms that silence the mutagenic ability of these RE as well strategically express the pieces of the incorporated RE that are utilized to silence human endogenous retroviruses (HERVs) or invading exogenous retroviruses (IERV). We have hypothesized that small endogenous RNA originally evolved to quell "foreign" IERV-genes and subsequently emerged into elaborate silencing systems that include RNA interference, miRNA-based gene regulation and other gene silencing mechanisms. Here, we present evidence that the replication of complex RE are most likely silenced or regulated by homologous miRNA that are found as a part of the cellular repertoire. We analyzed Homo sapiens miRNAs for possible target genetic sequences in selected HERVs and IERV found in humans and other large primates. We identified several miRNAs that have >80% sequence homology with human HERVs; -L, -W, and -K, and IERV like SIVcpz, HTLV-1, and HTLV-2. We found an inverse correlation between the numbers and relative degree of homology of miRNAs to the relative replication capacity of a specific RE. Therefore, larger numbers of miRNAs with greater degree of homology are found against the least active RE and the least numbers of miRNAs with smaller degree of homology are found against the most active RE (i.e. HERV-K). Implications of these observations in RE disease and therapy are discussed.

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.