Genetic excision of the regulatory cardiac troponin I extension in high-heart rate mammal clades.

Mammalian cardiac troponin I (cTnI) contains a highly conserved amino-terminal extension harboring protein kinase A targets [serine-23 and -24 (Ser23/24)] that are phosphorylated during ß-adrenergic stimulation to defend diastolic filling by means of an increased cardiomyocyte relaxation rate. In this work, we show that the Ser23/24-encoding exon 3 of TNNI3 was pseudoexonized multiple times in shrews and moles to mimic Ser23/24 phosphorylation without adrenergic stimulation, facilitating the evolution of exceptionally high resting heart rates (~1000 beats per minute). We further reveal alternative exon 3 splicing in distantly related bat families and confirm that both cTnI splice variants are incorporated into cardiac myofibrils. Because exon 3 of human TNNI3 exhibits a relatively low splice strength score, our findings offer an evolutionarily informed strategy to excise this exon to improve diastolic function during heart failure.

Sigmoid carcinoma contained within a scrotal hernia in an octogenarian: case report.

Scrotal hernias are common in the general population. Patients often present acutely reporting pain or sometimes with more severe symptoms if the hernia is strangulated or incarcerated. An 81-year-old man presented with left-sided iliac fossa pain with no other associated symptoms. On clinical exam, a left-sided non-reducible inguinoscrotal hernia was detected with no evidence to suggest strangulation. Imaging revealed a probable colorectal cancer with likely liver metastases. The patient went on to have open surgery to excise the tumour with clear oncological margins. Colorectal cancers contained within scrotal hernias are very rare occurrences. In this case, the surgeon had the advantage of preoperative images that identified the cancer. In some cases, this cohort of patients do not have such scans prior to surgery and the surgical team can be faced with a much more complex operation than anticipated.

Readmission rates following major colorectal surgery.

BACKGROUND: Readmissions following colorectal surgery (CRS) have negative clinical, psychological and financial implications. Identifying patients at risk of readmission remains challenging. AIMS: To determine factors predictive of those likely to require readmission at 40-days following major CRS and to identify novel strategies capable of reducing readmissions. METHODS: Consecutive patients were studied from a prospectively maintained database. All patients were operated on by a single surgeon in a high-volume centre. Where applicable, photography was recorded by patients and emailed directly to the institutional email of the consultant surgeon. Data was recorded and analysed using descriptive statistics. RESULTS: 515 patients were included over a 15-year period (2007-2022). The mean age at surgery was 64 years (18-93). The majority of patients were male (56.9%, n=293) and underwent cancer surgery (58.2%, n=299). Overall, 55 patients were readmitted within 40 days of major CRS (10.7%). Patients with pre-treatment diagnoses of heart failure (P=0.012), ischemic heart disease (P=0.002), renal impairment (P<0.001), atrial fibrillation (P=0.006), hypercholesterolemia (P=0.001), asthma (P=0.013) and hypertension (P=0.001) were more likely to require readmission. The majority of patients were readmitted for definitive management of surgical site issues (SSIs) (43.7% n=24). Other reasons included bowel obstruction (9.1%, n=5), pelvic sepsis (7.3%, n=4) and gastrointestinal upset (7.3%, n=4). CONCLUSION: This series demonstrated that patients with cardiopulmonary comorbidities were more likely to be readmitted following major CRS and most readmissions are SSI related. Readmissions for SSIs can be reduced by patients sending photography to the treating surgeon which could reduce readmissions and A&E attendances.

Evaluating the safety profile of anti-platelet therapy in patients undergoing elective inguinal hernia repair: a systematic review and meta-analysis.

INTRODUCTION: There remains no consensus surrounding the safety of prescribing anti-platelet therapies (APT) prior to elective inguinal hernia repair (IHR). AIMS: To perform a systematic review and meta-analysis evaluating the safety profile of APT use in patients indicated to undergo elective IHR. METHODS: A systematic review was performed in accordance with PRISMA guidelines. Meta-analyses were performed using the Mantel-Haenszel method using the Review Manager version 5.4 software. RESULTS: Five studies including outcomes in 344 patients were included. Of these, 65.4% had APT discontinued (225/344), and 34.6% had APT continued (119/344). The majority of included patients were male (94.1%, 288/344). When continuing or discontinuing APT, there was no significant difference in overall haemorrhage rates (odds ratio (OR): 1.86, 95% confidence interval (CI): 0.29-11.78, P = 0.130) and in sensitivity analysis using only RCT data (OR: 0.63, 95% CI: 0.03-12.41, P = 0.760). Furthermore, there was no significant difference in reoperation rates (OR: 6.27, 95% CI: 0.72-54.60, P = 0.590); however, a significant difference was observed for readmission rates (OR: 5.67, 95% CI: 1.33-24.12, P = 0.020) when APT was continued or stopped pre-operatively. There was no significant difference in the estimated blood loss, intra-operative time, transfusion of blood products, rates of complications, cerebrovascular accidents, myocardial infarctions, or mortality observed. CONCLUSION: This study illustrates the safety of continuing APT pre-operatively in patients undergoing elective IHR, with similar rates of haemorrhage, reoperation, and readmission observed. Clinical trials with larger patient recruitment will be required to fully establish the safety profile of prescribing APT in the pre-operative setting prior to elective IHR.

Evolution and divergence of teleost adrenergic receptors: why sometimes 'the drugs don't work' in fish.

Adrenaline and noradrenaline, released as hormones and/or neurotransmitters, exert diverse physiological functions in vertebrates, and teleost fishes are widely used as model organisms to study adrenergic regulation; however, such investigations often rely on receptor subtype-specific pharmacological agents (agonists and antagonists; see Glossary) developed and validated in mammals. Meanwhile, evolutionary (phylogenetic and comparative genomic) studies have begun to unravel the diversification of adrenergic receptors (ARs) and reveal that whole-genome duplications and pseudogenization events in fishes results in notable distinctions from mammals in their genomic repertoire of ARs, while lineage-specific gene losses within teleosts have generated significant interspecific variability. In this Review, we visit the evolutionary history of ARs (including α1-, α2- and ß-ARs) to highlight the prominent interspecific differences in teleosts, as well as between teleosts and other vertebrates. We also show that structural modelling of teleost ARs predicts differences in ligand binding affinity compared with mammalian orthologs. To emphasize the difficulty of studying the roles of different AR subtypes in fish, we collate examples from the literature of fish ARs behaving atypically compared with standard mammalian pharmacology. Thereafter, we focus on specific case studies of the liver, heart and red blood cells, where our understanding of AR expression has benefited from combining pharmacological approaches with molecular genetics. Finally, we briefly discuss the ongoing advances in 'omics' technologies that, alongside classical pharmacology, will provide abundant opportunities to further explore adrenergic signalling in teleosts.

Pneumothorax, pneumomediastinum, and subcutaneous emphysema in hospitalized COVID-19 patients: incidence, clinical characteristics, and outcomes.

BACKGROUND: Limited data is available on the incidence and outcomes of pneumothorax (PTX), pneumomediastinum (PNM), and subcutaneous emphysema (SCE) in COVID-19 patients. This study aimed to investigate the characteristics of these complications in hospitalized COVID-19 patients. RESEARCH DESIGN AND METHODS: A retrospective study was conducted, involving adult COVID-19 patients admitted to Mayo Clinic Florida from 03/2020-06/2022. Patients were divided into two groups based on the presence or absence of PTX/PNM/SCE. RESULTS: 1926 hospitalized patients with COVID-19 were included, of which 518 were admitted to the ICU. The incidence of PTX/PNM/SCE was 6.3%. Patients with these complications were more likely to be male, Asian, and unvaccinated. Conversely, they were less likely to have chronic obstructive pulmonary disease. Patients who developed PTX/PNM/SCE after 72 hours of admission were more likely to receive high-dose corticosteroids and for an extended duration. The affected group had an adjusted odds ratio for in-hospital mortality of 13.32 (95%CI, 8.19-21.59) and ICU admission of 9.14 (95%CI, 5.3-12.78) compared to the unaffected group. CONCLUSION: Although the occurrence of PTX/PNM/SCE in hospitalized COVID-19 patients was rare, it was associated with worse outcomes. Corticosteroids may contribute to the pathogenesis of these complications; however, further studies are needed to investigate this relationship in more detail.

Rectal cancer surgery: does low volume imply worse outcome-a single surgeon experience.

BACKGROUND: The centralisation of rectal cancer management to high-volume oncology centres has translated to improved oncological and survival outcomes. We hypothesise that individual surgeon caseload, specialisation, and experience may be as significant in determining oncologic and postoperative outcomes in rectal cancer surgery. METHODS: A prospectively maintained colorectal surgery database was reviewed for patients undergoing rectal cancer surgery between January 2004 and June 2020. Data studied included demographics, Dukes' and TNM staging, neoadjuvant treatment, preoperative risk assessment scores, postoperative complications, 30-day readmission rates, length of stay (LOS), and long-term survival. Primary outcome measures were 30-day mortality and long-term survival compared to national and international standards and best practice guidelines. RESULTS: In total, 87 patients were included (mean age: 66 years [range: 36-88]). The mean length of stay (LOS) was 16.5 days (SD 6.0). The median ICU LOS was 3 days (range 2-17). Overall, 30-day readmission rate was 16.4%. Twenty-four patients (26.4%) experienced ≥ 1 postoperative complication. The 30-day operative mortality rate was 3.45%. Overall 5-year survival rate was 66.6%. A significant correlation was observed between P-POSSUM scores and postoperative complications (p = 0.041), and all four variants of POSSUM, CR-POSSUM, and P-POSSUM scores and 30-day mortality. CONCLUSION: Despite improved outcomes seen with centralisation of rectal cancer services at an institutional level, surgeon caseload, experience, and specialisation is of similar importance in obtaining optimal outcomes within institutions.

Evaluating opioid prescribing patterns following discharge from elective surgical procedures: a worrying trend during the 'opioid crisis' - an audit of elective surgical procedures.

BACKGROUND: The 'opioid crisis' has reached epidemic proportions globally. Importantly, 30% of opioid dependency stem from opioids obtained on hospital discharge prescriptions. AIM: The aim of this study is to evaluate opioid prescription patterns on discharge of post-operative patients in an Irish Hospital. METHODS: A retrospective cohort study was undertaken in a single institution during the 5 year eligibility period (January 2017-October 2021). Comparisons in opioid prescription patterns following minor (inguinal hernia repair (IHR), intermediate (laparoscopic cholecystectomy (LC)) and major (colonic resection (CR)) were made. Descriptive statistics were performed using SPSS version 26.0 RESULTS: In total, 300 patients were included in this study with mean age 59.6 years (range: 20-92). Of these, 112 patients underwent IHR (37.3%), 116 patients underwent LC (38.7%), and 72 patients underwent CR (24.0%). The mean age at diagnosis was 61 years, 53 years and 58 years for IHR, LC and CR, respectively (P < 0.001). Patients undergoing CR were more likely to have greater comorbidity burden (3.1 vs. 1.2 (IHR) vs. 1.8 (LC) respectively (P = 0.030). On discharge, 27.8% of CR patients received opioids (20/72) compared to 24.1% of IHR (28/116) and 15.9% of LC (18/113) patients, respectively (P = 0.126). CONCLUSION: We observed considerable variability in opioid prescribing patterns following minor, intermediate and major operations in our centre. Care is required when prescribing opioids in the post-operative setting, and opioid prescription guidelines are required to both tackle and prevent an escalation of this 'opioid crisis'.

Evolutionary loss of the ß1-adrenergic receptor in salmonids.

Whole-genome duplications (WGDs) have been at the heart of the diversification of ß-adrenergic receptors (ß-ARs) in vertebrates. Non-teleost jawed vertebrates typically possess three ß-AR genes: adrb1 (ß1-AR), adrb2 (ß2-AR), and adrb3 (ß3-AR), originating from the ancient 2R (two rounds) WGDs. Teleost fishes, owing to the teleost-specific WGD, have five ancestral adrb paralogs (adrb1, adrb2a, adrb2b, adrb3a and adrb3b). Salmonids are particularly intriguing from an evolutionary perspective as they experienced an additional WGD after separating from other teleosts. Moreover, adrenergic regulation in salmonids, especially rainbow trout, has been intensively studied for decades. However, the repertoire of adrb genes in salmonids has not been yet characterized. An exhaustive genome survey of diverse salmonids, spanning five genera, complemented by phylogenetic sequence analysis, revealed each species has seven adrb paralogs: two adrb2a, two adrb2b, two adrb3a and one adrb3b. Surprisingly, salmonids emerge as the first known jawed vertebrate lineage to lack adrb1. adrb1 is nevertheless highly expressed in the hearts of non-salmonid teleosts, indicating that the wealth of data on adrenergic regulation in salmonids should be generalised to other teleost fishes with caution. It is hypothesised that the loss of adrb1 could have been viable because of the evolutionary radiation of adrb2 and adrb3 genes attributable to the salmonid WGD.

Impact of frailty on oncological outcomes in patients undergoing surgery for colorectal cancer - A systematic review and meta-analysis.

INTRODUCTION: Frailty describes patients who are at an extreme risk of vulnerability to stressors that may lead to adverse clinical outcomes. The impact of frailty on clinical, oncological and survival outcomes in colorectal cancer (CRC) remains unclear. AIM: To determine the anticipated oncological and survival outcomes for patients who are frail when diagnosed and undergo treatment with curative intent for CRC. METHODS: A systematic review and meta-analysis was performed as per PRISMA guidelines. Descriptive statistics were used to determine associations between frailty and survival outcomes. The impact of frailty on disease-free and overall survival were expressed as hazard Ratios (HRs) and 95% confidence intervals (CIs) were estimated using the time-to-effect generic inverse variance and Mantel-Haenszel method. RESULTS: Nine studies including 15,555 patients were included, of whom 8.1% were frail (1206/14,831). The mean age was 77.1 years (range: 42-94 years), 61.1% were female (9510/15,555) and mean follow-up was 48.0 months. Overall, frailty was associated with an increased risk of mortality (HR: 2.95, 95% CI: 1.64-5.29, P < 0.001) and worse disease-free survival (HR: 1.80, 95% CI: 1.34-2.41, P < 0.001). Frailty was also associated with an increased risk of mortality at 1-year (HR: 3.70, 95% CI: 1.00-13.66, P = 0.050) and 5-years (HR: 2.79, 95% CI: 1.65-4.71, P < 0.001) follow-up respectively. CONCLUSION: Frailty is associated with poorer oncological and survival outcomes in patients diagnosed and treated with curative intent for CRC. CRC multidisciplinary team meetings should incorporate these findings into the management paradigm for these patients and patient counselling should be tailored to include these findings.

A Revised Perspective on the Evolution of Troponin I and Troponin T Gene Families in Vertebrates.

The troponin (Tn) complex, responsible for the Ca2+ activation of striated muscle, is composed of three interacting protein subunits: TnC, TnI, and TnT, encoded by TNNC, TNNI, and TNNT genes. TNNI and TNNT are sister gene families, and in mammals the three TNNI paralogs (TNNI1, TNNI2, TNNI3), which encode proteins with tissue-specific expression, are each in close genomic proximity with one of the three TNNT paralogs (TNNT2, TNNT3, TNNT1, respectively). It has been widely presumed that all vertebrates broadly possess genes of these same three classes, although earlier work has overlooked jawless fishes (cyclostomes) and cartilaginous fishes (chimeras, rays, and sharks), which are distantly related to other jawed vertebrates. With a new phylogenetic and synteny analysis of a diverse array of vertebrates including these taxonomic groups, we define five distinct TNNI classes (TNNI1-5), with TNNI4 and TNNI5 being only present in non-amniote vertebrates and typically found in tandem, and four classes of TNNT (TNNT1-4). These genes are located in four genomic loci that were generated by the 2R whole-genome duplications. TNNI3, encoding "cardiac TnI" in tetrapods, was independently lost in cartilaginous and ray-finned fishes. Instead, ray-finned fishes predominantly express TNNI1 in the heart. TNNI5 is highly expressed in shark hearts and contains a N-terminal extension similar to that of TNNI3 found in tetrapod hearts. Given that TNNI3 and TNNI5 are distantly related, this supports the hypothesis that the N-terminal extension may be an ancestral feature of vertebrate TNNI and not an innovation unique to TNNI3, as has been commonly believed.

Patient reported satisfaction levels with the use of telemedicine for general surgery-A systematic review of randomized control trials.

Background: As healthcare continues to evolve in the wake of COVID-19 pandemic, surgeons are presented with the opportunity to integrate telemedicine into healthcare in tandem with in-person consultations. We aimed to perform a systematic review of randomized controlled trials to assess patient satisfaction with telemedicine interventions in general surgery. Methods: A systematic review was performed in accordance to the PRISMA guidelines. Randomized control trials (RCTs) were included. The risk of bias 2.0 assessment was used to determine potential bias. Results: In total, 11 prospective, randomized trials involving 1,598 patients (mean age: 49.1 years) were included. Overall 45.5% (5/11) of the trials compared videoconferencing or telephone follow up to traditional in person follow up. Three studies used smart technologies which include activity tracking devices in combination with a website and mobile application (27.3%). The other 3 interventions involved accelerated discharge on post operative day (POD) 1 with tele videoconferencing on POD 2, Post-operative daily text messages with education videos and video calling capability, and supportive text messages post-operatively. Telemedicine was shown to provide similar levels of patient satisfaction compared to controls in all 11 included RCTs. Conclusion: Patient reported satisfaction with the use of telemedicine is similar to standard of care models in general surgery. With several shortcomings confounding the results in support of telemedicine, further experimentation with telemedicine interventions will likely improve patient reported satisfaction with using telemedicine for peroperative surgical care.

Absence of atrial smooth muscle in the heart of the loggerhead sea turtle (Caretta caretta): a re-evaluation of its role in diving physiology.

Contraction of atrial smooth muscle in the hearts of semi-aquatic emydid turtles regulates ventricular filling, and it has been proposed that it could regulate stroke volume during characteristic rapid transitions in cardiac output associated with diving. For this hypothesis to be supported, atrial smooth muscle should be widely distributed in diving Testudines. To further understand the putative function and evolutionary significance of endocardial smooth muscle in Testudines, we studied the hearts of loggerhead sea turtles, Caretta caretta (n=7), using immunohistochemistry and histology. Surprisingly, we found no evidence of prominent atrial smooth muscle in C. caretta. However, smooth muscle was readily identified in the sinus venosus. Our results suggest that atrial smooth muscle does not contribute to the diving capabilities of C. caretta, indicating that the possible roles of smooth muscle in emydid turtle hearts require a re-evaluation. In sea turtles, the sinus venosus may instead contribute to regulate cardiac filling.

Regulation of heart rate following genetic deletion of the ß1 adrenergic receptor in larval zebrafish.

AIM: Although zebrafish are gaining popularity as biomedical models of cardiovascular disease, our understanding of their cardiac control mechanisms is fragmentary. Our goal was to clarify the controversial role of the ß1-adrenergic receptor (AR) in the regulation of heart rate in zebrafish. METHODS: CRISPR-Cas9 was used to delete the adrb1 gene in zebrafish allowing us to generate a stable adrb1-/- line. Larval heart rates were measured during pharmacological protocols and with exposure to hypercapnia. Expression of the five zebrafish adrb genes were measured in larval zebrafish hearts using qPCR. RESULTS: Compared with genetically matched wild-types (adrb1+/+ ), adrb1-/- larvae exhibited ~20 beats min-1 lower heart rate, measured from 2 to 21 days post-fertilization (dpf). Nevertheless, adrb1-/- larvae exhibited preserved positive chronotropic responses to pharmacological treatment with AR agonists (adrenaline, noradrenaline, isoproterenol), which were blocked by propranolol (general ß-AR antagonist). Regardless of genotype, larvae exhibited similar increases in heart rate in response to hypercapnia (1% CO2 ) at 5 dpf, but tachycardia was blunted in adrb1-/- larvae at 6 dpf. adrb1 gene expression was abolished in the hearts of adrb1-/- larvae, confirming successful knockout. While gene expression of adrb2a and adrb3a was unchanged, adrb2b and adrb3b mRNA levels increased in adrb1-/- larval hearts. CONCLUSION: Despite adrb1 contributing to the setting of resting heart rate in larvae, it is not strictly essential for zebrafish, as we generated a viable and breeding adrb1-/- line. The chronotropic effects of adrenergic stimulation persist in adrb1-/- zebrafish, likely due to the upregulation of other ß-AR subtypes.

No evidence for pericardial restraint in the snapping turtle (Chelydra serpentina) following pharmacologically induced bradycardia at rest or during exercise.

Most animals elevate cardiac output during exercise through a rise in heart rate (fH), whereas stroke volume (VS) remains relatively unchanged. Cardiac pacing reveals that elevating fH alone does not alter cardiac output, which is instead largely regulated by the peripheral vasculature. In terms of myocardial oxygen demand, an increase in fH is more costly than that which would incur if VS instead were to increase. We hypothesized that fH must increase because any substantial rise in VS would be constrained by the pericardium. To investigate this hypothesis, we explored the effects of pharmacologically induced bradycardia, with ivabradine treatment, on VS at rest and during exercise in the common snapping turtle (Chelydra serpentina) with intact or opened pericardium. We first showed that, in isolated myocardial preparations, ivabradine exerted a pronounced positive inotropic effect on atrial tissue but only minor effects on ventricle. Ivabradine reduced fH in vivo, such that exercise tachycardia was attenuated. Pulmonary and systemic VS rose in response to ivabradine. The rise in pulmonary VS largely compensated for the bradycardia at rest, leaving total pulmonary flow unchanged by ivabradine, although ivabradine reduced pulmonary blood flow during swimming (exercise × ivabradine interaction, P < 0.05). Although systemic VS increased, systemic blood flow was reduced by ivabradine both at rest and during exercise, despite ivabradine's potential to increase cardiac contractility. Opening the pericardium had no effect on fH, VS, or blood flows before or after ivabradine, indicating that the pericardium does not constrain VS in turtles, even during pharmacologically induced bradycardia.

Regulation of heart rate in vertebrates during hypoxia: A comparative overview.

Acute exposure to low oxygen (hypoxia) places conflicting demands on the heart. Whilst an increase in heart rate (tachycardia) may compensate systemic oxygen delivery as arterial oxygenation falls, the heart itself is an energetically expensive organ that may benefit from slowing (bradycardia) to reduce work when oxygen is limited. Both strategies are apparent in vertebrates, with tetrapods (mammals, birds, reptiles, and amphibians) classically exhibiting hypoxic tachycardia and fishes displaying characteristic hypoxic bradycardia. With a richer understanding of the ontogeny and evolution of the responses, however, we see similarities in the underlying mechanisms between vertebrate groups. For example, in adult mammals, primary bradycardia results from the hypoxic stimulation of carotid body chemoreceptors that are overwhelmed by mechano-sensory feedback from the lung associated with hyperpnoea. Fish-like bradycardia prevails in the mammalian foetus (which, at this stage, is incapable of pulmonary ventilation), and in fish and foetus alike, the bradycardia ensues despite an elevation of circulating catecholamines. In both cases, the reduced heart rate may primarily serve to protect the heart. Thus, the comparative perspective offers fundamental insight into how and why different vertebrates regulate heart rate in different ways during periods of hypoxia.

Catecholamines are key modulators of ventricular repolarization patterns in the ball python (Python regius).

Ectothermic vertebrates experience daily changes in body temperature, and anecdotal observations suggest these changes affect ventricular repolarization such that the T-wave in the ECG changes polarity. Mammals, in contrast, can maintain stable body temperatures, and their ventricular repolarization is strongly modulated by changes in heart rate and by sympathetic nervous system activity. The aim of this study was to assess the role of body temperature, heart rate, and circulating catecholamines on local repolarization gradients in the ectothermic ball python (Python regius). We recorded body-surface electrocardiograms and performed open-chest high-resolution epicardial mapping while increasing body temperature in five pythons, in all of which there was a change in T-wave polarity. However, the vector of repolarization differed between individuals, and only a subset of leads revealed T-wave polarity change. RNA sequencing revealed regional differences related to adrenergic signaling. In one denervated and Ringer's solution-perfused heart, heating and elevated heart rates did not induce change in T-wave polarity, whereas noradrenaline did. Accordingly, electrocardiograms in eight awake pythons receiving intra-arterial infusion of the ß-adrenergic receptor agonists adrenaline and isoproterenol revealed T-wave inversion in most individuals. Conversely, blocking the ß-adrenergic receptors using propranolol prevented T-wave change during heating. Our findings indicate that changes in ventricular repolarization in ball pythons are caused by increased tone of the sympathetic nervous system, not by changes in temperature. Therefore, ventricular repolarization in both pythons and mammals is modulated by evolutionary conserved mechanisms involving catecholaminergic stimulation.

The evolutionary and physiological significance of the Hif pathway in teleost fishes.

The hypoxia-inducible factor (HIF) pathway is a key regulator of cellular O2 homeostasis and an important orchestrator of the physiological responses to hypoxia (low O2) in vertebrates. Fish can be exposed to significant and frequent changes in environmental O2, and increases in Hif-α (the hypoxia-sensitive subunit of the transcription factor Hif) have been documented in a number of species as a result of a decrease in O2. Here, we discuss the impact of the Hif pathway on the hypoxic response and the contribution to hypoxia tolerance, particularly in fishes of the cyprinid lineage, which includes the zebrafish (Danio rerio). The cyprinids are of specific interest because, unlike in most other fishes, duplicated paralogs of the Hif-α isoforms arising from a teleost-specific genome duplication event have been retained. Positive selection has acted on the duplicated paralogs of the Hif-α isoforms in some cyprinid sub-families, pointing to adaptive evolutionary change in the paralogs. Thus, cyprinids are valuable models for exploring the evolutionary significance and physiological impact of the Hif pathway on the hypoxic response. Knockout in zebrafish of either paralog of Hif-1α greatly reduces hypoxia tolerance, indicating the importance of both paralogs to the hypoxic response. Here, with an emphasis on the cardiorespiratory system, we focus on the role of Hif-1α in the hypoxic ventilatory response and the regulation of cardiac function. We explore the effects of the duration of the hypoxic exposure (acute, sustained or intermittent) on the impact of Hif-1α on cardiorespiratory function and compare relevant data with those from mammalian systems.

Distinct neuropeptide-receptor modules regulate a sex-specific behavioral response to a pheromone.

Dioecious species are a hallmark of the animal kingdom, with opposing sexes responding differently to identical sensory cues. Here, we study the response of C. elegans to the small-molecule pheromone, ascr#8, which elicits opposing behavioral valences in each sex. We identify a novel neuropeptide-neuropeptide receptor (NP/NPR) module that is active in males, but not in hermaphrodites. Using a novel paradigm of neuropeptide rescue that we established, we leverage bacterial expression of individual peptides to rescue the sex-specific response to ascr#8. Concurrent biochemical studies confirmed individual FLP-3 peptides differentially activate two divergent receptors, NPR-10 and FRPR-16. Interestingly, the two of the peptides that rescued behavior in our feeding paradigm are related through a conserved threonine, suggesting that a specific NP/NPR combination sets a male state, driving the correct behavioral valence of the ascr#8 response. Receptor expression within pre-motor neurons reveals novel coordination of male-specific and core locomotory circuitries.