Copper-mediated synthesis of drug-like bicyclopentanes.

Multicomponent reactions are relied on in both academic and industrial synthetic organic chemistry owing to their step- and atom-economy advantages over traditional synthetic sequences1. Recently, bicyclo[1.1.1]pentane (BCP) motifs have become valuable as pharmaceutical bioisosteres of benzene rings, and in particular 1,3-disubstituted BCP moieties have become widely adopted in medicinal chemistry as para-phenyl ring replacements2. These structures are often generated from [1.1.1]propellane via opening of the internal C-C bond through the addition of either radicals or metal-based nucleophiles3-13. The resulting propellane-addition adducts are then transformed to the requisite polysubstituted BCP compounds via a range of synthetic sequences that traditionally involve multiple chemical steps. Although this approach has been effective so far, a multicomponent reaction that enables single-step access to complex and diverse polysubstituted drug-like BCP products would be more time efficient compared to current stepwise approaches. Here we report a one-step three-component radical coupling of [1.1.1]propellane to afford diverse functionalized bicyclopentanes using various radical precursors and heteroatom nucleophiles via a metallaphotoredox catalysis protocol. This copper-mediated reaction operates on short timescales (five minutes to one hour) across multiple (more than ten) nucleophile classes and can accommodate a diverse array of radical precursors, including those that generate alkyl, α-acyl, trifluoromethyl and sulfonyl radicals. This method has been used to rapidly prepare BCP analogues of known pharmaceuticals, one of which is substantially more metabolically stable than its commercial progenitor.

Identification of small-molecule protein-protein interaction inhibitors for NKG2D.

NKG2D (natural-killer group 2, member D) is a homodimeric transmembrane receptor that plays an important role in NK, γδ+, and CD8+ T cell-mediated immune responses to environmental stressors such as viral or bacterial infections and oxidative stress. However, aberrant NKG2D signaling has also been associated with chronic inflammatory and autoimmune diseases, and as such NKG2D is thought to be an attractive target for immune intervention. Here, we describe a comprehensive small-molecule hit identification strategy and two distinct series of protein-protein interaction inhibitors of NKG2D. Although the hits are chemically distinct, they share a unique allosteric mechanism of disrupting ligand binding by accessing a cryptic pocket and causing the two monomers of the NKG2D dimer to open apart and twist relative to one another. Leveraging a suite of biochemical and cell-based assays coupled with structure-based drug design, we established tractable structure-activity relationships with one of the chemical series and successfully improved both the potency and physicochemical properties. Together, we demonstrate that it is possible, albeit challenging, to disrupt the interaction between NKG2D and multiple protein ligands with a single molecule through allosteric modulation of the NKG2D receptor dimer/ligand interface.

Comparing English- and Spanish-Reading Patients' Comprehension of the Drug Facts Label for a New Over-The-Counter Oral Contraceptive.

BACKGROUND: Health literacy is known to impact health outcomes in a multitude of ways and is impacted by language barriers. Lower health literacy is also associated with higher rates of unintended pregnancies. A progestin-only oral hormonal contraception product, norgestrel (Opill-Perrigo), was approved for over-the-counter (OTC) use in the United States in July 2023. OBJECTIVE: (s): The objective was to utilize a knowledge assessment survey to determine participants' comprehension of norgestrel from its drug facts label and compare the comprehension between primarily English- and Spanish-reading participants. METHODS: A 7-item knowledge assessment was developed and distributed to English and Spanish readers at one site within a network of federally qualified health centers. English-reading participants completed the English survey alongside use of an English copy of norgestrel's drug facts label. Spanish-reading participants completed the Spanish survey and were randomized in a 1:1 fashion to either receive an English or Spanish copy of norgestrel's drug facts label. RESULTS: The English-reading/English label (E/E) group had a higher level of comprehension of norgestrel's drug facts label compared to the Spanish-reading/English label (S/E) or Spanish-reading/Spanish label (S/S) groups. CONCLUSION: Differences exist in OTC label comprehension for norgestrel based on primary language able to be read. Advocacy for OTC labels to be readily available in languages other than English is imperative to mitigate unintended pregnancies associated with lower levels of health literacy.

Evaluation of tricyclic antidepressant deprescribing in the treatment of diabetic peripheral neuropathy within Federally Qualified Health Centers.

BACKGROUND: Tricyclic antidepressants (TCAs) are a treatment option for diabetic peripheral neuropathy (DPN). Existing evidence demonstrates the prolonged use of TCA therapy increases the risk of cognitive decline and dementia, likely due to the anticholinergic effects of these medications. Anticholinergic activity is thought to contribute significantly to the observed increase in cognitive decline and dementia risks associated with long-term TCA use. There is little information available to describe the usage patterns of TCAs in DPN, particularly within underserved populations who receive care at Federally Qualified Health Centers. OBJECTIVES: The objective of this study was to characterize (1) prescribing patterns of TCAs as a treatment for DPN and (2) evidence of deprescribing attempts in a Federally Qualified Health Center population. METHODS: A retrospective chart review of electronic medical record data for patients at 2 different Federally Qualified Health Centers was performed. A convenience sample of 100 adults ≥ 18 years of age was stratified into 2 age groups, 18-55 years and 55+ years. All patients had a diagnosis of type 1 or type 2 diabetes mellitus and had been prescribed TCAs in the previous 4 years and had a visit with a primary care provider in the past 12 months. RESULTS: The study population was comprised of 100 individuals. Seventy-four of 100 were persistent users of TCAs at the time of data collection, and the mean duration of utilization was 54.8 months. In total, 104 TCAs were prescribed across 100 individual patients. Of all 104 prescribed TCAs, 66 (63%) were prescribed at a rate that exceeded thresholds associated with a higher risk of dementia. Black older adults prescribed TCAs were more likely to exceed this dose threshold. CONCLUSION: Sixty-five percent of patients used TCAs with a strength, frequency, and duration that exceeded risk thresholds for dementia in an older adult population. Interventions preventing use of or deprescribing TCAs in patients with DPN should be conducted for the potential benefits of preventing or delaying cognitive impairment and promoting equitable care.

Development of small molecule inhibitors of natural killer group 2D receptor (NKG2D).

Natural killer group 2D (NKG2D) is a homodimeric activating immunoreceptor whose function is to detect and eliminate compromised cells upon binding to the NKG2D ligands (NKG2DL) major histocompatibility complex (MHC) molecules class I-related chain A (MICA) and B (MICB) and UL16 binding proteins (ULBP1-6). While typically present at low levels in healthy cells and tissue, NKG2DL expression can be induced by viral infection, cellular stress or transformation. Aberrant activity along the NKG2D/NKG2DL axis has been associated with autoimmune diseases due to the increased expression of NKG2D ligands in human disease tissue, making NKG2D inhibitors an attractive target for immunomodulation. Herein we describe the discovery and optimization of small molecule PPI (protein-protein interaction) inhibitors of NKG2D/NKG2DL. Rapid SAR was guided by structure-based drug design and accomplished by iterative singleton and parallel medicinal chemistry synthesis. These efforts resulted in the identification of several potent analogs (14, 21, 30, 45) with functional activity and improved LLE.

Pharmacist-led hormonal contraceptive prescribing service in a Federally Qualified Health Center: Initial implementation outcomes.

BACKGROUND: The United States has a higher rate of unintended pregnancy than many other developed countries, and Indiana's unintended pregnancy rate is above the national average. Unintended pregnancy rates are highest among low-income women. Federally Qualified Health Centers (FQHC) provide care for the underserved and uninsured patient population. OBJECTIVE: To determine the acceptability, adoption, appropriateness, and feasibility of a pharmacist-led hormonal contraception prescribing service within a FQHC through a collaborative drug therapy management protocol. METHODS: An explanatory mixed methods analysis included surveys followed by semistructured interviews. A survey was created and distributed to all patients who received the service and all providers (physicians and nurse practitioners) employed at the FQHC during service implementation. Semistructured interviews were conducted with a subset of patients and providers. RESULTS: A total of 11 patients and 8 providers completed the survey between January 1, 2022 and June 10, 2022. Of these participants, 4 patients and 4 providers completed an interview between May 1, 2022 and June 30, 2022. Both patients and providers perceived the service as acceptable and appropriate, and providers perceived implementation of the service within clinic as feasible. Ten patients received a prescription from the pharmacist; 1 patient was referred to a provider as the pharmacist was unable to prescribe the medication requested. CONCLUSION: Implementation of pharmacist prescribed hormonal contraception was perceived as acceptable, appropriate, and feasible by patients and providers. Pharmacists are perceived by patients and providers as an additional resource for hormonal contraception prescribing within a FQHC due to their clinical knowledge, efficiency, and attention paid to patients' concerns.

Impact of nicotine and cotinine on macrophage inflammatory plasticity via vesicular modifications in gastrointestinal bacteria.

OBJECTIVES: This study aimed to elucidate mechanistic explanation(s) for compositional changes to enteric microbiota by determining the impacts of continuous nicotine/cotinine exposure on representative gastrointestinal bacteria and how these alterations impact innate immune cell plasticity. METHODS: In vitro cultures of the gastrointestinal bacteria (Bacteroides fragilis 25285, Prevotella bryantii B14, and Acetoanaerobium sticklandii SR) were continuously exposed to nicotine or cotinine. Supernatant samples were collected for fermentation acid analysis. Vesicles were collected and analyzed for physiological changes in number, size, and total protein cargo. Cultured macrophages were stimulated to a tolerogenic phenotype, exposed to control or altered (nicotine or cotinine - exposed) vesicles, and inflammatory plasticity assessed via inflammatory cytokine production. RESULTS: Nicotine/cotinine exposure differentially affected metabolism of all bacteria tested in a Gram (nicotine) and concentration-dependent (cotinine) manner. Physiological studies demonstrated changes in vesiculation number and protein cargo following nicotine/cotinine exposures. Continuous exposure to 1 µM nicotine and 10 µM cotinine concentrations reduced total protein cargo of Gram (-) - 25285 and B14 vesicles, while cotinine generally increased total protein in Gram (+) - SR vesicles. We found that theses physiological changes to the vesicles of 25285 and SR formed under nicotine and cotinine, respectively, challenged the plasticity of tolerogenic macrophages. Tolerogenic macrophages exposed to vesicles from 1 µM nicotine, and 5 or 10 µΜ cotinine cultures produced significantly less IL-12p70, TNFα, or KC/GRO, regardless of macrophage exposure to nicotine/cotinine. CONCLUSIONS: Nicotine/cotinine exposure differentially alters bacterial metabolism and vesicle physiology, ultimately impacting the inflammatory response of tolerogenic macrophages.

Provider and health care team member insights for implementing a transitions of care clinic in a federally qualified health center.

OBJECTIVES: To identify medical professionals' specific insights to implementing a transitions of care (TOC) clinic in a federally qualified health center (FQHC). DESIGN: The investigators conducted focus groups during the structured 1-hour provider meetings that take place at each clinic. Each meeting was split into two 30-minute group sessions that consisted of licensed providers and of other health care team members. During the focus groups, investigators explored past experiences of care provided to patients recently discharged from hospitalizations, and the perceived benefits, barriers, and workflow for a TOC clinic. Questions used were based on the consolidated framework for implementation research (CFIR). Transcriptions were coded with the use of qualitative research data analysis software by 2 investigators independently. Initial codes were based on the CFIR constructs to identify themes in responses while remaining adaptable for any themes or discussion that the participants found important. SETTING AND PARTICIPANTS: Participants were selected via purposive sampling within FQHCs of northwest Indiana. Participants included physicians, nurse practitioners, team care nurses, pharmacists, and behavioral health consultants. RESULTS: A total of 40 participants took part in 8 focus groups. Major themes identified were inaccessibility to patient information, apprehension about implementation, lack of familiarity with transitions of care service, and FQHC patient-centered factors. Aspects of each of the 5 CFIR constructs are discussed. CONCLUSION: Participants provided numerous factors that may affect the success of this patient care intervention in an FQHC. Proper external communication with other health care providers, comprehensive assessment of patient access to necessary resources, and collaboration at the site are the most crucial factors. Many FQHCs work with scarce resources and high patient volumes; being able to develop appropriate processes for a patient care service as encompassing and important as a TOC will affect both patient and provider experience in primary care.

Increased food availability raises eviction rate in a cooperative breeding mammal.

In group-living mammals, the eviction of subordinate females from breeding groups by dominants may serve to reduce feeding competition or to reduce breeding competition. Here, we combined both correlational and experimental approaches to investigate whether increases in food intake by dominant females reduces their tendency to evict subordinate females in wild meerkats (Suricata suricatta). We used 20 years of long-term data to examine the association between foraging success and eviction rate, and provisioned dominant females during the second half of their pregnancy, when they most commonly evict subordinates. We show that rather than reducing the tendency for dominants to evict subordinates, foraging success of dominant females is positively associated with the probability that pregnant dominant females will evict subordinate females and that experimental feeding increased their rates of eviction. Our results suggest that it is unlikely that the eviction of subordinate females serves to reduce feeding competition and that its principal function may be to reduce reproductive competition. The increase in eviction rates following experimental feeding also suggests that rather than feeding competition, energetic constraints may normally constrain eviction rates.

Evidence for a spin-aligned neutron-proton paired phase from the level structure of (92)Pd.

Shell structure and magic numbers in atomic nuclei were generally explained by pioneering work that introduced a strong spin-orbit interaction to the nuclear shell model potential. However, knowledge of nuclear forces and the mechanisms governing the structure of nuclei, in particular far from stability, is still incomplete. In nuclei with equal neutron and proton numbers (N = Z), enhanced correlations arise between neutrons and protons (two distinct types of fermions) that occupy orbitals with the same quantum numbers. Such correlations have been predicted to favour an unusual type of nuclear superfluidity, termed isoscalar neutron-proton pairing, in addition to normal isovector pairing. Despite many experimental efforts, these predictions have not been confirmed. Here we report the experimental observation of excited states in the N = Z = 46 nucleus (92)Pd. Gamma rays emitted following the (58)Ni((36)Ar,2n)(92)Pd fusion-evaporation reaction were identified using a combination of state-of-the-art high-resolution γ-ray, charged-particle and neutron detector systems. Our results reveal evidence for a spin-aligned, isoscalar neutron-proton coupling scheme, different from the previous prediction. We suggest that this coupling scheme replaces normal superfluidity (characterized by seniority coupling) in the ground and low-lying excited states of the heaviest N = Z nuclei. Such strong, isoscalar neutron-proton correlations would have a considerable impact on the nuclear level structure and possibly influence the dynamics of rapid proton capture in stellar nucleosynthesis.

AAGBI: Consent for anaesthesia 2017: Association of Anaesthetists of Great Britain and Ireland.

Previous guidelines on consent for anaesthesia were issued by the Association of Anaesthetists of Great Britain and Ireland in 1999 and revised in 2006. The following guidelines have been produced in response to the changing ethical and legal background against which anaesthetists, and also intensivists and pain specialists, currently work, while retaining the key principles of respect for patients' autonomy and the need to provide adequate information. The main points of difference between the relevant legal frameworks in England and Wales and Scotland, Northern Ireland and the Republic of Ireland are also highlighted.

Characterisation of Clostridium difficile strains isolated from Groote Schuur Hospital, Cape Town, South Africa.

The C. difficile infection rate in South Africa is concerning. Many strains previously isolated from diarrhetic patients at Groote Schuur Hospital were ribotype 017. This study further characterised these strains with respect to their clonal relationships, antibiotic susceptibility, toxin production and various attributes impacting on pathogen colonisation. Multilocus variable-number tandem-repeat analysis (MLVA) was used to characterise all C. difficile isolates. Antibiotic susceptibility was determined by E-test and PCR-based analysis of the ermB, gyrA and gyrB genes. Auto-aggregation of cells was measured in broth, and biofilm formation observed in 24-well plates. Toxins were measured using the Wampole C DIFF TOX A/B II kit. Most isolates belonged to the ribotype 017 group. Identical MLVA types occurred in different wards over time, and several patients were infected with identical strains. All isolates were susceptible to vancomycin and metronidazole, but some ribotype 017 isolates showed reduced metronidazole susceptibility (≥2 mg l(-1)). Sixty-nine percent of ribotype 017 isolates were resistant to moxifloxacin, and 94 % to erythromycin, compared to 0 % and 17 % resistance, respectively, in non-ribotype 017 isolates. The ermB gene and mutations in the gyrA and/or gyrB genes were linked to erythromycin and moxifloxacin resistance, respectively. Ribotype 017 isolates auto-aggregated more strongly than other isolates and produced lower levels of the TcdB toxin than a reference strain. Certain strains produced strong biofilms. Patient-to-patient transfer and unique infection events could cause the predominance of ribotype 017 strains in the cohort. Multi-drug resistant strains are a potential reservoir for future infections.

Survivorship After Periprosthetic Femur Fracture: Factors Affecting Outcome.

BACKGROUND: Data addressing risk factors predictive of mortality and reoperation after periprosthetic femur fractures (PPFxs) are lacking. This study examined survivorship and risk ratios for mortality and reoperation after surgical treatment for PPFx and associated clinical risk factors. METHODS: A retrospective review was performed for 291 patients treated surgically for PPFx between 2004 and 2013. Primary outcomes were death and reoperation. RESULTS: Mortality at 1 year was 13%, whereas the rate of reoperation was 12%. Greater span of fixation and revision arthroplasty (vs open reduction internal fixation) trended toward a lower likelihood of reoperation. CONCLUSION: After PPFx, patients have a 24% risk of either death or reoperation at 1 year. Factors contributing to increased mortality are nonmodifiable. Risk of reoperation is minimized with greater span of fixation and performance of revision arthroplasty.

Electrocardiographic Responses to Deer Hunting in Men and Women.

OBJECTIVE: Deer hunting includes various stimuli resulting in augmented sympathetic activity, increased heart rate (HR) response, and rhythm changes. Collectively, these superimposed stresses may increase an individual's risk for cardiovascular events. We undertook this study to evaluate HR and rhythm responses in multiple phases of deer hunting in men and women with and without cardiovascular disease (CVD). METHODS: Nineteen participants age 38.3 ± 13.8 years (mean ± SD) with body mass index 29.2 ± 6.9 kg/m(2) followed their normal hunting routine. HR and rhythm were recorded continuously during the hunt using a small leadless electrocardiogram (ECG) patch monitor. RESULTS: Data were collected on 13 of 19 hunters while hiking. Three hunters recorded HR ≥85% of their age-predicted heart rate maximum (HRmax) for 1 to 2 minutes. Arrhythmias were detected in both participants with CVD and in 8 without CVD. Recorded rhythms included premature atrial, junctional, and ventricular complexes. Six hunters climbed a tree stand; 3 of them recorded HR ≥85% HRmax with sustained elevated HR response for 2 to 3 minutes with premature junctional contractions. Four of 19 participants dragged deer carcasses. During the drag, 1 male hunter recorded an HR of 91% HRmax, and another male hunter without CVD recorded an exercise-induced ischemic ECG. Fifteen of 19 hunters experienced "buck fever" (acute extreme excitation), with 7 reaching ≥85% HRmax for up to 1 minute. Ventricular bigeminy and trigeminy and ventricular couplets were observed in 1 subject during buck fever. CONCLUSIONS: Men and women with and without CVD recorded substantial increases in HR and clinically relevant arrhythmias while deer hunting.

A selective orexin-1 receptor antagonist attenuates stress-induced hyperarousal without hypnotic effects.

Orexins (OXs) are peptides produced by perifornical (PeF) and lateral hypothalamic neurons that exert a prominent role in arousal-related processes, including stress. A critical role for the orexin-1 receptor (OX1R) in complex emotional behavior is emerging, such as overactivation of the OX1R pathway being associated with panic or anxiety states. Here we characterize a brain-penetrant, selective, and high-affinity OX1R antagonist, compound 56 [N-({3-[(3-ethoxy-6-methylpyridin-2-yl)carbonyl]-3-azabicyclo[4.1.0]hept-4-yl}methyl)-5-(trifluoromethyl)pyrimidin-2-amine]. Ex vivo receptor binding studies demonstrated that, after subcutaneous administration, compound 56 crossed the blood-brain barrier and occupied OX1Rs in the rat brain at lower doses than standard OX1R antagonists GSK-1059865 [5-bromo-N-({1-[(3-fluoro-2-methoxyphenyl)carbonyl]-5-methylpiperidin-2-yl}methyl)pyridin-2-amine], SB-334867 [1-(2-methyl-1,3-benzoxazol-6-yl)-3-(1,5-naphthyridin-4-yl)urea], and SB-408124 [1-(6,8-difluoro-2-methylquinolin-4-yl)-3-[4-(dimethylamino)phenyl]urea]. Although compound 56 did not alter spontaneous sleep in rats and in wild-type mice, its administration in orexin-2 receptor knockout mice selectively promoted rapid eye movement sleep, demonstrating target engagement and specific OX1R blockade. In a rat model of psychological stress induced by cage exchange, the OX1R antagonist prevented the prolongation of sleep onset without affecting sleep duration. In a rat model of panic vulnerability (involving disinhibition of the PeF OX region) to threatening internal state changes (i.e., intravenous sodium lactate infusion), compound 56 attenuated sodium lactate-induced panic-like behaviors and cardiovascular responses without altering baseline locomotor or autonomic activity. In conclusion, OX1R antagonism represents a novel therapeutic strategy for the treatment of various psychiatric disorders associated with stress or hyperarousal states.

Cooperative personalities and social niche specialization in female meerkats.

The social niche specialization hypothesis predicts that group-living animals should specialize in particular social roles to avoid social conflict, resulting in alternative life-history strategies for different roles. Social niche specialization, coupled with role-specific life-history trade-offs, should thus generate between-individual differences in behaviour that persist through time, or distinct personalities, as individuals specialize in particular nonoverlapping social roles. We tested for support for the social niche specialization hypothesis in cooperative personality traits in wild female meerkats (Suricata suricatta) that compete for access to dominant social roles. As cooperation is costly and dominance is acquired by heavier females, we predicted that females that ultimately acquired dominant roles would show noncooperative personality types early in life and before and after role acquisition. Although we found large individual differences in repeatable cooperative behaviours, there was no indication that individuals that ultimately acquired dominance differed from unsuccessful individuals in their cooperative behaviour. Early-life behaviour did not predict social role acquisition later in life, nor was cooperative behaviour before and after role acquisition correlated in the same individuals. We suggest that female meerkats do not show social niche specialization resulting in cooperative personalities, but that they exhibit an adaptive response in personality at role acquisition.

Additive genetic variance and developmental plasticity in growth trajectories in a wild cooperative mammal.

Individual variation in growth is high in cooperative breeders and may reflect plastic divergence in developmental trajectories leading to breeding vs. helping phenotypes. However, the relative importance of additive genetic variance and developmental plasticity in shaping growth trajectories is largely unknown in cooperative vertebrates. This study exploits weekly sequences of body mass from birth to adulthood to investigate sources of variance in, and covariance between, early and later growth in wild meerkats (Suricata suricatta), a cooperative mongoose. Our results indicate that (i) the correlation between early growth (prior to nutritional independence) and adult mass is positive but weak, and there are frequent changes (compensatory growth) in post-independence growth trajectories; (ii) among parameters describing growth trajectories, those describing growth rate (prior to and at nutritional independence) show undetectable heritability while associated size parameters (mass at nutritional independence and asymptotic mass) are moderately heritable (0.09 ≤ h(2) < 0.3); and (iii) additive genetic effects, rather than early environmental effects, mediate the covariance between early growth and adult mass. These results reveal that meerkat growth trajectories remain plastic throughout development, rather than showing early and irreversible divergence, and that the weak effects of early growth on adult mass, an important determinant of breeding success, are partly genetic. In contrast to most cooperative invertebrates, the acquisition of breeding status is often determined after sexual maturity and strongly impacted by chance in many cooperative vertebrates, who may therefore retain the ability to adjust their morphology to environmental changes and social opportunities arising throughout their development, rather than specializing early.

Endurance exercise attenuates cardiotoxicity induced by androgen deprivation and doxorubicin.

Doxorubicin (DOX) is associated with cardiac dysfunction and irreversible testicular damage. Androgen deprivation therapy (ADT) is administered prior to DOX treatment to preserve testicular function. However, ADT may exacerbate DOX-induced cardiac dysfunction. Exercise is cardioprotective, but the effects of exercise on cardiac function during combined ADT and DOX treatment are currently unknown. In this study, male Sprague-Dawley rats were randomly assigned to experimental groups: control (CON), ADT, DOX, or ADT+DOX. Animals received ADT or control implants on days 1 and 29 of the 56-day protocol. Animals remained sedentary (SED) or engaged in treadmill endurance exercise (TM) beginning on day 1. On day 15, the animals received DOX at 1 mg·(kg body mass)(-1)·d(-1) by intraperitoneal injection for 10 consecutive days, or an equivalent volume of saline. On day 57, cardiac function was assessed in vivo and ex vivo. Animals treated with DOX alone, or with combined ADT+DOX, showed significant (P < 0.05) reductions in left ventricular developed pressure (-21% and -27%), maximal rate of pressure development (-29% and -32%), and maximal rate of pressure decline (25% and 31%), respectively when compared with the sedentary control animals. Endurance exercise training attenuated (P > 0.05) cardiac dysfunction associated with combined ADT+DOX treatment, indicating that exercise during simultaneous ADT+DOX treatment is cardioprotective.

Structure-Based Optimization of Selective and Brain Penetrant CK1δ Inhibitors for the Treatment of Circadian Disruptions.

Neuropsychiatric disorders such as major depressive disorders and schizophrenia are often associated with disruptions to the normal 24 h sleep wake cycle. Casein kinase 1 (CK1δ) is an integral part of the molecular machinery that regulates circadian rhythms. Starting from a cluster of bicyclic pyrazoles identified from a virtual screening effort, we utilized structure-based drug design to identify and reinforce a unique "hinge-flip" binding mode that provides a high degree of selectivity for CK1δ versus the kinome. Pharmacokinetics, brain exposure, and target engagement as measured by ex vivo autoradiography are described for advanced analogs.