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Combined-Arms Cyber Warfare utilizes cyber-attack, sabotage of infrastructural elements and Electromagnetic Pulse (EMP) attack, alone or in combination with conventional military tactics, to conduct warfare against opposing military forces and the civilian populations and/or infrastructures which they defend. Nuclear EMP attacks have been acknowledged to constitute a central component of the military doctrines, plans and exercises of the Combined-Arms Cyber Warfare doctrines of multiple nations. A Nuclear EMP attack consists of the detonation of thermonuclear weapons in a manner that minimizes the energy liberated in the form of blast (overpressure) andthermaleffects, while ensuring an increased proportion of detonation energy is directedto the targeted area as prompt radiation emissions and an associated electrical field. Significant overlap exists between the design and function of Nuclear EMP weapons and that of Enhanced Radiation Weapons (ERW), colloquially known as “Neutron bombs”. ERW are also a class of fission-fusion devices specifically designed to limit the energy of detonation manifested as blast and thermal effects while maximizing the percentage of energetic yield released as prompt radiation, with a particular emphasis on gamma-neutron emissions. Neutrons have been reported to be more biologically hazardous than ionizing photons on a per-dose basis. Slow and Thermal neutrons have been reported to possess a greater relative biological effectiveness (RBE) for cell death, single-strand DNA breakage and double-strand DNA breakage, relative to an equivalent dose of gamma-radiation. The full-length SARS-CoV2 spike glycoprotein has been reported to directly inhibit double-strand break (DSB) DNA repair in the absence of SARS-CoV-2 infection. Additionally, the spike glycoprotein of SARS-CoV-2 impairs the expansion of hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) in the absence of active SARS-CoV-2 infection. Viral-vector and mRNA vaccines against SARS-CoV-2, may be engineered to compel the protein synthetic apparatus of recipient patientsto synthesize the full-length SARS-CoV-2 spike glycoprotein in a non-throttleable manner. NATO and NATO-aligned countries, (such as Australia, Japan and Israel), have almost exclusively utilized viral-vector and mRNA vaccines, which forcibly compels the protein synthetic apparatus of recipient patients to engage in the self-synthesis of the full-length SARS-CoV-2 spike glycoprotein. Conversely, non-NATO, nuclear capable nations such as: China, Russia, India, Pakistan, North Korea and Iran have utilized a variety of SARS-CoV-2 vaccines, including inactivated-virus vaccines, subunit vaccines and nucleotide vaccines which do not compel the self-synthesis of the full-length SARS-CoV-2 spike glycoproteins. This report examines the strategic sequelae resulting from the disparity in SARS-CoV-2 vaccination policies between NATO/NATO-aligned nations and non-NATO, nuclear-capable nations such as: China, Russia, North Korea and Iran, in the context of the doctrine of Combined-Arms Cyber Warfare.

SARS-CoV-2, a human β-coronavirus implicated as thecausative agent in the COVID-19 pandemic, has been the subject of the most globally intensive vaccine development effort inrecorded history. The spectrum of SARS-CoV-2 vaccine candidates, deployedglobally, demonstrates an expansive diversity in regardsto design philosophies and immunological mechanisms of action. In the context of an aging, physically deconditioned, and overweight global population, which finds itself heavily burdened by a high prevalence of non-communicable chronic disease; elite strength, power and endurance athletes represent a minority population comprised of extreme physiological outliers. This report explores the molecular toxicity and pathophysiology of the SARS-CoV-2 spike protein, the design and immunological strategies embodied by the spectrum of SARS-CoV-2 vaccine candidates, and the intersection of these phenomena with the demographic, lifestyle and physiological characteristics of elite athletes; so as to inform vaccination strategies against SARS-CoV-2 which most protect this outlying minority population.

Shale gas development continues to outpace the implementation of best management practices for wildlife affected by development. We examined demographic responses of the Louisiana Waterthrush (Parkesia motacilla) to shale gas development during 2009–2011 and 2013–2015 in a predominantly forested landscape in West Virginia, USA. Forest cover across the study area decreased from 95% in 2008 to 91% in 2015, while the area affected by shale gas development increased from 0.4% to 3.9%. We quantified nest survival and productivity, a source–sink threshold, riparian habitat quality, territory density, and territory length by monitoring 58.1 km of forested headwater streams (n = 14 streams). Across years, we saw annual variability in nest survival, with a general declining trend over time. Of 11 a priori models tested to explain nest survival (n = 280 nests), 4 models that included temporal, habitat, and shale gas covariates were supported, and 2 of these models accounted for most of the variation in dai...

The purpose of this article is to develop a deeper understanding of a negative behavior at work through a study of the lived experience of bullying in Australian workplaces. Although there is considerable research available on workplace bullying, extant research largely provides empirical examinations of the prevalence, causes, and consequences of the phenomenon. By contrast, the research herein reported offers an in-depth account of bullying from the frame of reference of those who have experienced it and demonstrates the difficulties faced by them when coping with it. The study’s data source is drawn from reports submitted to the Australian Parliamentary Inquiry on workplace bullying. The reports were analyzed by using the principles of interpretative phenomenological analysis. The study highlights the impact of bullying at work on individuals’ lives and the coping mechanisms used for dealing with the impact. This article also reveals that bullying destroys organizations’ succession planning eff...

Unconventional shale gas development is a rapidly expanding driver of forest loss and fragmentation in the central Appalachian region. We evaluated the relationship between breeding passerine abundances and distance from shale gas development at a long-term (2008–2017) study site in northern West Virginia, USA. We examined responses of 27 species within 3 habitat guilds: forest interior, early successional, and synanthropic. More than half of the species evaluated showed sensitivity to distance from unconventional shale gas infrastructure (e.g., well pads, access roads, pipelines). Five forest interior species occurred in greater abundances farther from shale gas development, whereas 3 forest interior gap specialists increased in abundance closer to shale gas. Early successional and synanthropic species, including the nest-parasitic Brown-headed Cowbird (Molothrus ater), generally occurred in greater abundances closer to shale gas infrastructure. We used interpolated distributions of 4 focal species to assess their spatial response to unconventional shale gas development over time. Our results indicate that breeding passerine distributions and community composition are changing with forest disturbance driven by unconventional shale gas energy development.

In the last decade, unconventional drilling for natural gas from the Marcellus-Utica shale has increased exponentially in the central Appalachians. This heavily forested region contains important breeding habitat for many neotropical migratory songbirds, including several species of conservation concern. Our goal was to examine effects of unconventional gas development on forest habitat and breeding songbirds at a predominantly forested site from 2008 to 2015. Construction of gas well pads and infrastructure (e.g., roads, pipelines) contributed to an overall 4.5% loss in forest cover at the site, a 12.4% loss in core forest, and a 51.7% increase in forest edge density. We evaluated the relationship between land-cover metrics and species richness within three avian guilds: forest-interior, early-successional, and synanthropic, in addition to abundances of 21 focal species. Land-cover impacts were evaluated at two spatial extents: a point-level within 100-m and 500-m buffers of each avian survey station, and a landscape-level across the study area (4326 ha). Although we observed variability in species-specific responses, we found distinct trends in long-term response among the three avian guilds. Forest-interior guild richness declined at all points across the site and at points impacted within 100 m by shale gas but did not change at unimpacted points. Early-successional and synanthropic guild richness increased at all points and at impacted points. Our results suggest that shale gas development has the potential to fragment regional forests and alter avian communities, and that efforts to minimize new development in core forests will reduce negative impacts to forest dependent species.

Couchioplanes caeruleus DSM43634 synthesises 67–121C, an aromatic heptaene macrolide that contains a mannosyl-mycosaminyl disaccharide. An improved draft genome sequence was used to obtain the biosynthetic gene cluster for this antifungal. Bioinformatic analysis of the polyketide synthase indicated that extension modules 7 and 8 contain A-type ketoreductase and dehydratase domains. These modules are therefore predicted to form cis double bonds. The deduced stereostructure of the 67–121C macrolactone is identical to that experimentally determined for the partricin subgroup of aromatic heptaenes. Some of these polyenes are N-methylated on the aminoacetophenone moiety. The C. caeruleus AceS protein was shown to methylate 4-aminoacetophenone and esters of 4-aminobenzoate, but not 4-aminobenzoate. This suggests that the substrate specificity of AceS prevents it from interfering with folate biosynthesis. The methyltransferase should be valuable for chemoenzymatic alkylation of compounds that contain aminobenzoyl moieties. Science Foundation Ireland University College Dublin

Timber harvesting has been proposed as a management tool to enhance breeding habitat for the Cerulean Warbler (Setophaga cerulea), a declining Neotropical–Nearctic migratory songbird that nests in the canopy of mature eastern deciduous forests. To evaluate how this single-species management focus might fit within an ecologically based management approach for multiple forest birds, we performed a manipulative experiment using four treatments (three intensities of timber harvests and an unharvested control) at each of seven study areas within the core Cerulean Warbler breeding range. We collected pre-harvest (one year) and post-harvest (four years) data on the territory density of Cerulean Warblers and six additional focal species, avian community relative abundance, and several key habitat variables. We evaluated the avian and habitat responses across the 3–32 m2 ha−1 residual basal area (RBA) range of the treatments. Cerulean Warbler territory density peaked with medium RBA (∼16 m2 ha−1). In contrast, territory densities of the other focal species were negatively related to RBA (e.g., Hooded Warbler [Setophaga citrina]), were positively related to RBA (e.g., Ovenbird [Seiurus aurocapilla]), or were not sensitive to this measure (Scarlet Tanager [Piranga olivacea]). Some species (e.g., Hooded Warbler) increased with time post-treatment and were likely tied to a developing understory, whereas declines (e.g., Ovenbird) were immediate. Relative abundance responses of additional species were consistent with the territory density responses of the focal species. Across the RBA gradient, greatest separation in the avian community was between early successional forest species (e.g., Yellow-breasted Chat [Icteria virens]) and closed-canopy mature forest species (e.g., Ovenbird), with the Cerulean Warbler and other species located intermediate to these two extremes. Overall, our results suggest that harvests within 10–20 m2 ha−1 RBA yield the largest increases in Cerulean Warblers, benefit additional disturbance-dependent species, and may retain closed-canopy species but at reduced levels. Harvests outside the optimum RBA range for Cerulean Warblers can support bird assemblages specifically associated with early or late (closed-canopy) successional stages.

We quantified Louisiana Waterthrush (Parkesia motacilla) site fidelity and apparent survival across a 6 year period in an area undergoing shale gas development.Waterthrush initially exhibited high site fidelity that declined over time. At the same time, the number of unpaired males defending territories increased as did natal fidelity. We identified site fidelity factors that influenced if adult males and females returned. More males returned either due to or regardless of amount of shale gas disturbance and lower riparian habitat quality. Females were less likely to return with increased number of breeding attempts. Females in shale gas disturbed areas had a higher number of breeding attempts and lower individual productivity. We saw a general nonsignificant trend in declining apparent survival over time. Overall apparent survival estimates for adult males (0.56) and females (0.44) were similar to those reported for other populations. Apparent survival candidate models suggested weak, positive relationships of increased survival with shale gas territory disturbance, disturbance with year, and year for adult males, and a positive relationship of increased survival with hydraulic fracturing runoff for adult females although regression coefficients overlapped zero for all model-supported covariates implying no statistical significance. Since waterthrush can maintain pair bonds from the previous year and females must pick a nest site within the defended male's territory, there are potential conflicts between factors that influence adult survival and site fidelity that may affect long-term population persistence. Our study adds to previous evidence that shale gas disturbed areas may serve as sink habitats.

Point counts are commonly used to assess changes in bird abundance, including analytical approaches such as distance sampling that estimate density. Point-count methods have come under increasing scrutiny because effects of detection probability and field error are difficult to quantify. For seven forest songbirds, we compared fixed-radii counts (50 m and 100 m) and density estimates obtained from distance sampling to known numbers of birds determined by territory mapping. We applied point-count analytic approaches to a typical forest management question and compared results to those obtained by territory mapping. We used a before–after control impact (BACI) analysis with a data set collected across seven study areas in the central Appalachians from 2006 to 2010. Using a 50-m fixed radius, variance in error was at least 1.5 times that of the other methods, whereas a 100-m fixed radius underestimated actual density by >3 territories per 10 ha for the most abundant species. Distance sampling improved accuracy and precision compared to fixed-radius counts, although estimates were affected by birds counted outside 10-ha units. In the BACI analysis, territory mapping detected an overall treatment effect for five of the seven species, and effects were generally consistent each year. In contrast, all point-count methods failed to detect two treatment effects due to variance and error in annual estimates. Overall, our results highlight the need for adequate sample sizes to reduce variance, and skilled observers to reduce the level of error in point-count data. Ultimately, the advantages and disadvantages of different survey methods should be considered in the context of overall study design and objectives, allowing for trade-offs among effort, accuracy, and power to detect treatment effects.

We describe a cellular assay for detection of phosphorylation of endogenous proteins, whereby cells are seeded, treated, and assayed for modulation of phosphorylation in a single microplate well. The procedure is coupled to a rapid, one-wash sandwich enzyme-linked immuno-sorbent assay, enabling results to be obtained within 3-4 h from cell seeding. The assay was tested in two separate cellular systems, namely, HeLa and MCF-7 cells. When using the one-well protocol with Akt phosphorylation as a model, the response to a number of agonists was the same as the response obtained using cells treated in a separate microplate, using a conventional lysate transfer approach. The assay procedure was automated, and quantitative pharmacological data on three known inhibitors of the PI3-kinase signaling pathway was obtained within 4 h from seeding cells, with six dispense steps, and a single wash cycle. Thus, the protocol affords a reliable means of assaying for cellular signaling events in different cell types, and is amenable to automation.

We report the SAR around a series of 2,4-diaminopyrimidine-5-carboxamide inhibitors of Sky kinase. 2-Aminophenethyl analogs demonstrate excellent potency but moderate kinase selectivity, while 2-aminobenzyl analogs that fill the Ala571 subpocket exhibit good inhibition activity and excellent kinase selectivity.

Studies of habitat selection are often of limited utility because they focus on small geographic areas, fail to examine behavior at multiple scales, or lack an assessment of the fitness consequences of habitat decisions. These limitations can hamper the identification of successful site-specific management strategies, which are urgently needed for severely declining species like Cerulean Warblers (Setophaga cerulea). We assessed how breeding habitat decisions made by Cerulean Warblers at multiple scales, and the subsequent effects of these decisions on nest survival, varied across the Appalachian Mountains. Selection for structural habitat features varied substantially among areas, particularly at the territory scale. Males within the least-forested landscapes selected microhabitat features that reflected more closed-canopy forest conditions, whereas males in highly forested landscapes favored features associated with canopy disturbance. Selection of nest-patch and nest-site attributes by female...

Background Understanding the patient perspective on healthcare is central to the evaluation of quality. This study measured selected patient-reported outcomes after anaesthesia in order to identify targets for research and quality improvement. Methods This cross-sectional observational study in UK National Health Service hospitals, recruited adults undergoing non-obstetric surgery requiring anaesthesia care over a 48 h period. Within 24 h of surgery, patients completed the Bauer questionnaire (measuring postoperative discomfort and satisfaction with anaesthesia care), and a modified Brice questionnaire to elicit symptoms suggestive of accidental awareness during general anaesthesia (AAGA). Patient, procedural and pharmacological data were recorded to enable exploration of risk factors for these poor outcomes. Results 257 hospitals in 171 NHS Trusts participated (97% of eligible organisations). Baseline characteristics were collected on 16,222 patients; 15,040 (93%) completed postoperative questionnaires. Anxiety was most frequently cited as the worst aspect of the perioperative experience. Thirty-five per cent of patients reported severe discomfort in at least one domain: thirst (18.5%; 95% CI 17.8-19.1), surgical pain (11.0%; 10.5-11.5) and drowsiness (10.1%; 9.6-10.5) were most common. Despite this, only 5% reported dissatisfaction with any aspect of anaesthesia-related care. Regional anaesthesia was associated with a reduced burden of side-effects. The incidence of reported AAGA was one in 800 general anaesthetics (0.12%) Conclusions Anxiety and discomfort after surgery are common; despite this, satisfaction with anaesthesia care in the UK is high. The inconsistent relationship between patient-reported outcome, patient experience and patient satisfaction supports using all three of these domains to provide a comprehensive assessment of the quality of anaesthesia care.

The polyene macrolide group includes important antifungal drugs, to which resistance does not arise readily. Chemical and biological methods have been used in attempts to make polyene antibiotics with fewer toxic side effects. Genome sequencing of producer organisms is contributing to this endeavour, by providing access to new compounds and by enabling yield improvement for polyene analogues obtained by engineered biosynthesis. This recent work is also enhancing bioinformatic methods for deducing the structures of cryptic natural products from their biosynthetic enzymes. The stereostructure of candicidin D has recently been determined by NMR spectroscopy. Genes for the corresponding polyketide synthase have been uncovered in several different genomes. Analysis of this new information strengthens the view that protein sequence motifs can be used to predict double bond geometry in many polyketides. Chemical studies have shown that improved polyenes can be obtained by modifying the mycosamine sugar that is common to most of these compounds. Glycoengineered analogues might be produced by biosynthetic methods, but polyene glycosyltransferases show little tolerance for donors other than GDP-α-D-mycosamine. Genome sequencing has revealed extending glycosyltransferases that add a second sugar to the mycosamine of some polyenes. NppY of Pseudonocardia autotrophica uses UDP-N-acetyl-α-D-glucosamine as donor whereas PegA from Actinoplanes caeruleus uses GDP-α-D-mannose. These two enzymes show 51 % sequence identity and are also closely related to mycosaminyltransferases. These findings will assist attempts to construct glycosyltransferases that transfer alternative UDP- or (d)TDP-linked sugars to polyene macrolactones. Science Foundation Ireland

We report the discovery of a novel series of spiroindoline-based inhibitors of Sky kinase that bind in the ATP-binding site and exhibit high levels of kinome selectivity through filling the Ala571-subpocket. These inhibitors exhibit moderate oral bioavailability in the rat due to low absorption across the gut wall.

Invasive insects pose a significant threat to biodiversity, often affecting entire communities through the destruction of foundation species. Eastern Hemlock (Tsuga canadensis [L.] Carr.) forests, which are unique habitats in eastern North America, are threatened by an introduced insect, the Hemlock Woolly Adelgid (Adelges tsugae Annand). Previous studies have found declines in the abundance of some forest bird species, including the Acadian Flycatcher (Empidonax virescens), with increasing infestation by Hemlock Woolly Adelgids. To identify potential mechanisms behind these declines, we studied abundance, breeding biology, and habitat selection of Acadian Flycatchers in 11 Eastern Hemlock-dominated riparian sites in Pennsylvania and New Jersey, representing a continuum of infestation levels, in 2001–2002 and 2006–2007. Eastern Hemlock supported 90% of all nests and was used more as a nesting substrate than expected at most sites. We found ∼70% fewer breeding pairs at heavily infested sites, tho...

Background Patient satisfaction is an important metric of health-care quality. Accidental awareness under general anaesthesia (AAGA) is a serious complication of anaesthesia care which may go unrecognised in the immediate perioperative period but leads to long-term psychological harm for affected patients. The SNAP-1 study aimed to measure patient satisfaction with anaesthesia care and the incidence of AAGA, reported on direct questioning within 24 h of surgery, in a large multicentre cohort. A secondary aim of SNAP-1 was to test the effectiveness of a new network of Quality Audit and Research Coordinators in NHS anaesthetic departments, to achieve widespread study participation and high patient recruitment rates. This manuscript describes the study methodology. Methods SNAP-1 was a prospective observational cohort study. The study protocol was approved by the National Research Ethics Service. All UK NHS hospitals with anaesthetic departments were invited to participate. Adult patients undergoing any type of non-obstetric surgery were recruited in participating hospitals on 13th and 14th May 2014. Demographic data were collected by anaesthetists providing perioperative care. Patients were then approached within 24 h of surgery to complete two questionnaires—the Bauer patient satisfaction questionnaire (to measure patient reported outcome) and the modified Brice questionnaire (to detect possible accidental awareness). Completion of postoperative questionnaires was taken as evidence of implied consent. Results were recorded on a standard patient case report form, and local investigators entered anonymised data into an electronic database for later analysis by the core research team. Results Preliminary analyses indicate that over 15,000 patients were recruited across the UK, making SNAP-1 the largest NIHR portfolio-adopted study in anaesthesia to date. Both descriptive and analytic epidemiological analyses will be used to answer specific questions about the patient perception of anaesthesia care overall and in surgical sub-specialties and to determine the incidence of AAGA. Conclusions The SNAP-1 study recruited a large number of UK hospitals and thousands of perioperative patients using newly established networks in the UK anaesthetic profession. The results will provide benchmarking information to aid interpretation of patient satisfaction data and also determine the incidence of AAGA reported on a single postoperative visit. Electronic supplementary material The online version of this article (doi:10.1186/s13741-015-0011-2) contains supplementary material, which is available to authorized users.

Awards for business excellence are difficult for SMEs to achieve. This paper describes the case of a Merseyside SME that gained ISO 9000 certification in 1991 as well as a Business Excellence award from Excellence North West. Despite these achievements, the organisation soon became aware that business growth could not be absorbed into the ISO 9000 standard and resources for continual improvement were non existent. In order to comply with the new ISO 9000 requirements this situation would have to change. The paper details how the new ISO 9001 guidelines are facilitating the re‐definition of standards within the business and how, in partnership with Liverpool John Moores University the company is undertaking business process re‐engineering, identifying key performance measures at both managerial and operational levels, to establish a learning culture to promote continual improvement. The paper offers a model for the management of an ISO 9000 system within a SME, and documents the many lessons learned from the study.

Social studies and science education professors collaborated to introduce preservice teachers to the evolution vs. creationism debate via a mock trial. A hypothetical situation was created in which a sixth-grade teacher was fired for not balancing evolution and creationism in his teaching. Preservice teachers represented either the fired teacher or the school board in a trial that would reinstate the educator and affirm the right of the teacher to determine lesson content, or to uphold the decision for the teacher’s dismissal. Results suggested that the mock trial slightly increased students’ understanding of evolutionary principles. Students also reported themselves to be more aware of the difficulties of balancing evolution and creationism in science pedagogy.

Deep Vein Thrombosis (DVT) is a life threatening condition and a serious concern among hospitalised patients, with death occurring in approximately 6% of cases. Intermittent pneumatic compression (IPC) is commonly used for DVT prevention, however suffers from low compliance and issues of usability and portability. Neuromuscular electrical stimulation (NMES) has been shown to improve lower limb hemodynamics but direct comparison with IPC in terms of hemodynamics is rare but very important to determine the potential effectiveness of NMES in DVT prevention.Lower limb IPC was compared to calf NMES, in 30 healthy volunteers (18–23 years). Each intervention was carried out on each leg, on the popliteal vein measured using Doppler ultrasound. All interventions produced significantly greater haemodynamic responses compared to baseline. Calf-IPC and NMES produced significant increases in venous blood velocity (cm/s) and volume of blood ejected per cycle (1 cycle of NMES expels 23.22 ml compared to the baseline ejected volume of 2.52 ml, measured over 1 s (p < 0.001 versues baseline).Improving lower limb hemodynamics is vital in preventing DVT. NMES resulted in larger ejected volumes compared to IPC (x3 greater than foot-IPC and x1.7 greater than calf-IPC) more effectively emptying the veins and soleal sinuses. This is an important finding as DVT occurs predominantly in the soleal sinuses. NMES is silent and portable and thus does not suffer many of the issues associated with IPC. This work supports the potential widespread application of NMES in hospital and home settings where the risk of DVT formation is high.

Discovery of novel agonists and antagonists for G protein-coupled receptors (GPCRs) relies heavily on cell-based assays because determination of functional consequences of receptor engagement is often desirable. Currently, there are several key parameters measured to achieve this, including mobilization of intracellular Ca2+ and formation of cyclic adenosine monophosphate or inositol triphosphate. However, no single assay platform is suitable for all situations, and all of the assays have limitations. The authors have developed a new high-throughput homogeneous assay platform for GPCR discovery as an alternative to current assays, which employs detection of phosphorylation of the key signaling molecule p42/44 MAP kinase (ERK 1/2). The authors show that ERK 1/2 is consistently activated in cells stimulated by Gq-coupled GPCRs and provides a new high-throughput platform for screening GPCR drug candidates. The activation of ERK 1/2 in Gq-coupled GPCR systems generates comparable pharmacological data for receptor agonist and antagonist data obtained by other GPCR activation measurement techniques.

A pharmacological approach to inhibition of cyclin-dependent kinases 4 and 6 (Cdk4/6) using highly selective small molecule inhibitors has the potential to provide novel cancer therapies for clinical use. Achieving high levels of selectivity for Cdk4/6, versus other ATP-dependent kinases, presents a significant challenge. The pyrido[2,3-d]pyrimidin-7-one template provides an effective platform for the inhibition of a broad cross-section of kinases, including Cdks. It is now demonstrated that the modification of pyrido[2,3-d]pyrimidin-7-ones to include a 2-aminopyridine side chain at the C2-position provides inhibitors with exquisite selectivity for Cdk4/6 in vitro. This selectivity profile is recapitulated in cells where the most selective inhibitors create a G(1) block at concentrations up to 100-fold the IC(50) for cell proliferation. On the basis of its selectivity profile and pharmacokinetic profile, compound 43 (PD 0332991) was identified as a drug candidate for the treatment of cancer.