Definitions,measurements, and classifications of stimuli,situations, and environments

A review is presented of issues relevant to the definition, measurement, and classification of stimuli, situations, and environments. Problems such as the lack of adequate definitions of concepts, error and bias in measurement procedures, confusion between measurement of a concept and measurement of its behavioral effects, and the lack of agreement among alternative measures are emphasized. It is suggested that concepts be defined in terms of objective characteristics while allowing for the study of the transactional relationship between organism and environment. The work of the ethologists in defining stimuli while studying their relationship to different organismic states and situational contexts is emphasized in this regard. Following Brunswik, it is also suggested that wherever possible there be a representative sampling of variables in natural settings. Note from the editors: From time to time, Human Ecology will publish a review article. Our first in this series is a review by a psychologist of basic definitional and conceptual problems in environmental studies.This paper was prepared while the author was a Visiting Research Fellow at the Educational Testing Service. The support of ETS and my colleagues in the Division of Psychological Studies is gratefully acknowledged. The review was also supported in part by a grant from the Rutgers University Research Council.     

Incorporating Science,Technology, Fairness,and Accountability in Environmental,Health, and Safety Decisions

The Precautionary Principle is in sharp political focus today because (1) the nature of scientific uncertainty is changing and (2) there is increasing pressure to base governmental action on more “rational” schemes, such as cost-benefit analysis and quantitative risk assessment, the former being an embodiment of ‘rational choice theory’ promoted by the Chicago school of law and economics. The Precautionary Principle has been criticized as being both too vague and too arbitrary to form a basis for rational decision making. The assumption underlying this criticism is that any scheme not based on cost-benefit analysis and risk assessment is both irrational and without secure foundation in either science or economics. This paper contests that view and makes explicit the rational tenets of the Precautionary Principle within an analytical framework as rigorous as uncertainties permit, and one that mirrors democratic values embodied in regulatory, compensatory, and common law. Unlike other formulations that reject risk assessment, this paper argues that risk assessment can be used within the formalism of tradeoff analysis—a more appropriate alternative to traditional cost-benefit analysis and one that satisfies the need for well-grounded public policy decision making. This paper will argue that the precautionary approach is the most appropriate basis for policy, even when large uncertainties do not exist, especially where the fairness of the distributions of costs and benefits of hazardous activities and products are a concern. Furthermore, it will offer an approach to making decisions within an analytic framework, based on equity and justice, to replace the economic paradigm of utilitarian cost-benefit analysis.     

Genes, exercise, growth, and the sedentary, obese child.

It is still not possible to provide an evidence-based answer to the question of whether regular exercise is essential for normal growth. It is also unclear whether very low levels of exercise result in growth deficits. Regular exposure to exercise is characterized by heterogeneity in responsiveness, with most individuals experiencing improvements in fitness traits but a significant proportion showing only very minor gains. Whether a sedentary mode of life during the growing years results in a permanent deficit in cardiorespiratory fitness or a diminished ability to respond favorably to regular exercise later in life remains to be investigated. Although several genes have been associated with fitness levels or response to regular exercise, the quality of the evidence is weak mainly because studies are statistically underpowered. The special case of the obese, sedentary child is discussed, and the importance of the "energy gap" in the excess weight gain during growth is highlighted. Obese, sedentary children have high blood pressure, dyslipidemia, elevated glycemia and type 2 diabetes, hepatic steatosis, respiratory problems, orthopedic complications, and other health disorders more frequently than normal weight, physically active children. The role of genetic differences in the inclination to be sedentary or physically active is reviewed. An understanding of the true role of genetic differences and regular exercise on the growth of children will require more elaborate paradigms incorporating not only DNA sequence variants and exercise exposure but also information on nutrition, programming, and epigenetic events during fetal life and early postnatal years.     

Scaling of differentiation in networks: nervous systems,organisms, ant colonies,ecosystems, businesses,universities, cities,electronic circuits,and Legos

Nodes in networks are often of different types, and in this sense networks are differentiated. Here we examine the relationship between network differentiation and network size in networks under economic or natural selective pressure, such as electronic circuits (networks of electronic components), Legos (networks of Lego pieces), businesses (networks of employees), universities (networks of faculty), organisms (networks of cells), ant colonies (networks of ants), and nervous systems (networks of neurons). For each of these we find that (i) differentiation increases with network size, and (ii) the relationship is consistent with a power law. These results are explained by a hypothesis that, because nodes are costly to build and maintain in such "selected networks", network size is optimized, and from this the power-law relationship may be derived. The scaling exponent depends on the particular kind of network, and is determined by the degree to which nodes are used in a combinatorial fashion to carry out network-level functions. We find that networks under natural selection (organisms, ant colonies, and nervous systems) have much higher combinatorial abilities than the networks for which human ingenuity is involved (electronic circuits, Legos, businesses, and universities). A distinct but related optimization hypothesis may be used to explain scaling of differentiation in competitive networks (networks where the nodes themselves, rather than the entire network, are under selective pressure) such as ecosystems (networks of organisms).     

Substance,rights, value,and abortion

Most serious contemporary opposition to abortion is grounded on the belief that human fetuses are members of the same moral category as beings like us, and that the loss of any such life is one of the worst possible losses. Substance view theorists oppose abortion for this reason: in their view beings like us are essentially rational substances with inherent moral worth, and those who perform induced abortion fail to recognize this moral worth. In a recent series of articles, Rob Lovering presents reductio‐style arguments against the substance view, in part arguing that it is inconsistent with our intuitions in rescue and spontaneous abortion cases. In a recent reply, Henrik Friberg‐Fernros argues that the substance view can evade these problematic implications because of a distinction between killing and letting die. According to this argument, the fetus’s right to life is a negative right not to be killed, not a positive right to be rescued, thus the anti‐abortion theorist who lets fetuses die acts acceptably. I argue this stance fails to recognize the inherent moral worth that the substance view contends fetuses possess. One who refrains from saving a person, or doesn’t care how many people she saves, cannot reasonably claim to value life. Furthermore, this stance is at odds with most contemporary anti‐abortion views that oppose induced abortions of both the killing and letting die variety.     

Potential Compounds for Oral Cancer Treatment: Resveratrol,Nimbolide, Lovastatin,Bortezomib, Vorinostat,Berberine, Pterostilbene,Deguelin, Andrographolide,and Colchicine

Oral cancer is one of the main causes of cancer-related deaths in South-Asian countries. There are very limited treatment options available for oral cancer. Research endeavors focused on discovery and development of novel therapies for oral cancer, is necessary to control the ever rising oral cancer related mortalities. We mined the large pool of compounds from the publicly available compound databases, to identify potential therapeutic compounds for oral cancer. Over 84 million compounds were screened for the possible anti-cancer activity by custom build SVM classifier. The molecular targets of the predicted anti-cancer compounds were mined from reliable sources like experimental bioassays studies associated with the compound, and from protein-compound interaction databases. Therapeutic compounds from DrugBank, and a list of natural anti-cancer compounds derived from literature mining of published studies, were used for building partial least squares regression model. The regression model thus built, was used for the estimation of oral cancer specific weights based on the molecular targets. These weights were used to compute scores for screening the predicted anti-cancer compounds for their potential to treat oral cancer. The list of potential compounds was annotated with corresponding physicochemical properties, cancer specific bioactivity evidences, and literature evidences. In all, 288 compounds with the potential to treat oral cancer were identified in the current study. The majority of the compounds in this list are natural products, which are well-tolerated and have minimal side-effects compared to the synthetic counterparts. Some of the potential therapeutic compounds identified in the current study are resveratrol, nimbolide, lovastatin, bortezomib, vorinostat, berberine, pterostilbene, deguelin, andrographolide, and colchicine.     

Effects of GTP,forskolin, sodium fluoride,serotonin, dopamine,and carbachol on adenylate cyclase inTeleost retina

Adenylate cyclase activity can be stimulated in goldfish retina by forskolin, GTP, NaF, dopamine and serotonin. Pharmacological characterisation of the dopamine and serotonin responses shows them to be mediated through specific receptors. A synergistic increase in the level of C-AMP is observed following application of forskolin together with NaF, GTP, dopamine, or serotonin. Dopamine and serotonin with or without GTP produced an additive response. When NaF and GTP are both together their combined effect in elevating C-AMP levels in the presence or absence of forskolin is less than additive. These results suggest that forskolin may be interacting with a G_s protein as well as directly stimulating adenylate cyclase. Increases in the level of C-AMP observed following application of forskolin or dopamine are decreased by carbachol in a dose-dependent manner. The carbachol response is blocked by pertussis toxin and is insensitive to the phosphodiesterase inhibitor, IBMX, suggesting an involvement of a G_i protein. Carbachol attenuation of elevated C-AMP levels is inhibited by atropine while pirenzapine has little effect suggesting the presence of a M2-type receptor.     

Earth, sky, wind, and weather

This paper seeks to understand what it means to live 'in the open'. It begins with an account of experiments that test whether children have acquired a scientifically correct understanding of the shape of the earth, according to which people live all around on the outside of a solid sphere. This understanding cannot accommodate the phenomenon of the sky, in relation to which the earth can appear only as the ground of human habitation. James Gibson's ecological approach to perception offers a possible alternative, depicting earth and sky as complementary hemispheres. Yet for Gibson, this earth-sky can be inhabited only insofar as it is furnished with objects. To that extent, it ceases to be open. Drawing on elements of Merleau-Ponty's phenomenology, it is argued that in the open world persons and things relate not as closed forms but by virtue of their common immersion in the generative fluxes of the medium – in wind and weather. Fundamental to life is the process of respiration, by which organisms continually disrupt any boundary between earth and sky, binding substance and medium together in forging their own growth and movement. Thus to inhabit the open is not to be stranded on the outer surface of the earth but to be caught up in the transformations of the weather-world.     

Soil chemical properties affect the concentration of elements (N,P, K,Ca, Mg,As, Cd,Cr, Cu,Fe, Mn,Ni, Pb,and Zn) and their distribution between organs of Rumex obtusifolius

Background and aims

The ionome (elemental composition) of grassland species has rarely been studied at the level of individual organs and little is known about effects of soil chemical properties on the ionome. Using the model oxalate plant Rumex obtusifolius, we asked how its biomass production and the distribution of elements between its organs is affected by soil chemical properties.

Methods

We established a pot experiment with R. obtusifolius planted in acidic non-contaminated control and in slightly acidic and alkaline soils anthropogenically contaminated by the risk elements As, Cd, Pb, and Zn. Both contaminated soils were untreated and treated by lime and superphosphate. We determined biomass production and the concentrations of elements in its organs.

Results

Biomass production was negatively related to the mobility of micro- and risk elements. Restricted transport of micro- and risk elements from belowground organs into leaves was recorded in untreated contaminated soils. In both lime-treated soils and in superphosphate-treated alkaline soil, elevated transport of micro- and risk elements from belowground organs into leaves was recorded in comparison to untreated contaminated soils. The lowest concentrations of micro- and risk elements were recorded in stems and seeds, followed by belowground organs and leaves.

Conclusions

R. obtusifolius is an As-, Cd-, Pb-, and Zn-excluder and is sensitive to high availability of micro- and risk elements in the soil. Soil chemical properties affect the distribution of essential elements within the plant greatly.     

Biofuels, facts, fantasy, and feasibility

It is frequently claimed that green algae are intrinsically more productive, often by orders of magnitude, than higher plants commonly grown as crops for food. There is no firm evidence for this belief. On the contrary, there is much experience which shows that algae are not more but less productive. Under optimal conditions, all green organisms photosynthesize at the same rate in low light and, whilst commonly cultivated ‘sun’ species show some differences in rate in full light, these do not translate into widely different rates of accumulation of biomass. Accordingly, irrespective of crop, one acre of land, pond or bioreactor, can annually yield about enough biomass to fuel one motor vehicle or meet the calorific requirement of several people. This amount of biomass is not sufficient to make other than a very small contribution to our present road transport requirements and yet contributes significantly to global food shortages and rising prices. Reliable evidence also suggests that, if all of the inputs are taken into account, the net energy gain of liquid biofuels, derived either from algae or terrestrial crops, is either very modest or non-existent and will therefore bring about little or no sparing of carbon dioxide emissions.     

Cadmium transport, resistance, and toxicity in bacteria, algae, and fungi

Cadmium is an important environmental pollutant and a potent toxicant to bacteria, algae, and fungi. Mechanisms of Cd toxicity and resistance are variable, depending on the organism. It is very clear that the form of the metal and the environment it is studied in, play an important role in how Cd exerts its effect and how the organism(s) responds. A wide range of Cd concentrations have been used to designate resistance in organisms. To date, no concentration has been specified that is applicable to all species studied under standardized conditions. Cadmium exerts its toxic effect(s) over a wide range of concentrations. In most cases, algae and cyanobacteria are the most sensitive organisms, whereas bacteria and fungi appear to be more resistant. In some bacteria, plasmid-encoded resistance can lead to reduced Cd2+ uptake. However, some Gram-negative bacteria without plasmids are just as resistant to Cd as are bacteria containing plasmids encoding for Cd resistance. According to Silver and Misra (1984), there is no evidence for enzymatic or chemical transformations associated with Cd resistance. Insufficient information is available on the genetics of Cd uptake and resistance in cyanobacteria and algae. Mechanisms remain largely unknown at this point in time. Cadmium is toxic to these organisms, causing severe inhibition of such physiological processes as growth, photosynthesis, and nitrogen fixation at concentrations less than 2 ppm, and often in the ppb range (Tables 2 and 3). Cadmium also causes pronounced morphological aberrations in these organisms, which are probably related to deleterious effects on cell division. This may be direct or indirect, as a result of Cd effects on protein synthesis and cellular organelles such as mitochondria and chloroplasts. Cadmium is accumulated internally in algae (Table 4) as a result of a two-phase uptake process. The first phase involves a rapid physicochemical adsorption of Cd onto cell wall binding sites, which are probably proteins and (or) polysaccharides. This is followed by a lag period and then a slow, steady intracellular uptake. This latter phase is energy dependent and may involve transport systems used to accumulate other divalent cations, such as Mn2+ and Ca2+. Some data indicate that Cd resistance, and possibly uptake, in algae and cyanobacteria is controlled by a plasmid-encoded gene(s). Although considerable information is available on Cd toxicity to, and uptake in fungi, further work is clearly needed in several areas. There is little information about Cd uptake by filamentous fungi, and even in yeasts, information on the specificity, kinetics, and mechanisms of Cd uptake is limited.(ABSTRACT TRUNCATED AT 400 WORDS)     

Super-motifs and evolution of tandem leucine-rich repeats within the small proteoglycans--biglycan, decorin, lumican, fibromodulin, PRELP, keratocan, osteoadherin, epiphycan, and osteoglycin

Leucine-rich repeats (LRRs) with 20-30 amino acids in unit length are present in many proteins from prokaryotes to eukaryotes. The LRR-containing proteins include a family of nine small proteoglycans, forming three distinct subfamilies: class I contains biglycan/PG-I and decorin/PG-II; class II: lumican, fibromodulin, PRELP, keratocan, and osteoadherin; and class III: epiphycan/PG-Lb and osteoglycin or osteoinductive factor. Comparative sequence analysis of the 34 available protein sequences reveals that these proteoglycans have two types of LRRs, which we call S and T. The type S LRR is 21 residues long and has the consensus sequence of xxaPzxLPxxLxxLxLxxNxI. The type T LRR has 26 residues; its consensus sequence is zzxxaxxxxFxxaxxLxxLxLxxNxL. In both "x" indicates variable residue; "z" is frequently a gap; "a" is Val, Leu, or Ile; and I is Ile or Leu. These type S and TLRRs are ordered into two super-motifs--STT with about 73 residues in classes I and II and ST with about 47 residues in class III. The 12 LRRs in the small proteoglycans of I and II are best represented as (STT)4; the seven LRRs of class III as (ST)T(ST)2. Our analyses indicate that classes I/II and III evolved along different paths after the establishment of the precursor ST, and classes I and II also diverged after the establishment of the precursor (STT)4.     

New Coleoptera records from New Brunswick, Canada: Stenotrachelidae, Oedemeridae, Meloidae, Myceteridae, Boridae, Pythidae, Pyrochroidae, Anthicidae, and Aderidae

We report 19 new species records for the faunal list of Coleoptera in New Brunswick, Canada, six of which are new records for the Maritime provinces, and one of which is new Canadian record. We also provide the first recent records for five additional species in New Brunswick. One new species of Stenotrachelidae, Cephaloon ungulare LeConte, is added to the New Brunswick faunal list. Additional records are provided for Cephaloon lepturides Newman, as well the first recent record of Nematoplus collaris LeConte. Two species of Oedemeridae, Asclera puncticollis (Say) and Asclera ruficollis (Say), are newly reported for New Brunswick, and additional locality and bionomic data are provided for Calopus angustus LeConte and Ditylus caeruleus (Randall). The records of Ditylus caerulus are the first recent records for the province. Three species of Meloidae, Epicauta pestifera Werner, Lytta sayi LeConte, and Meloe augustcollis Say are reported the first time for New Brunswick; Epicauta pestifera is newly recorded in Canada. Lacconotus punctatus LeConte and the family Mycteridaeis newly recorded for New Brunswick. The first recent records of Borus unicolor Say (Boridae) are reported from the province. One new species of Pythidae, Pytho siedlitzi Blair, and the first recent records of Pytho niger Kirby are added to the faunal list of New Brunswick. Three species of Pyrochroidae are newly reported for the province, including Pedilus canaliculatus (LeConte) and Pedilus elegans (Hentz), which are new for the Maritime provinces. Five species of Anthicidae and the first recent record of Anthicus cervinus LaFerté-Sénectére are newly reported for New Brunswick. Anthicus melancholicus LaFerté-Sénectère, Sapintus pubescens (LaFerté-Sénectère), Notoxus bifasciatus (LeConte), and Stereopalpus rufipes Casey are new to the Maritime provinces faunal list. Ambyderus granularis (LeConte) is removed from the faunal list of the province. Three species of Aderidae, Vanonus huronicus Casey, Zonantes fasciatus (Melsheimer), and Zonantes pallidusWerner, are newly recorded for New Brunswick; Zonantes fasciatus and Vanonus huronicus are new for the Maritime provinces' faunal list. Collection data, bionomic data, and distribution maps are presented for all these species.     

Life,information theory,probability, and physics

A purely information-theoretical approach to the problem of self-replication of elementary living units implies that pure chance is the determining factor in the formation of the first living unit. The probability of such a spontaneous formation can be calculated from the minimum amount of information which an organism must possess in order to replicate itself. An estimation of this amount of information is made here by two different methods. First by a “paper and pencil experiment” which indicates the minimum amount of information needed on a printed page in order that with given tools the page could be reproduced. Second—by an analytical consideration of some hypothetical molecular mechanisms. A general method for handling such problems is suggested. On the basis of estimated information contents it is shown that under most favorable conditions the probability of a spontaneous generation by pure chance during the lifetime of the earth is vanishingly small. It is concluded that dynamic factors, which may reduce tremendously the information content, must play a role in the genesis of life on earth.     

Geological History,Flora, and Vegetation of Xishuangbanna,Southern Yunnan,China1

Xishuangbanna of southern Yunnan is biogeographically located at a transitional zone from tropical Southeast (SE) Asia to subtropical East Asia, and is at the junction of the Indian and Burmese plates of Gondwana and the Eurasian plate of Laurasia. The flora of the region consists of a recorded 3336 native seed plant species, belonging to 1140 genera in 197 families, among which 83.5 percent are tropical genera and 32.8 percent are endemic to tropical Asia, suggesting a strong affinity to tropical Asian flora. The vegetation of Xishuangbanna is organized into four forest types: tropical rain forest, tropical seasonal moist forest, tropical montane evergreen broad‐leaved forest, and tropical monsoon forest. The tropical rain forest in Xishuangbanna has the same floristic composition of families and genera as some lowland equatorial rain forests in SE Asia, and is dominated (with a few exceptions) by the same families both in species richness and stem dominance. The exceptions include some deciduous trees in the canopy layer, fewer megaphanerophytes and epiphytes, and a higher abundance of lianas and microphyllic plants. We consider the tropical rain forest of Xishuangbanna as a type of tropical Asian rain forest, based on their conspicuous similarities in ecological and floristic characteristics.     

Physiology, biomedicine, medicine

The physiology throughout centuries was considered as the basic fundamental science in medicine. Rapid development of molecular biology, genetics and of some other natural sciences in 2nd half XX demanded century not only the answer to a question on the sciences defining the base of development of medicine, but also key problems of its progress. The biomedicine is formed, its methods are discussed, is frequent in system of natural sciences, parities with physiology. The special attention is given unconditional necessity of finding-out of molecular mechanisms of functions, targets of action of physiologically active substances and obligatory correlation of data of modeling with the same processes in conditions in vivo in whole body. The role of various sciences in the decision of fundamental problems of medicine, a place and role of physiology in modern medicine is shown.     

Caffeoylquinic acids: chemistry,biosynthesis, occurrence,analytical challenges,and bioactivity

Caffeoylquinic acids (CQAs) are specialized plant metabolites we encounter in our daily life. Humans consume CQAs in mg-to-gram quantities through dietary consumption of plant products. CQAs are considered beneficial for human health, mainly due to their anti-inflammatory and antioxidant properties. Recently, new biosynthetic pathways via a peroxidase-type p-coumaric acid 3-hydroxylase enzyme were discovered. More recently, a new GDSL lipase-like enzyme able to transform monoCQAs into diCQA was identified in Ipomoea batatas. CQAs were recently linked to memory improvement; they seem to be strong indirect antioxidants via Nrf2 activation. However, there is a prevalent confusion in the designation and nomenclature of different CQA isomers. Such inconsistencies are critical and complicate bioactivity assessment since different isomers differ in bioactivity and potency. A detailed explanation regarding the origin of such confusion is provided, and a recommendation to unify nomenclature is suggested. Furthermore, for studies on CQA bioactivity, plant-based laboratory animal diets contain CQAs, which makes it difficult to include proper control groups for comparison. Therefore, a synthetic diet free of CQAs is advised to avoid interferences since some CQAs may produce bioactivity even at nanomolar levels. Biotransformation of CQAs by gut microbiota, the discovery of new enzymatic biosynthetic and metabolic pathways, dietary assessment, and assessment of biological properties with potential for drug development are areas of active, ongoing research. This review is focused on the chemistry, biosynthesis, occurrence, analytical challenges, and bioactivity recently reported for mono-, di-, tri-, and tetraCQAs.     

New Coleoptera records for New Brunswick, Canada: Kateretidae, Nitidulidae, Cerylonidae, Endomychidae, Coccinellidae, and Latridiidae

We report 20 new species records for the Coleoptera fauna in New Brunswick, Canada, five of which are new records for the Maritime provinces, including one species that is new for Canada. One species of Kateretidae, Kateretes pusillus (Thunberg) is newly recorded for New Brunswick and the Maritime provinces. Stelidota octomaculata (Say), Phenolia grossa (Fabricius), andCryptarcha strigatula Parsons of the family Nitidulidae are added to the faunal list of New Brunswick; the latter species is new to the Maritime provinces. Two species of Cerylonidae, Philothermus glabriculus LeConte and Cerylon unicolor (Ziegler), are reported for the first time for New Brunswick. Philothermus glabriculus is new for the Maritime provinces. Two species of Endomychidae, Hadromychus chandleri Bousquet and Leschen and Danae testacea (Ziegler) are newly recorded for New Brunswick. Three species of Coccinelidae, Stethorus punctum punctum (LeConte), Naemia seriata seriata Melsheimer, and Macronaemia episcopalis (Kirby) are added to the provincial list. Macronaemia episcopalis (Kirby) is a species new to the Maritime provinces. Nine species of Latridiidae, Cartodere nodifer (Westwood), Dienerella ruficollis (Marsham), Enicmus aterrimus Motschulsky, Enicmus fictus Fall, Encimus histrio Jay and Tomlin, Lathridius minutus (Linnaeus), Stephostethus productus Rosenhauer, Corticaria elongata (Gyllenhal), and Corticarina longipennis (LeConte) are newly recorded for New Brunswick. Stephostehus productus is newly recorded from Canada. Collection and habitat data are presented for all these species.     

Treatment-resistant depression: definition,prevalence, detection,management, and investigational interventions

Treatment-resistant depression (TRD) is common and associated with multiple serious public health implications. A consensus definition of TRD with demonstrated predictive utility in terms of clinical decision-making and health outcomes does not currently exist. Instead, a plethora of definitions have been proposed, which vary significantly in their conceptual framework. The absence of a consensus definition hampers precise estimates of the prevalence of TRD, and also belies efforts to identify risk factors, prevention opportunities, and effective interventions. In addition, it results in heterogeneity in clinical practice decision-making, adversely affecting quality of care. The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have adopted the most used definition of TRD (i.e., inadequate response to a minimum of two antidepressants despite adequacy of the treatment trial and adherence to treatment). It is currently estimated that at least 30% of persons with depression meet this definition. A significant percentage of persons with TRD are actually pseudo-resistant (e.g., due to inadequacy of treatment trials or non-adherence to treatment). Although multiple sociodemographic, clinical, treatment and contextual factors are known to negatively moderate response in persons with depression, very few factors are regarded as predictive of non-response across multiple modalities of treatment. Intravenous ketamine and intranasal esketamine (co-administered with an antidepressant) are established as efficacious in the management of TRD. Some second-generation antipsychotics (e.g., aripiprazole, brexpiprazole, cariprazine, quetiapine XR) are proven effective as adjunctive treatments to antidepressants in partial responders, but only the olanzapine-fluoxetine combination has been studied in FDA-defined TRD. Repetitive transcranial magnetic stimulation (TMS) is established as effective and FDA-approved for individuals with TRD, with accelerated theta-burst TMS also recently showing efficacy. Electroconvulsive therapy is regarded as an effective acute and maintenance intervention in TRD, with preliminary evidence suggesting non-inferiority to acute intravenous ketamine. Evidence for extending antidepressant trial, medication switching and combining antidepressants is mixed. Manual-based psychotherapies are not established as efficacious on their own in TRD, but offer significant symptomatic relief when added to conventional antidepressants. Digital therapeutics are under study and represent a potential future clinical vista in this population.     

The genetic immunodeficiency disease, leukocyte adhesion deficiency, in humans, dogs, cattle, and mice

This review highlights the genotype-phenotype relationship of the genetic immunodeficiency disease leukocyte adhesion deficiency (LAD) in humans, dogs, cattle, and mice, and provides assessment of the opportunities that each animal species provides in the understanding of leukocyte biology and in developing new therapeutic approaches to LAD in humans. This comparison is important since animal models of genetic diseases in humans provide the opportunity to test new therapeutic approaches in an appropriate, disease-specific model. The success of this approach is dependent on the relationship of the phenotype in the animal to the phenotype of the disease in humans.