Cyclin-dependent kinases and cell-cycle transitions: does one fit all?

Cell-cycle transitions in higher eukaryotes are regulated by different cyclin-dependent kinases (CDKs) and their activating cyclin subunits. Based on pioneering findings that a dominant-negative mutation of CDK1 blocks the cell cycle at G2-M phase, whereas dominant-negative CDK2 inhibits the transition into S phase, a model of cell-cycle control has emerged in which each transition is regulated by a specific subset of CDKs and cyclins. Recent work with gene-targeted mice has led to a revision of this model. We discuss cell-cycle control in light of overlapping and essential functions of the different CDKs and cyclins.     

Medical professionalism: one size fits all?

A number of medical specialties have recently developed their own specialty-specific charters. This proliferation of charters is representative of an unease about medical professionalism that has arisen not just from increasing medical specialization, but also from evolving needs as physicians progress through their careers. The development of such specialty-specific definitions of professionalism is undesirable: all specialties should adhere to the same basic principles. These charters and "definitions" should be incorporated into a formal developmental model, derived from needs assessments from the level of medical school through the level of specialization. Such a model would provide physicians with more concrete guidance regarding professional behavior at each stage of their careers, address unmet needs in neglected areas such as mid- and late career, and help alleviate the tension associated with expressing these ideas. Incorporating concepts derived from more classic models of development may create opportunities to address the teaching of values and identify barriers to success.     

Biological invasions in developing and developed countries: does one model fit all?

There is a strong bias concerning the regions of the globe where research on biological invasions is conducted, with notably lower representation of developing countries. However, in developing countries, effective management strategies to control invasions could be more beneficial in conserving global biodiversity since these countries tend to have larger, highly diverse natural habitats. Lower levels of development are seen as an obstacle to tackling biological invasions, but little thought is given to the advantages of developing countries in dealing with invasive species. We analyzed differences between developed and developing countries regarding the problem of invasive species and their historical and current patterns of international trade, disturbance levels and land use, research and monitoring, control and mitigation, and social awareness. Developed nations have some advantages, especially in levels of social awareness and means for controlling and studying exotics, but developing nations also enjoy important advantages given their lower levels of international trade and the availability of low-cost labor. Also, there is evidence that the process of economic development, which results in more efficient ways to transform landscapes and increases international trade, is strongly associated with increasing rates of biological invasion. Differences in data quality and availability between developed and developing countries make comparative analyses of biological invasions a difficult task. Thus, these differences creates a challenge in forming global strategies to deal with invasions. There have been calls for creating international plans to deal with invasive species, but we believe that it is important first to acknowledge the challenges and understand both the advantages and disadvantages of developing countries.     

Does one size fit all? A multispecies approach to regional landscape corridor planning

Aim

The practical value of the single‐species approach to conserve biodiversity could be minimal or negligible when sympatric species are limited by factors that are not relevant to the proposed umbrella species. In this study, we quantitatively evaluated as follows: (1) habitat suitability and potential movement corridors of a single umbrella species, giant panda (Ailuropoda melanoleuca); (2) habitat suitability of sympatric mammals; and (3) the potential effectiveness of the single‐species corridor planning to preserve suitable habitat and its connectivity of other focal species.

Location

Qinling Mountains, central part of China (15,000 km²).

Methods

We collected species distribution, environmental and anthropogenic data and conducted species occupancy modelling for giant panda and six other sympatric species (i.e., takin Budorcas taxicolor, tufted deer Elaphodus cephalophus, Chinese goral Naemorhedus griseus, Reeve's muntjac Muntiacus reevesi, leopard cat Prionailurus bengalensis and yellow‐throated marten Martes flavigula). We then conducted circuit models to identify potential corridors for each species and evaluated the effectiveness of giant panda corridors to restore the habitat connectivity for these sympatric mammals.

Results

Occupancy modelling revealed that each species had a unique set of environmental variables associated with its distribution in the Qinling Mountains. We found that giant panda and all other focal species had some degree of fragmentation to their suitable habitat that required restoring habitat connectivity. Among the eight potential giant panda corridors, conservation efforts to reduce anthropogenic impacts would significantly improve the effectiveness of six corridors, while the other two corridors would require altering the vegetation. Five proposed giant panda corridors had remarkable overlap with corridors proposed for other species. We suggest two giant panda corridors as a priority due to their potential to maximize the benefits to both giant panda and a broader suite of mammals.

Main conclusions

Corridor planning in this region of China will likely continue using the single‐species policy, but our results highlight that not all potential giant panda corridors have equal effectiveness for other wildlife species. When offered multiple alternative actions, conservation planners can prioritize corridor development based on a multispecies perspective without loss of connectivity for the priority species. This approach has strong implications to the conservation of wildlife communities in China, and elsewhere, where conservation plans developed for a single‐species garner most available funding and institutional support.

     

Parkinson's disease: one biochemical pathway to fit all genes?

Although originally discounted, hereditary factors have emerged as the focus of research in Parkinson's disease (PD). Genetic studies have identified mutations in alpha-synuclein and ubiquitin C-terminal hydrolase as rare causes of autosomal dominant PD and mutations in parkin as a cause of autosomal recessive PD. Functional characterization of the identified disease genes implicates the ubiquitin-mediated protein degradation pathway in these hereditary forms of PD and also in the more common sporadic forms of PD. Subsequent identification of further loci in familial PD and diverse genetic factors modulating the risk for sporadic PD point to substantial genetic heterogeneity in the disease. Thus, new candidate genes are expected to encode proteins either involved in ubiquitin-mediated protein degradation or sequestrated in intracytoplasmic protein aggregations. Future identification of disease genes is required to confirm this hypothesis, thereby unifying the clinical and genetic heterogeneity of PD, including the common sporadic form of the disease, by one biochemical pathway.     

Ion channels: does each subunit do something on its own?

The advent of the patch-clamp technique 25 years ago revolutionized the study of ion channels. This method also made it possible to measure the kinetic behavior of single protein molecules. The low-noise recordings of ionic currents through single channels, coupled with other cutting-edge technologies, have revealed a rich complexity of functional states that are not readily explained by simple allosteric protein models such as the popular concerted model and the sequential model. Although these models can each account for elements of ion channel function, we propose that variations or extensions of the lesser-known general allosteric model provide a more promising framework for explaining the intricate behaviors of ion channels.     

Cardiovascular effects of music by entraining cardiovascular autonomic rhythms music therapy update: tailored to each person, or does one size fit all?

Music goes back a very long way in human experience. Music therapy is now used in many disparate areas—from coronary care units to rehabilitation after a stroke. But its widespread adoption has a poor scientific evidence base, founded more on enthusiasm than on proper evaluation in any controlled way. This has led to a lack of clarity about whether any particular type of music is superior, or whether different types of music should be tailored to differing individuals. We therefore conducted a series of controlled studies in which we examined the effects of different styles of music—from raga to jazz—presented in random order to normal young subjects (both musically trained or not). We found that contrary to many beliefs the effect of a style of music was similar in all subjects, whatever their individual music taste. We also found that this effect appeared to operate at a sub-conscious level through the autonomic nervous system. Furthermore, musical or verbal phrases of a 10 s duration (which coincided with the normal circulatory ‘Mayer’ waves) induced bigger excursions in blood pressure and heart rate (reciprocal of pulse interval) and so triggered more vagal slowing and feelings of calm. These findings need to now be tested in the clinical setting since, if confirmed, this would greatly simplify the practical use of this promising tool.     

Pointer years revisited: Does one method fit all? A clarifying discussion

The identification of pointer years is central in tree-ring studies, for example, for crossdating or describing growth responses of trees to extreme events. Various methods exist to define pointer years. To these methods, a presumably new method was recently added, i.e. the standardized growth change (SGC) method (Buras et al., 2020; 2022), which was claimed by the authors to outperform existing methods. In this Communication, we perform a concise method review and compare the SGC method with existing pointer year detection methods using simulated tree-ring data that contain diverse signal patterns. We not only provide evidence that the SGC method has already been proposed in 1994, but furthermore show that each method for pointer year detection, including SGC, has its own strengths and weaknesses. Given that each method highlights different aspects of extraordinary growth, we repeat our conclusion from Jetschke et al. (2019), namely that no method can be substituted by others completely, and thus be claimed as being ‘best’. As applies to all methods for pointer year detection, SGC is a complementary but certainly powerful method. We request the dendro-community to provide clear explanations in future studies on how the term pointer year was used to prevent unnecessary confusion and misunderstanding.     

Genome size: does bigger mean worse?

Genome sizes vary enormously. This variation in DNA content correlates with effective population size, suggesting that deleterious additions to the genome can accumulate in small populations. On this view, the increased complexity of biological functions associated with large genomes partly reflects evolutionary degeneration.     

Cdk-mediated phosphorylation of the Kvβ2 auxiliary subunit regulates Kv1 channel axonal targeting

Kv1 channels are concentrated at specific sites in the axonal membrane, where they regulate neuronal excitability. Establishing these distributions requires regulated dissociation of Kv1 channels from the neuronal trafficking machinery and their subsequent insertion into the axonal membrane. We find that the auxiliary Kvβ2 subunit of Kv1 channels purified from brain is phosphorylated on serine residues 9 and 31, and that cyclin-dependent kinase (Cdk)-mediated phosphorylation at these sites negatively regulates the interaction of Kvβ2 with the microtubule plus end-tracking protein EB1. Endogenous Cdks, EB1, and Kvβ2 phosphorylated at serine 31 are colocalized in the axons of cultured hippocampal neurons, with enrichment at the axon initial segment (AIS). Acute inhibition of Cdk activity leads to intracellular accumulation of EB1, Kvβ2, and Kv1 channel subunits within the AIS. These studies reveal a new regulatory mechanism for the targeting of Kv1 complexes to the axonal membrane through the reversible Cdk phosphorylation-dependent binding of Kvβ2 to EB1.     

The single transmembrane segment determines the modulatory function of the BK channel auxiliary γ subunit

The large-conductance, calcium-activated potassium (BK) channels consist of the pore-forming, voltage- and Ca²⁺-sensing α subunits (BKα) and the tissue-specific auxiliary β and γ subunits. The BK channel γ1 subunit is a leucine-rich repeat (LRR)–containing membrane protein that potently facilitates BK channel activation in many tissues and cell types through a vast shift in the voltage dependence of channel activation by ∼140 mV in the hyperpolarizing direction. In this study, we found that the single transmembrane (TM) segment together with its flanking charged residues is sufficient to fully modulate BK channels upon its transplantation into the structurally unrelated β1 subunit. We identified Phe273 and its neighboring residues in the middle of the TM segment and a minimum of three intracellular juxtamembrane Arg residues as important for the γ1 subunit’s modulatory function and observed functional coupling between residues of these two locations. We concluded that the TM segment is a key molecular determinant for channel association and modulation and that the intracellular positively charged cluster is involved mainly in channel association, likely through its TM-anchoring effect. Our findings provide insights into the structure–function relationship of the γ1 subunit in understanding its potent modulatory effects on BK channels.     

Multicomponent phytotherapeutic approach gaining momentum: Is the “one drug to fit all” model breaking down?

Natural product based drugs constitute a substantial proportion of the pharmaceutical market particularly in the therapeutic areas of infectious diseases and oncology. The primary focus of any drug development program so far has been to design selective ligands (drugs) that act on single selective disease targets to obtain highly efficacious and safe drugs with minimal side effects. Although this approach has been successful for many diseases, yet there is a significant decline in the number of new drug candidates being introduced into clinical practice over the past few decades. This serious innovation deficit that the pharmaceutical industries are facing is due primarily to the post-marketing failures of blockbuster drugs. Many analysts believe that the current capital-intensive model-“the one drug to fit all” approach will be unsustainable in future and that a new “less investment, more drugs” model is necessary for further scientific growth. It is now well established that many diseases are multi-factorial in nature and that cellular pathways operate more like webs than highways. There are often multiple ways or alternate routes that may be switched on in response to the inhibition of a specific target. This gives rise to the resistant cells or resistant organisms under the specific pressure of a targeted agent, resulting in drug resistance and clinical failure of the drug. Drugs designed to act against individual molecular targets cannot usually combat multifactorial diseases like cancer, or diseases that affect multiple tissues or cell types such as diabetes and immunoinflammatory diseases. Combination drugs that affect multiple targets simultaneously are better at controlling complex disease systems and are less prone to drug resistance. This multicomponent therapy forms the basis of phytotherapy or phytomedicine where the holistic therapeutic effect arises as a result of complex positive (synergistic) or negative (antagonistic) interactions between different components of a cocktail. In this approach, multicomponent therapy is considered to be advantageous for multifactorial diseases, instead of a “magic bullet” the metaphor of a “herbal shotgun” might better explain the state of affairs. The different interactions between various components might involve the protection of an active substance from decomposition by enzymes, modification of transport across membranes of cells or organelles, evasion of multidrug resistance mechanisms among others.     

Benign prostatic hyperplasia: does prostate size matter?

Recent studies and analyses have confirmed that baseline prostate volume is related to progression of benign prostatic hyperplasia (BPH) as well as to negative outcomes related to BPH, such as acute urinary retention (AUR) and need for surgery, and can also predict response to therapy. Other investigations have determined that prostate-specific antigen (PSA) level has good predictive value for assessing prostate volume. Strong evidence exists that baseline serum PSA level, like baseline prostate volume, predicts future prostate growth. Randomized placebo-controlled finasteride trials have shown that men with larger prostate volumes and higher PSA levels experience a clinically significant response to therapy compared with those with smaller prostate volumes and lower PSA levels. It has also been demonstrated that men with larger prostate glands and higher PSA levels are at increased risk for AUR and BPH-related surgery but that finasteride reduces these risks. Moreover, doxazosin and finasteride, alone and in combination, have been shown to significantly reduce BPH clinical progression.     

Fungal septins: one ring to rule it all?

Septins are a conserved family of GTP-binding proteins found in living organisms ranging from yeasts to mammals. They are able to polymerize and form hetero-oligomers that assemble into higher-order structures whose detailed molecular architecture has recently been described in different organisms. In Saccharomyces cerevisiae, septins exert numerous functions throughout the cell cycle, serving as scaffolds for many different proteins or as diffusion barriers at the bud neck. In other fungi, septins are required for the proper completion of diverse functions such as polarized growth or pathogenesis. Recent results from several fungi have revealed important differences in septin organization and regulation as compared with S. cerevisiae, especially during Candida albicans hyphal growth and in Ashbya gossypii. Here we focus on these recent findings, their relevance in the biology of these eukaryotes and in consequence the “renaissance” of the study of septin structures in cells showing a different kind of morphological behaviour.