Tubulin CFEOM mutations both inhibit or activate kinesin motor activity.

Kinesin-mediated transport along microtubules is critical for axon development and health. Mutations in the kinesin Kif21a, or the microtubule subunit ß-tubulin, inhibit axon growth and/or maintenance resulting in the eye-movement disorder congenital fibrosis of the extraocular muscles (CFEOM). While most examined CFEOM-causing ß-tubulin mutations inhibit kinesin-microtubule interactions, Kif21a mutations activate the motor protein. These contrasting observations have led to opposed models of inhibited or hyperactive Kif21a in CFEOM. We show that, contrary to other CFEOM-causing ß-tubulin mutations, R380C enhances kinesin activity. Expression of ß-tubulin-R380C increases kinesin-mediated peroxisome transport in S2 cells. The binding frequency, percent motile engagements, run length and plus-end dwell time of Kif21a are also elevated on ß-tubulin-R380C compared with wildtype microtubules in vitro. This conserved effect persists across tubulins from multiple species and kinesins from different families. The enhanced activity is independent of tail-mediated kinesin autoinhibition and thus utilizes a mechanism distinct from CFEOM-causing Kif21a mutations. Using molecular dynamics, we visualize how ß-tubulin-R380C allosterically alters critical structural elements within the kinesin motor domain, suggesting a basis for the enhanced motility. These findings resolve the disparate models and confirm that inhibited or increased kinesin activity can both contribute to CFEOM. They also demonstrate the microtubule's role in regulating kinesins and highlight the importance of balanced transport for cellular and organismal health.

The Promise of Grassroots Approaches to Solving Absenteeism in Primary Health-Care Facilities in Nigeria: Evidence from a Qualitative Study.

Absenteeism among primary health-care (PHC) workers in Nigeria is widespread and is a major obstacle to achieving Universal Health Coverage (UHC). There is increasing research on the forms it takes and what drives them, but limited evidence on how to address it. The dominant approach has involved government-led topdown solutions (vertical approach). However, these have rarely been successful in countries such as Nigeria. This paper explores alternative approaches based on grassroots (horizontal) approaches. Data collected from interviews with 40 PHC stakeholders in Enugu, Nigeria, were organized in thematic clusters that explored the contribution of horizontal interventions to solving absenteeism in primary health-care facilities. We applied phenomenology to analyze the lived (practical) experiences of respondents. Absenteeism by PHC workers was prevalent and is encouraged by the complex configuration of the PHC system and its operating environment, which constrains topdown interventions. We identified several horizontal approaches that may create effective incentives and compulsions to reduce absenteeism, which include leveraging community resources to improve security of facilities, tapping the resources of philanthropic individuals and organizations to provide accommodation for health workers, and engaging trained health workers as volunteers or placeholders to address shortages of health-care staff. Nevertheless, a holistic response to absenteeism must complement horizontal approaches with vertical measures, with the government supporting and encouraging the health system to develop self-enforcing mechanisms to tackle absenteeism.

Absenteeism in primary health centres in Nigeria: leveraging power, politics and kinship.

BACKGROUND: Primary health centres (PHCs) in Nigeria suffer critical shortages of health workers, aggravated by chronic absenteeism that has been attributed to insufficient resources to govern the system and adequately meet their welfare needs. However, the political drivers of this phenomenon are rarely considered. We have asked how political power and networks influence absenteeism in the Nigerian health sector, information that can inform the development of holistic solutions. METHODS: Data were obtained from in-depth interviews with three health administrators, 30 health workers and 6 health facility committee chairmen in 15 PHCs in Enugu State, Nigeria. Our analysis explored how political configurations and the resulting distribution of power influence absenteeism in Nigeria's health systems. RESULTS: We found that health workers leverage social networks with powerful and politically connected individuals to be absent from duty and escape sanctions. This reflects the dominant political settlement. Thus, the formal governance structures that are meant to regulate the operations of the health system are weak, thereby allowing powerful individuals to exert influence using informal means. As a result, health managers do not confront absentees who have a relationship with political actors for fear of repercussions, including retaliation through informal pressure. In addition, we found that while health system structures cannot effectively handle widespread absenteeism, networks of local actors, when interested and involved, could address absenteeism by enabling health managers to call politically connected staff to order. CONCLUSION: The formal governance mechanisms to reduce absenteeism are insufficient, and building alliances (often informal) with local elites interested in improving service delivery locally may help to reduce interference by other powerful actors.

An adaptive governance and health system response for the COVID-19 emergency.

In the absence of an efficacious and affordable vaccine, the current crisis of COVID-19 is likely to be a long drawn one for many developing countries. In Bangladesh, where the entire population is susceptible and strict lockdown has been relaxed (as of May 31st 2020) due to concerns over saving livelihoods, the best available resources and capacities in the country have to be mobilized for an integrated and adaptive response strategy. In this paper we argue that a suitable response strategy for a country with highly constrained health system, must consider how response components will be delivered at scale, along with what can be delivered. In order to save maximum number of lives, an optimal strategy will be one that is able to iteratively select the most feasible set of health response and the network of organizations that can deliver most effectively at scale. This might require thinking outside of the conventional vertical network of public health system. Given its history of high-capacity non-government organizations in Bangladesh, it is likely that there are multiple alternative horizontal network options for delivering any set of response interventions. In fact many horizontal networks are already actively engaged in COVID-19 response work. The goal should be to identify and coordinate these networks, create new networks, and embed mechanisms for scaling up what works and scaling down what does not work. For a rapidly escalating and unpredictable crisis such as COVID-19, an adaptive response strategy is needed which allows for old and new networks of organizations to align and work collectively with minimum loss of lives.

Targeting anticorruption interventions at the front line: developmental governance in health systems.

In 2008, Vian reported an increasing interest in understanding how corruption affects healthcare outcomes and asked what could be done to combat corruption in the health sector. Eleven years later, corruption is seen as a heterogeneous mix of activity, extensive and expensive in terms of loss of productivity, increasing inequity and costs, but with few examples of programmes that have successfully tackled corruption in low-income or middle-income countries. The commitment, by multilateral organisations and many governments to the Sustainable Development Goals and Universal Health Coverage has renewed an interest to find ways to tackle corruption within health systems. These efforts must, however, begin with a critical assessment of the existing theoretical models and approaches that have underpinned action in the health sector in the past and an assessment of the potential of innovations from anticorruption work developed in sectors other than health. To that end, this paper maps the key debates and theoretical frameworks that have dominated research on corruption in health. It examines their limitations, the blind spots that they create in terms of the questions asked, and the capacity for research to take account of contextual factors that drive practice. It draws on new work from heterodox economics which seeks to target anticorruption interventions at practices that have high impact and which are politically and economically feasible to address. We consider how such approaches can be adopted into health systems and what new questions need to be addressed by researchers to support the development of sustainable solutions to corruption. We present a short case study from Bangladesh to show how such an approach reveals new perspectives on actors and drivers of corruption practice. We conclude by considering the most important areas for research and policy.

Checkpoint Proteins Bub1 and Bub3 Delay Anaphase Onset in Response to Low Tension Independent of Microtubule-Kinetochore Detachment.

The spindle assembly checkpoint (SAC) delays anaphase onset until sister chromosomes are bound to microtubules from opposite spindle poles. Only then can dynamic microtubules produce tension across sister kinetochores. The interdependence of kinetochore attachment and tension has proved challenging to understanding SAC mechanisms. Whether the SAC responds simply to kinetochore attachment or to tension status remains obscure. Unlike higher eukaryotes, budding yeast kinetochores bind only one microtubule, simplifying the relation between attachment and tension. We developed a Taxol-sensitive yeast model to reduce tension in fully assembled spindles. Our results show that low tension on bipolar-attached kinetochores delays anaphase onset, independent of detachment. The delay is transient relative to that imposed by unattached kinetochores. Furthermore, it is mediated by Bub1 and Bub3, but not Mad1, Mad2, and Mad3 (BubR1). Our results demonstrate that reduced tension delays anaphase onset via a signal that is temporally and mechanistically distinct from that produced by unattached kinetochores.

Intron-specific Single Nucleotide Polymorphisms of Fat Mass and Obesity- Associated Gene in Obese and Overweight Individuals of the Indian Adult Population- A Pilot Study.

BACKGROUND: The Fat mass and obesity-associated gene (FTO) and its involvement in weight gain and obesity is well-known. However, no reports have been published on the Indian population regarding the relationship between single nucleotide polymorphisms (SNPs) in its intronic region and obesity. The aim of this pilot study was to evaluate the frequency and association of SNPs in intron-1 of the FTO gene in obese and overweight Indian adults. METHODS: This study group consisted of 80 adults, aged 23.5 ± 8.9 yr, with a mean BMI of 28.8 ± 6.2 kg/m2. Genomic DNA was isolated, exons1-3 & intron1 of FTO were amplified using polymerase chain reaction and sequenced by ABI sequencing detection system. The reported SNPs rs1420185, rs8050136, rs1121980 and rs55872725 were checked for their presence or absence in this group of the adult Indian population. RESULTS: No mutations were found in the exonic sequence of FTO, however, the association of rs1420185, rs8050136, rs1121980 and rs55872725 SNPs was identified in this population. The genotypic frequency at FTO rs8050136 was 32.2% for C>A, at rs55872725 it was 45.7% for C>T, at rs1420185 it was 27.1% for T>C and at rs1121980 it was 30.5% for G>A. All four SNPs in combination were observed in 6 participants (10.2%), all of whom were found to be either obese or overweight. CONCLUSION: These findings indicate that Indians with these SNPs are most likely to be at increased risk of obesity.

Discrete regions of the kinesin-8 Kip3 tail differentially mediate astral microtubule stability and spindle disassembly.

To function in diverse cellular processes, the dynamic properties of microtubules must be tightly regulated. Cellular microtubules are influenced by a multitude of regulatory proteins, but how their activities are spatiotemporally coordinated within the cell, or on specific microtubules, remains mostly obscure. The conserved kinesin-8 motor proteins are important microtubule regulators, and family members from diverse species combine directed motility with the ability to modify microtubule dynamics. Yet how kinesin-8 activities are appropriately deployed in the cellular context is largely unknown. Here we reveal the importance of the nonmotor tail in differentially controlling the physiological functions of the budding yeast kinesin-8, Kip3. We demonstrate that the tailless Kip3 motor domain adequately governs microtubule dynamics at the bud tip to allow spindle positioning in early mitosis. Notably, discrete regions of the tail mediate specific functions of Kip3 on astral and spindle microtubules. The region proximal to the motor domain operates to spatially regulate astral microtubule stability, while the distal tail serves a previously unrecognized role to control the timing of mitotic spindle disassembly. These findings provide insights into how nonmotor tail domains differentially control kinesin functions in cells and the mechanisms that spatiotemporally control the stability of cellular microtubules.