Helical motion and torque generation by microtubule motors.

Microtubule motors play key roles in cellular functions, such as transport, mitosis and cell motility. Fueled by ATP hydrolysis, they convert chemical energy into mechanical work, which enables their movement on microtubules. While their motion along the long axis of microtubules has been studied extensively, some motors display an off-axis component, which results in helical motion around microtubules and the generation of torque in addition to linear forces. Understanding these nuanced movements expands our comprehension of motor protein dynamics and their impact on cellular processes.

Human kinesin-5 KIF11 drives the helical motion of anti-parallel and parallel microtubules around each other.

During mitosis, motor proteins and microtubule-associated protein organize the spindle apparatus by cross-linking and sliding microtubules. Kinesin-5 plays a vital role in spindle formation and maintenance, potentially inducing twist in the spindle fibers. The off-axis power stroke of kinesin-5 could generate this twist, but its implications in microtubule organization remain unclear. Here, we investigate 3D microtubule-microtubule sliding mediated by the human kinesin-5, KIF11, and found that the motor caused right-handed helical motion of anti-parallel microtubules around each other. The sidestepping ratio increased with reduced ATP concentration, indicating that forward and sideways stepping of the motor are not strictly coupled. Further, the microtubule-microtubule distance (motor extension) during sliding decreased with increasing sliding velocity. Intriguingly, parallel microtubules cross-linked by KIF11 orbited without forward motion, with nearly full motor extension. Altering the length of the neck linker increased the forward velocity and pitch of microtubules in anti-parallel overlaps. Taken together, we suggest that helical motion and orbiting of microtubules, driven by KIF11, contributes to flexible and context-dependent filament organization, as well as torque regulation within the mitotic spindle.

[Scabies-Renaissance of an ectoparasite infection : Diagnosis and therapy-How to proceed in practice]. / Skabies ­ Renaissance einer Ektoparasitose : Diagnostik und Therapie ­ Vorgehen in der Praxis.

Scabies or mange is currently a common dermatosis in Germany and other countries, and should be more important in health policy. It affects a cross-section of society, including all age groups, from infants to the aged. Locals and people with a migration background both suffer from this highly contagious ectoparasite infection with excessive, predominately nocturnal itching. Clinical diagnosis represents a challenge for the experienced dermatologist due to the variety of dermatosis to be considered in the differential diagnosis. It is still unclear whether treatment failure or the recurrences observed everywhere are due to in vitro and in vivo resistance of the pathogen agent Sarcoptes scabiei against permethrin or ivermectin. Therapeutic errors seem to play a role as often not all direct contact persons are recorded and treated with antiscabious treatment. They form the reservoir for reinfections. In the event of repeated nonresponse to topical (permethrin) and/or oral antiscabious treatment, alternative topical preparations-benzyl benzoate or crotamiton-should be used. Combination with ivermectin is mandatory.

DYRK1A pathogenic variants in two patients with syndromic intellectual disability and a review of the literature.

BACKGROUND: DYRK1A-Related Intellectual Disability Syndrome is a rare autosomal dominant condition characterized by intellectual disability, speech and language delays, microcephaly, facial dysmorphism, and feeding difficulties. Affected individuals represent simplex cases that result from de novo heterozygous pathogenic variants in DYRK1A (OMIM 614104), or chromosomal structural rearrangements involving the DYRK1A locus. Due to the rarity of DYRK1A-Related Intellectual Disability Syndrome, the spectrum of symptoms associated with this disease has not been completely defined. METHODS AND RESULTS: We present two unrelated cases of DYRK1A-Related Intellectual Disability Syndrome resulting from variants in DYRK1A. Both probands presented to the National Institutes of Health (NIH) with multiple dysmorphic facial features, primary microcephaly, absent or minimal speech, feeding difficulties, and cognitive impairment; features that have been previously reported in individuals with DYRK1A. During NIH evaluation, additional features of enlarged cerebral subarachnoid spaces, retinal vascular tortuosity, and bilateral anomalous large optic discs with increased cup-to-disc ratio were identified in the first proband and multiple ophthalmologic abnormalities and sensorineural hearing loss were identified in the second proband. CONCLUSION: We recommend that the workup of future of patients include a comprehensive eye exam. Early establishment of physical, occupational, and speech therapy may help in the management of ataxia, hypertonia, and speech impairments common in these patients.

Kinesin-14 motors drive a right-handed helical motion of antiparallel microtubules around each other.

Within the mitotic spindle, kinesin motors cross-link and slide overlapping microtubules. Some of these motors exhibit off-axis power strokes, but their impact on motility and force generation in microtubule overlaps has not been investigated. Here, we develop and utilize a three-dimensional in vitro motility assay to explore kinesin-14, Ncd, driven sliding of cross-linked microtubules. We observe that free microtubules, sliding on suspended microtubules, not only rotate around their own axis but also move around the suspended microtubules with right-handed helical trajectories. Importantly, the associated torque is large enough to cause microtubule twisting and coiling. Further, our technique allows us to measure the in situ spatial extension of the motors between cross-linked microtubules to be about 20 nm. We argue that the capability of microtubule-crosslinking kinesins to cause helical motion of overlapping microtubules around each other allows for flexible filament organization, roadblock circumvention and torque generation in the mitotic spindle.

The Complement Regulator Susd4 Influences Nervous-System Function and Neuronal Morphology in Mice.

The SUSD4 (Sushi domain-containing protein 4) gene encodes a complement inhibitor that is frequently deleted in 1q41q42 microdeletion syndrome, a multisystem congenital disorder that includes neurodevelopmental abnormalities. To understand SUSD4's role in the mammalian nervous system, we analyzed Susd4 knockout (KO) mice. Susd4 KO mice exhibited significant defects in motor performance and significantly higher levels of anxiety-like behaviors. Susd4 KO brain had abnormal "hairy" basket cells surrounding Purkinje neurons within the cerebellum and significantly reduced dendritic spine density in hippocampal pyramidal neurons. Neurons and oligodendrocyte lineage cells of wild-type mice were found to express Susd4 mRNA. Protein expression of the complement component C1q was increased in the brains of Susd4 KO mice. Our data indicate that SUSD4 plays an important role in neuronal functions, possibly via the complement pathway, and that SUSD4 deletion may contribute to the nervous system abnormalities in patients with 1q41q42 deletions.

[Quality of and Attendance at Healthy Child Clinics in Germany]. / Qualität und Inanspruchnahme von Kindervorsorgeuntersuchungen in Deutschland.

Background For several years the German healthy child clinics program has been a highly appreciated preventive measure and is subject to constant development. However, attendance depends on the families' sociodemographic situation. Findings are documented in a medical checkup booklet (the so-called Gelbes Heft). Currently, there is no procedure to use the data collected for epidemiological purposes nor to evaluate the pediatric prevention measures in Germany. Methods Between 2011 and 2016, we recruited 3480 study participants for our population-based cohort study LIFE Child in Leipzig. 90.6 % submitted their check-up booklets which were subsequently scanned, the data was digitalized and transmitted to a computerized form. Furthermore, data on social status (so-called Winkler-Index) were collected for each family using a structured questionnaire. The study population consisted of the families' oldest child for whom both data sets were available. Results The transmission of data from the check-up booklets was time-consuming and cost-intensive due to large datasets, uncoded diagnoses as well as the necessity of trained employees for transferring often illegible handwriting. Early diagnostic tests for children enjoy a high level of acceptance among all social classes. With increasing age, attendance rate decreases gradually. Only 83 % of the population with a lower social status attend the U9 test. The documentation of diagnoses in the check-up booklets was implausible because the frequency fluctuated heavily between the different check-up time points. With only less than 2 %, the documentation of psychosocial difficulties in a child was particularly surprising Conclusion It is not possible to draw conclusions regarding the prevalence of target diseases from the frequency of documented findings in the check-up booklets. In order to make the data both comparable and evaluable, documentation must be digitalized in the future.

The role of evidence in humanitarian assessment: the Seed System Security Assessment and the Emergency Market Mapping and Analysis.

This paper reviews advances in the development and use of two evidence-based assessment toolkits: the Seed System Security Assessment (SSSA) and the Emergency Market Mapping and Analysis (EMMA). Both were created in the past five years and have been employed in a range of acute and chronic stress contexts across Africa, Asia, and parts of the Americas, in periods of civil strife, displacement, and drought, as well as following earthquakes, flooding, and political instability. The aims of this paper are threefold: to review advances with regard to each tool; to compare how each toolkit gathers and uses evidence, while considering possibilities for greater complementarity; and to reflect on the nature of 'evidence' used to guide humanitarian response in sudden-onset and chronic crisis situations. A comparison highlights the importance of triangulation and informed analysis for drawing conclusions from imperfect evidence, understanding the limitations of each assessment methodology, and confronting tacit assumptions.