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Synapse development and neuronal activity represent fundamental processes for the establishment of cognitive function. Structural organization as well as signalling pathways from receptor stimulation to gene expression regulation are mediated by synaptic activity and misregulated in neurodevelopmental disorders such as autism spectrum disorder (ASD) and intellectual disability (ID). Deleterious mutations in the PTCHD1 (Patched domain containing 1) gene have been described in male patients with X-linked ID and/or ASD. The structure of PTCHD1 protein is similar to the Patched (PTCH1) receptor; however, the cellular mechanisms and pathways associated with PTCHD1 in the developing brain are poorly determined. Here we show that PTCHD1 displays a C-terminal PDZ-binding motif that binds to the postsynaptic proteins PSD95 and SAP102. We also report that PTCHD1 is unable to rescue the canonical sonic hedgehog (SHH) pathway in cells depleted of PTCH1, suggesting that both proteins are involved in distinct cellular signalling pathways. We find that Ptchd1 deficiency in male mice (Ptchd1-/y ) induces global changes in synaptic gene expression, affects the expression of the immediate-early expression genes Egr1 and Npas4 and finally impairs excitatory synaptic structure and neuronal excitatory activity in the hippocampus, leading to cognitive dysfunction, motor disabilities and hyperactivity. Thus our results support that PTCHD1 deficiency induces a neurodevelopmental disorder causing excitatory synaptic dysfunction.

X-linked intellectual disability (XLID) is a clinically and genetically heterogeneous disorder. During the past two decades in excess of 100 X-chromosome ID genes have been identified. Yet, a large number of families mapping to the X-chromosome remained unresolved suggesting that more XLID genes or loci are yet to be identified. Here, we have investigated 405 unresolved families with XLID. We employed massively parallel sequencing of all X-chromosome exons in the index males. The majority of these males were previously tested negative for copy number variations and for mutations in a subset of known XLID genes by Sanger sequencing. In total, 745 X-chromosomal genes were screened. After stringent filtering, a total of 1297 non-recurrent exonic variants remained for prioritization. Co-segregation analysis of potential clinically relevant changes revealed that 80 families (20%) carried pathogenic variants in established XLID genes. In 19 families, we detected likely causative protein truncating and missense variants in 7 novel and validated XLID genes ( CLCN4 , CNKSR2 , FRMPD4, KLHL15 , LAS1L , RLIM and USP27X ) and potentially deleterious variants in 2 novel candidate XLID genes ( CDK16 and TAF1 ). We show that the CLCN4 and CNKSR2 variants impair protein functions as indicated by electrophysiological studies and altered differentiation of cultured primary neurons from Clcn4 −/− mice or after mRNA knock-down. The newly identified and candidate XLID proteins belong to pathways and networks with established roles in cognitive function and intellectual disability in particular. We suggest that systematic sequencing of all X-chromosomal genes in a cohort of patients with genetic evidence for X-chromosome locus involvement may resolve up to 58% of Fragile X-negative cases.

Rucci, JA and Tomporowski, PD. Three types of kinematic feedback and the execution of the hang power clean. J Strength Cond Res 24(3)771-778, 2010-The type and quality of feedback provided during instruction influences motor skill learning. The purpose of the study is to gain a better understanding of how altering feedback can impact discrete dynamic movements that are integral to strength training programs. The effects of 3 types of feedback on the execution hang power clean (4 sets of 4 repetitions at 75% of 1 repetition maximum) were evaluated over 6 training sessions. Nine different movement indices of the hang power clean were assessed using Dartfish video analysis software and comparisons among groups were made for each individually. Participantsʼ performance was predicted to benefit more from a combination of visual and verbal feedback cues than from visual feedback alone or verbal feedback alone. Results showed that 5 of the movement indices yielded a statistically significant interaction (p < 0.05). Analyses of movement form indicated that with training participants in both the video + cues group and the verbal-only group improved, whereas individuals in the video-only group did not. These results have implications for instructors seeking efficient methods of improving the way in which to teach female athletes to perform complex, dynamic, and technical movements through altering the type of feedback given.

Many in the field of human resources (HR) will admit that the profession is at a perilous crossroads - that the next 10 years will spell either the demise or the ascendancy of the profession. HR's focus should not be on surviving or strengthening its status. Instead, HR should begin today to take actions which will eventually eliminate itself in major organizations. The issue to consider is not demise versus ascendancy, but rather demise under what circumstances. Those in HR must: 1. Create change. 2. Develop principled leaders. 3. Promote economic literacy. 4. Center on the customer. 5. Maximize services/minimize staff. 6. Steward the values.

This article describes the HR Management System in place at Sears. Key emphases of Sears' HR management infrastructure include: 1. formulating and communicating a corporate mission, vision, and goals, 2. employee education and development through the Sear University, 3. performance management and incentive compensation systems linked closely to the firms strategy, 4. validated employee selection systems, and 5. delivering the \"HR Basics\" very competently. Key challenges for the future include: 1. maintaining momentum in the performance improvement process, 2. identifying barriers to success, and 3. clearly articulating HR's role in the change management process.

Much has been written and heralded over the past few years regarding the Human Resource (HR) profession having achieved strategic partner status in major organizations. If one presses the issue with objective practitioners off-therecord, however, most will admit that the profession is at a perilous crossroads--that the next ten years will spell either the demise or ascendancy...

There is an \"ancient principle\" from general systems theory which states, \"If any part of a system is growing faster than the rest of the system, it is only a matter of time until it is the system.\" Such is the relationship between health care costs in the United States (US) and the country's Gross National Product (GNP). Late in the 1960s the cost of health care in the US began to outstrip the growth rate of the GNP. Costs have increased from 7.3 percent of the GNP in 1970 to a projected 13.4 percent in 1992. US business's share of this bill--$186 billion in 1990--now exceeds...

Companies are searching desperately for relief from the costs involved in providing quality health care for their employees. For the past decade, these costs have been the fastest growing portion of gross national product. To ensure that programs were meeting the needs of employees, in 1984 IBM implemented utilization reviews, focusing on substance abuse and psychiatric care. It was found that cost could be contained effectively and the length of stays in facilities could be reduced, while still providing employees complete freedom in their choice of facility. IBM is pleased with the balanced changes it has made in its benefits plan design and their effectiveness in controlling cost increases. Equally important is the acceptance of the changes by employees and the effect of the changes on employee morale.