The forelimbs and hindlimbs of vertebrates are bilaterally symmetric. The mechanisms that ensure symmetric limb formation are unknown but they can be disrupted in disease. In Holt-Oram Syndrome (HOS), caused by mutations in TBX5, affected individuals have left-biased upper/forelimb defects. We demonstrate a role for the transcription factor Tbx5 in ensuring the symmetric formation of the left and right forelimb. In our mouse model, bilateral hypomorphic levels of Tbx5 produces asymmetric forelimb defects that are consistently more severe in the left limb than the right, phenocopying the left-biased limb defects seen in HOS patients. In Tbx hypomorphic mutants maintained on an INV mutant background, with situs inversus, the laterality of defects is reversed. Our data demonstrate an early, inherent asymmetry in the left and right limb-forming regions and that threshold levels of Tbx5 are required to overcome this asymmetry to ensure symmetric forelimb formation.

We dissect genetically a gene regulatory network, including the transcription factors Tbx4, Pitx1 and Isl1 that act cooperatively to establish the hindlimb bud and identify key differences in the pathways that initiate formation of the hindlimb and forelimb. Using live image analysis of limb mesenchyme cells undergoing chondrogenesis in micromass culture, we distinguish a series of changes in cellular behaviours and cohesiveness that are required for chondrogenic precursors to undergo differentiation. Furthermore, we provide evidence that the proximal hindlimb defects in the Tbx4 mutant result from a failure in the early differentiation step of chondroprogenitors into chondrocytes, providing a novel explanation for the origins of proximally-biased limb defects.

External and internal stressors have been found to adversely affect skin health and overall wellness. There is growing interest in the use of anti-inflammatory and antioxidant plant-derived ingredients, such as ashwagandha, saffron, l-theanine, and tocopherol, to mitigate the impact of these stressors. In this study, we evaluate the effectiveness of oral and topical products (InnerCalm and SuperCalm, respectively) that contain naturally derived ingredients on skin redness, skin pigmentation, sleep, and mood in healthy females with Fitzpatrick skin type 1–4 and self-perceived sensitive skin. Subjects were randomized to an oral (oral group), a topical (topical group), or a combination of both the oral and topical interventions (combined group). Standardized photography-based image analysis was used to assess skin redness and pigment. Self-assessments of mood and sleep were measured with the abbreviated profile of mood states (POMS) questionnaire, and the Pittsburgh sleep-quality index (PSQI), respectively. Assessments were made at the baseline, 1-week, 4-weeks, and 8-weeks of the intervention. The average facial redness decreased in the topical group at 8-weeks (p < 0.001) and in the combined group at 4-weeks (p < 0.05) and 8-weeks (p < 0.001), relative to the baseline. The average facial pigmentation decreased in the oral (p < 0.05) and combined (p < 0.05) cohorts at 8-weeks, relative to the baseline. The oral group exhibited an improvement in sleep quality at 1-week relative to the baseline (p < 0.05) and at 8-weeks relative to the baseline (p < 0.05). Finally, the combined group demonstrated improvement in fatigue (p < 0.01) and confusion (p < 0.05) at 8-weeks relative to the baseline, though total mood disturbance increased in all 3 groups over the course of the study. Measured outcomes relating to mood may be confounded with the timing of the study, which ran during the COVID pandemic. Overall, we demonstrate the role of oral and topical herbs and of nutraceuticals for skin health and wellness. Further research will be needed to elucidate synergistic effects in oral and topical combination regimens.

BackgroundKetoconazole (Keto), an antifungal drug and a common therapeutic option in the treatment of advanced prostate cancer, is known to cause reproductive dysfunctions. Like Keto, melatonin has antifungal and anticarcinogenic actions. Moreover, the hormone has been used to reverse the damaging effects of different toxicants on the reproductive system. Therefore, this study investigated the effects of Keto with/without melatonin on selected biomarkers in rats.MethodsForty rats of 10 animals per group were used in this study, which lasted for 6 weeks. The control group was administered with saline (0.1 mL/day), while group 2 was administered with Keto during the last 3 weeks of experiment; however, in groups 3 and 4, Keto was administered during the first 3 weeks; thereafter, they were administered with saline and melatonin, respectively, during the subsequent 3 weeks. Keto and melatonin were administered at 100 and 10 mg/kg b.w./day (p.o.), respectively.ResultsThe central effects of Keto are independent of the follicle stimulating hormone (FSH) and prolactin; however, relative to the control group, the drug significantly decreased the gonadotrophin releasing hormone (GNRH) and the luteinizing hormone (LH), substantiated by the corresponding significant decreases in sperm count and sperm morphology. Keto caused significant elevations in malondialdehyde (MDA) and lactate dehydrogenase (LDH) and a significant decrease in catalase (CAT) compared with the control group. Moreover, the drug triggered pro-inflammatory events. In group 3 (Keto recovery), MDA and uric acid levels were returned to the baseline (i.e. control), but not GNRH, LH, C-reactive protein (CRP), LDH, and CAT. Treatment with melatonin after Keto administration caused significant increases in FSH, LH, superoxide dismutase, total antioxidant capacity (TAC), sperm count, and sperm morphology but significant decreases in MDA and CRP, relative to groups 2 and 3.ConclusionsMelatonin ameliorates some biochemical alterations following ketoconazole administration.

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