Pharmacologic inhibition of mTORC1 mimics dietary protein restriction in a mouse model of lactation

Background:Understanding the mechanisms of N utilization for lactation can lead to improved requirement estimates and increased efficiency,which modern dairy diets currently fail to maximize.The mechanistic target of rapamycin complex 1(mTORC1)is a central hub of translation regulation,processing extra-and intra-cellular signals of nutrient availability and physiological state,such as amino acids and energy.We hypothesized that dietary amino acids regulate lactation through mTORC1,such that inhibition of mTORC1 will lead to decreased lactation performance when amino acids are not limiting.Our objectives were to assess lactation performance in lactating mice undergoing dietary and pharmacologic interventions designed to alter mTORC1 activity.Methods:First lactation mice(N=18;n=6/treatment)were fed an adequate protein diet(18%crude protein),or an isocaloric protein-restricted diet(9%crude protein)from the day after parturition until lactation day 13.A third group of mice was fed an adequate protein diet and treated with the mTORC1 inhibitor rapamycin(4 mg/kg every other day)intraperitoneally,with the first two groups treated with vehicle as control.Dams and pups were weighed daily,and feed intake was recorded every other day.Milk production was measured every other day beginning on lactation day 4 by the weigh-suckle-weigh method.Tissues were collected after fasting and refeeding.Results:Milk production and pup weight were similarly decreased by both protein restriction and rapamycin treatment,with final production at 50%of control(P=0.008)and final pup weight at 85%of control(P<0.001).Mammary phosphorylation of mTORC1’s downstream targets were decreased by protein restriction and rapamycin treatment(P<0.05),while very little effect was observed in the liver of rapamycin treated mice,and none by protein restriction.Conclusions:Overall,sufficient supply of dietary amino acids was unable to maintain lactation performance status in mice with pharmacologically reduced mammary mTORC1 activity,as evidenced by diminished pup growth and milk production,supporting the concept that mTORC1 activation rather than substrate supply is the primary route by which amino acids regulate synthesis of milk components.

From potential to practice: how accelerating access to HPV tests and screen and treat programmes can help eliminate cervical cancer

Human papillomavirus(HPV)vaccination campaigns to prevent cervical cancer are being considered and implemented in countries around the world.While vaccination will protect future generations,it will not help the millions of women currently infected,leading to an estimated 311000 deaths per year globally.This paper examines a selection of strategies that when applied to both existing and new technologies,could accelerate access to HPV testing.Authors from the US Agency for International Development,the National Institutes of Health,and the Bridge to Health Medical and Dental,a non-governmental organisation,joined forces to propose a scalable and country-directed solution for preventing cervical cancer using an end-to end approach.Collectively,the authors offer seven evidence-based strategies,that when used alone or in combination have the ability to reduce HPV-caused cervical cancer deaths and disability.These strategies include(1)consistent HPV test intervals to decrease HPV DNA test costs;(2)exploring market shaping opportunities;(3)employing iterative user research methodologies like human-centred design;(4)target product profiles for new HPV tests;(5)encouraging innovation around cervical cancer screen and treat programmes;(6)developing national cancer control plans;and(7)integrating cervical cancer screen and treat services into existing infrastructure.By using the strategies outlined here,in combination with HPV vaccination campaigns,national governments will be able to scale and expand cervical cancer screening programmes and provide evidence-based treatment programmes for HPV-infected women.