Circadian rhythm and light

قَالَ مُوسَىٰٓ أَتَقُولُونَ لِلۡحَقِّ لَمَّا جَآءَكُمۡۖ أَسِحۡرٌ هَٰذَا وَلَا يُفۡلِحُ ٱلسَّٰحِرُونَ

Moses said, ‘Is this what you say about the Truth when it comes to you? Is this sorcery? Sorcerers never prosper.’

فَلَمَّا جَآءَ ٱلسَّحَرَةُ قَالَ لَهُم مُّوسَىٰٓ أَلۡقُواْ مَآ أَنتُم مُّلۡقُونَ

When the sorcerers came, Moses said to them, ‘Throw down whatever you have.’

فَلَمَّآ أَلۡقَوۡاْ قَالَ مُوسَىٰ مَا جِئۡتُم بِهِ ٱلسِّحۡرُۖ إِنَّ ٱللَّهَ سَيُبۡطِلُهُۥٓ إِنَّ ٱللَّهَ لَا يُصۡلِحُ عَمَلَ ٱلۡمُفۡسِدِينَ

When they did so, Moses said, ‘Everything you have brought is sorcery and God will show it to be false. God does not make the work of mischief-makers right

وَٱتَّبَعُواْ مَا تَتۡلُواْ ٱلشَّيَٰطِينُ عَلَىٰ مُلۡكِ سُلَيۡمَٰنَۖ وَمَا كَفَرَ سُلَيۡمَٰنُ وَلَٰكِنَّ ٱلشَّيَٰطِينَ كَفَرُواْ يُعَلِّمُونَ ٱلنَّاسَ ٱلسِّحۡرَ وَمَآ أُنزِلَ عَلَى ٱلۡمَلَكَيۡنِ بِبَابِلَ هَٰرُوتَ وَمَٰرُوتَۚ وَمَا يُعَلِّمَانِ مِنۡ أَحَدٍ حَتَّىٰ يَقُولَآ إِنَّمَا نَحۡنُ فِتۡنَةࣱ فَلَا تَكۡفُرۡۖ فَيَتَعَلَّمُونَ مِنۡهُمَا مَا يُفَرِّقُونَ بِهِۦ بَيۡنَ ٱلۡمَرۡءِ وَزَوۡجِهِۦۚ وَمَا هُم بِضَآرِّينَ بِهِۦ مِنۡ أَحَدٍ إِلَّا بِإِذۡنِ ٱللَّهِۚ وَيَتَعَلَّمُونَ مَا يَضُرُّهُمۡ وَلَا يَنفَعُهُمۡۚ وَلَقَدۡ عَلِمُواْ لَمَنِ ٱشۡتَرَىٰهُ مَا لَهُۥ فِي ٱلۡأٓخِرَةِ مِنۡ خَلَٰقࣲۚ وَلَبِئۡسَ مَا شَرَوۡاْ بِهِۦٓ أَنفُسَهُمۡۚ لَوۡ كَانُواْ يَعۡلَمُونَ

and followed what the evil ones had fabricated about the Kingdom of Solomon instead. Not that Solomon himself was a disbeliever; it was the evil ones who were disbelievers. They taught people witchcraft and what was revealed in Babylon to the two angels Harut and Marut. Yet these two never taught anyone without first warning him, ‘We are sent only to tempt- do not disbelieve.’ From these two, they learned what can cause discord between man and wife, although they harm no one with it except by God’s leave. They learned what harmed them, not what benefited them, knowing full well that whoever gained [this knowledge] would lose any share in the Hereafter. Evil indeed is the [price] for which they sold their souls, if only they knew

وَجَآءَ ٱلسَّحَرَةُ فِرۡعَوۡنَ قَالُوٓاْ إِنَّ لَنَا لَأَجۡرًا إِن كُنَّا نَحۡنُ ٱلۡغَٰلِبِينَ

The sorcerers came to Pharaoh and said, ‘Shall we be rewarded if we win?’

وَأُلۡقِيَ ٱلسَّحَرَةُ سَٰجِدِينَ

The sorcerers fell to their knees

(And follow that which the devils falsely related against the kingdom of Solomon�) [2:102]. Muhammad ibn 'Abd al-'Aziz al-Qantari informed us> Abu'l-Fadl al-Haddadi> Abu Yazid al-Khalidi> Ishaq ibn Ibrahim> Jarir> Husayn ibn 'Abd al-Rahman> 'Imran ibn al-Harith who said: �Once as we were sitting with Ibn 'Abbas when he said: 'The devils used to eavesdrop on heaven. One of them would bring a word of truth from therein, and when he is trusted for telling the truth, he would add to it seventy lies with which he earns the hearts of people. When Solomon came to know about it, he took it and buried it beneath his throne. When he died, a devil stood in the street and said: 'Shall I guide you to Solomon's guarded treasure, the like of which he does not have?' They said: 'Yes, do'. He said: 'It is under his throne; go and unearth it'. They said: 'This is magic'. Different nations then copied it f

And they follow wa’ttaba‘ū is a supplement to nabadha ‘it cast away’ what the devils used to relate during the time of Solomon’s kingdom in the way of sorcery it is said that they the devils buried these books of sorcery underneath his throne when his kingdom was taken from him; it is also said that they used to listen stealthily and add fabrications to what they heard and then pass it on to the priests who would compile it in books; this would be disseminated and rumours spread that the jinn had knowledge of the Unseen. Solomon gathered these books and buried them. When he died the devils showed people where these books were and the latter brought them out and found that they contained sorcery and said ‘Your kingdom was only thanks to what is in here’; they then took to learning them and rejected the Scriptures of their prophets. In order to demonstrate Solomon’s innocence and in repudi

And the sorcerers came to Pharaoh saying ‘Surely a-inna read pronouncing both hamzas or by not pronouncing the second one but inserting an alif between the two in both cases there will be a wage for us if we are the victors?’

And the sorcerers fell down in prostration.

And so the sorcerers came to Fir'awn. They said: "Indeed there will be a (good) reward for us if we are the victors. (113)He said: "Yes, and moreover you will (in that case) be of the nearest (to me). (114) The Magicians convene and change Their Ropes into Snakes before Musa Allah describes the conversation that took place between Fir'awn and the magicians he collected to defeat Musa, peace be upon him. Fir'awn told them that he will reward them and give them tremendous provisions. He made them hope in acquiring what they wished for and to make them among his private audience and best associates. When they were assured of the cursed Fir'awn's promises,

And We revealed to Musa (saying): "Throw your stick," and behold! It swallowed up straight away all the falsehood which they showed (117)Thus truth was confirmed, and all that they did was made of no effect (118)So they were defeated there and returned disgraced (119)And the sorcerers fell down prostrate (120)They said: "We believe in the Lord of all that exists (121)"The Lord of Musa and Harun. (122) Musa defeats the Magicians, Who believe in Him Allah states that at that tremendous moment, in which Allah differentiated between Truth and Falsehood, He sent a revelation to His servant and Messenger Musa, peace be upon him, ordering him to throw the stick that he held in his right hand, فَإِذَا هِيَ تَلْقَفُ (It swallowed straight away) and devoured, مَا يَأْفِكُونَ (all the falsehood which they showed.) the magic that they caused the illusion with, of magic with which they caused m

حَدَّثَنَا أَبُو نُعَيْمٍ، قَالَ حَدَّثَنَا سُفْيَانُ، عَنِ الأَسْوَدِ، قَالَ سَمِعْتُ جُنْدَبًا، يَقُولُ اشْتَكَى النَّبِيُّ صلى الله عليه وسلم فَلَمْ يَقُمْ لَيْلَةً أَوْ لَيْلَتَيْنِ‏.‏

Narrated Jundab:The Prophet (ﷺ) became sick and did not get up (for Tahajjud prayer) for a night or two

حَدَّثَنَا ابْنُ مُقَاتِلٍ، أَخْبَرَنَا عَبْدُ اللَّهِ، أَخْبَرَنَا مَعْمَرٌ، عَنِ الزُّهْرِيِّ، عَنْ هِنْدٍ بِنْتِ الْحَارِثِ، عَنْ أُمِّ سَلَمَةَ ـ رضى الله عنها ـ أَنَّ النَّبِيَّ صلى الله عليه وسلم اسْتَيْقَظَ لَيْلَةً فَقَالَ ‏ "‏ سُبْحَانَ اللَّهِ مَاذَا أُنْزِلَ اللَّيْلَةَ مِنَ الْفِتْنَةِ، مَاذَا أُنْزِلَ مِنَ الْخَزَائِنِ مَنْ يُوقِظُ صَوَاحِبَ الْحُجُرَاتِ، يَا رُبَّ كَاسِيَةٍ فِي الدُّنْيَا عَارِيَةٍ فِي الآخِرَةِ ‏"‏‏.‏

Narrated Um Salama:One night the Prophet (ﷺ) got up and said, "Subhan Allah! How many afflictions Allah has revealed tonight and how many treasures have been sent down (disclosed). Go and wake the sleeping lady occupants of these dwellings up (for prayers), perhaps a well dressed in this world may be naked in the Hereafter

حَدَّثَنَا عَبْدُ اللَّهِ بْنُ مَسْلَمَةَ، قَالَ قَرَأْتُ عَلَى مَالِكٍ عَنِ ابْنِ شِهَابٍ، أَنَّ عُمَرَ بْنَ عَبْدِ الْعَزِيزِ، أَخَّرَ الصَّلاَةَ يَوْمًا، فَدَخَلَ عَلَيْهِ عُرْوَةُ بْنُ الزُّبَيْرِ، فَأَخْبَرَهُ أَنَّ الْمُغِيرَةَ بْنَ شُعْبَةَ أَخَّرَ الصَّلاَةَ يَوْمًا وَهْوَ بِالْعِرَاقِ، فَدَخَلَ عَلَيْهِ أَبُو مَسْعُودٍ الأَنْصَارِيُّ فَقَالَ مَا هَذَا يَا مُغِيرَةُ أَلَيْسَ قَدْ عَلِمْتَ أَنَّ جِبْرِيلَ نَزَلَ فَصَلَّى، فَصَلَّى رَسُولُ اللَّهِ صلى الله عليه وسلم ثُمَّ صَلَّى فَصَلَّى رَسُولُ اللَّهِ صلى الله عليه وسلم ثُمَّ صَلَّى فَصَلَّى رَسُولُ اللَّهِ صلى الله عليه وسلم ثُمَّ صَلَّى فَصَلَّى رَسُولُ اللَّهِ صلى الله عليه وسلم ثُمَّ صَلَّى فَصَلَّى رَسُولُ اللَّهِ صلى الله عليه وسلم ثُمَّ قَالَ ‏ "‏ بِهَذَا أُمِرْتُ ‏"‏‏.‏ فَقَالَ عُمَرُ لِعُرْوَةَ اعْلَمْ مَا تُحَدِّثُ أَوَإِنَّ جِبْرِيلَ هُوَ أَقَامَ لِرَسُولِ اللَّهِ صلى الله عليه وسلم وَقْتَ الصَّلاَةِ‏.‏ قَالَ عُرْوَةُ كَذَلِكَ كَانَ بَشِيرُ بْنُ أَبِي مَسْعُودٍ يُحَدِّثُ عَنْ أَبِيهِ‏.‏ قَالَ عُرْوَةُ وَلَقَدْ حَدَّثَتْنِي عَائِشَةُ، أَنَّ رَسُولَ اللَّهِ صلى الله عليه وسلم كَانَ يُصَلِّي الْعَصْرَ، وَالشَّمْسُ فِي حُجْرَتِهَا قَبْلَ أَنْ تَظْهَرَ‏.‏

Narrated Ibn Shihab:Once `Umar bin `Abdul `Aziz delayed the prayer and `Urwa bin Az-Zubair went to him and said, "Once in 'Iraq, Al-Mughira bin Shu`ba delayed his prayers and Abi Mas`ud Al-Ansari went to him and said, 'O Mughira! What is this? Don't you know that once Gabriel came and offered the prayer (Fajr prayer) and Allah's Messenger (ﷺ) prayed too, then he prayed again (Zuhr prayer) and so did Allah's Apostle and again he prayed (`Asr prayers and Allah's Messenger (ﷺ) did the same; again he prayed (Maghrib-prayer) and so did Allah's Messenger (ﷺ) and again prayed (`Isha prayer) and so did Allah's Apostle and (Gabriel) said, 'I was ordered to do so (to demonstrate the prayers prescribed to you)?'" `Umar (bin `Abdul `Aziz) said to `Urwa, "Be sure of what you Say. Did Gabriel lead Allah's Messenger (ﷺ) at the stated times of the prayers?" `Urwa replied, "Bashir bin Abi Mas`ud narrated like this on the authority of his father." `Urwa added, "Aisha told me that Allah's Messenger (ﷺ) used to pray `Asr prayer when the sunshine was still inside her residence (during the early time of `Asr)

حَدَّثَنَا قُتَيْبَةُ بْنُ سَعِيدٍ، قَالَ حَدَّثَنَا عَبَّادٌ ـ هُوَ ابْنُ عَبَّادٍ ـ عَنْ أَبِي جَمْرَةَ، عَنِ ابْنِ عَبَّاسٍ، قَالَ قَدِمَ وَفْدُ عَبْدِ الْقَيْسِ عَلَى رَسُولِ اللَّهِ صلى الله عليه وسلم فَقَالُوا إِنَّا مِنْ هَذَا الْحَىِّ مِنْ رَبِيعَةَ، وَلَسْنَا نَصِلُ إِلَيْكَ إِلاَّ فِي الشَّهْرِ الْحَرَامِ، فَمُرْنَا بِشَىْءٍ نَأْخُذْهُ عَنْكَ، وَنَدْعُو إِلَيْهِ مَنْ وَرَاءَنَا‏.‏ فَقَالَ ‏ "‏ آمُرُكُمْ بِأَرْبَعٍ، وَأَنْهَاكُمْ عَنْ أَرْبَعٍ الإِيمَانِ بِاللَّهِ ـ ثُمَّ فَسَّرَهَا لَهُمْ شَهَادَةُ أَنْ لاَ إِلَهَ إِلاَّ اللَّهُ، وَأَنِّي رَسُولُ اللَّهِ، وَإِقَامُ الصَّلاَةِ، وَإِيتَاءُ الزَّكَاةِ، وَأَنْ تُؤَدُّوا إِلَىَّ خُمُسَ مَا غَنِمْتُمْ، وَأَنْهَى عَنِ الدُّبَّاءِ وَالْحَنْتَمِ وَالْمُقَيَّرِ وَالنَّقِيرِ ‏"‏‏.‏

Narrated Ibn `Abbas:"Once a delegation of `Abdul Qais came to Allah's Messenger (ﷺ) and said, "We belong to such and such branch of the tribe of Rabi'ah and we can only come to you in the sacred months. Order us to do something good so that we may take it from you and also invite to it those whom we have left behind (at home)." So he said, "I order you to do four things and forbid you from four things: To believe in Allah" - and then he explained it to them "to testify that none has the right to be worshipped but Allah and that I am Allah's Messenger (ﷺ), to establish the prayers (at the stated times), to pay the Zakat (obligatory charity), to hand me the Khumus (fifth) if you acquire spoils of war. And I forbid from (using) Dubba, Hantam, Muqaiyyar, and Naqir (all these were utensils used for the preparation of alcoholic drinks)

أَخْبَرَنَا قُتَيْبَةُ، قَالَ حَدَّثَنَا اللَّيْثُ بْنُ سَعْدٍ، عَنِ ابْنِ شِهَابٍ، أَنَّ عُمَرَ بْنَ عَبْدِ الْعَزِيزِ، أَخَّرَ الْعَصْرَ شَيْئًا فَقَالَ لَهُ عُرْوَةُ أَمَا إِنَّ جِبْرِيلَ عَلَيْهِ السَّلاَمُ قَدْ نَزَلَ فَصَلَّى أَمَامَ رَسُولِ اللَّهِ صلى الله عليه وسلم ‏.‏ فَقَالَ عُمَرُ اعْلَمْ مَا تَقُولُ يَا عُرْوَةُ ‏.‏ فَقَالَ سَمِعْتُ بَشِيرَ بْنَ أَبِي مَسْعُودٍ يَقُولُ سَمِعْتُ أَبَا مَسْعُودٍ يَقُولُ سَمِعْتُ رَسُولَ اللَّهِ صلى الله عليه وسلم يَقُولُ ‏ "‏ نَزَلَ جِبْرِيلُ فَأَمَّنِي فَصَلَّيْتُ مَعَهُ ثُمَّ صَلَّيْتُ مَعَهُ ثُمَّ صَلَّيْتُ مَعَهُ ثُمَّ صَلَّيْتُ مَعَهُ ثُمَّ صَلَّيْتُ مَعَهُ ‏"‏ ‏.‏ يَحْسُبُ بِأَصَابِعِهِ خَمْسَ صَلَوَاتٍ ‏.‏

It was narrated from Ibn Shihab that 'Umar bin 'Abdul-'Aziz delayed the 'Asr prayer a little. 'Urwah said to him:"Jibril came down and led the Messenger of Allah (ﷺ) in prayer." 'Umar said: "Watch what you are saying, O 'Urwah!" He said: "I heard Bashir bin Abi Mas'ud say: 'I heard Abu Mas'ud say: "I heard the Messenger of Allah (ﷺ) say: 'Jibril came down and led me in prayer, and I prayed with him, then I prayed with him, then I prayed with him, then I prayed with him, then I prayed with him - and he counted off five prayers on his fingers

أَخْبَرَنَا مُحَمَّدُ بْنُ عَبْدِ الأَعْلَى، قَالَ حَدَّثَنَا خَالِدٌ، قَالَ حَدَّثَنَا شُعْبَةُ، قَالَ حَدَّثَنَا سَيَّارُ بْنُ سَلاَمَةَ، قَالَ سَمِعْتُ أَبِي يَسْأَلُ أَبَا بَرْزَةَ، عَنْ صَلاَةِ، رَسُولِ اللَّهِ صلى الله عليه وسلم قُلْتُ أَنْتَ سَمِعْتَهُ قَالَ كَمَا أَسْمَعُكَ السَّاعَةَ فَقَالَ سَمِعْتُ أَبِي يَسْأَلُ عَنْ صَلاَةِ رَسُولِ اللَّهِ صلى الله عليه وسلم قَالَ كَانَ لاَ يُبَالِي بَعْضَ تَأْخِيرِهَا - يَعْنِي الْعِشَاءَ - إِلَى نِصْفِ اللَّيْلِ وَلاَ يُحِبُّ النَّوْمَ قَبْلَهَا وَلاَ الْحَدِيثَ بَعْدَهَا ‏.‏ قَالَ شُعْبَةُ ثُمَّ لَقِيتُهُ بَعْدُ فَسَأَلْتُهُ قَالَ كَانَ يُصَلِّي الظُّهْرَ حِينَ تَزُولُ الشَّمْسُ وَالْعَصْرَ يَذْهَبُ الرَّجُلُ إِلَى أَقْصَى الْمَدِينَةِ وَالشَّمْسُ حَيَّةٌ وَالْمَغْرِبَ لاَ أَدْرِي أَىَّ حِينٍ ذَكَرَ ثُمَّ لَقِيتُهُ بَعْدُ فَسَأَلْتُهُ فَقَالَ وَكَانَ يُصَلِّي الصُّبْحَ فَيَنْصَرِفُ الرَّجُلُ فَيَنْظُرُ إِلَى وَجْهِ جَلِيسِهِ الَّذِي يَعْرِفُهُ فَيَعْرِفُهُ ‏.‏ قَالَ وَكَانَ يَقْرَأُ فِيهَا بِالسِّتِّينَ إِلَى الْمِائَةِ ‏.‏

Shu'bah said:"Sayyar bin Salamah, narrated to us, he said: 'I heard my father ask Abu Barzah about the prayer of the Messenger of Allah (ﷺ).' I said: 'Did you really hear him?' He said: 'As I can hear you now.' He said: 'I heard my father ask about the prayer of the Messenger of Allah (ﷺ).' He said: 'He would not mind if he delayed it - meaning 'Isha' until midnight, and he did not like to sleep before it or speak after it.'" Shu'bah said: "Then I met him later on and asked him. He said: 'He used to pray Zauhr when the sun had passed its zenith, and (he would pray) 'Asr and a man could walk to the farthest point in Al-Madinah and the sun would still be clear and hot. And Maghrib, I do not know the time he mentioned.' After that I met him and asked him, and he said: 'He used to pray Fajr then after the prayer a man could regarding it, sitting next to him, look at the face of someone he knew and he could recognize it.' He said: 'And he used to recite in it between sixty and one hundred (verses)

وعبادته التي هو مشغول بها لا ينتقل إلى غيرها ولا يفتر عنها لا يستكبرون عن عبادته ولا يستحسرون يسبحون الليل والنهار لا يفترون ومفتاح مزيد الدرجات هي الصلوات

وينبغي أن لا ينفصل من طرف عرفة إلا بعد الغروب ليجمع في عرفة بين الليل والنهار وإن أمكنه الوقوف يوم الثامن ساعة عند إمكان الغلط في الهلال فهو الحزم وبه الأمن من الفوات

الباب الأول في فضيلة الأوراد وترتيبها في الليل والنهار

يشير إلى أنه غير متطلع إلى الأوقات بل هو مع الذي يقدر الليل والنهار

فهذا سؤال جاهل ظالم ضال مفرط في الجهل والظلم والضلال لأن خلق الأضداد والمتقابلات هو من كمال الربوبية كالليل والنهار والحر والبرد واللذة والألم والخير والشر والنعيم والجحيم

خلفة لمن أراد أن يذكر أو أراد شكورا} [الفرقان: 62]، أي يخلف أحدهما الآخر ليتدارك في أحدهما ما فات في الآخر. ### $ 2 - بيان عدد أوراد الليل والنهار وترتيبها

Diagnosis of circadian rhythm sleep disorders.: Insomnia and excessive sleepiness are common in the investigation of sleep-disordered breathing. Circadian rhythm sleep disorders are perhaps the most often overlooked conditions in the differential diagnosis of these symptoms. Circadian rhythm sleep disorders manifest as misalignment between the sleep period and the physical/social 24-h environmental cycle. The two most prevalent circadian rhythm sleep disorders are delayed sleep phase (common in adolescents) and advanced sleep phase (common in

Intrinsic circadian period of sighted patients with circadian rhythm sleep disorder, free-running type.: Background: Circadian rhythm sleep disorder, free-running type (FRT), is an intractable sleep disorder in which sleep and wake times progressively delay each day even in normal living environments. This disorder severely affects the social functioning of patients because of periodic nighttime insomnia, excessive daytime sleepiness, and a high rate of comorbid psychiatric disorders. Although abnormal regulation of the biological clock is suspected, the pathophysiology of FRT has yet to be elucida

Identification of a Preliminary Plasma Metabolome-based Biomarker for Circadian Phase in Humans.: Measuring individual circadian phase is important to diagnose and treat circadian rhythm sleep-wake disorders and circadian misalignment, inform chronotherapy, and advance circadian science. Initial findings using blood transcriptomics to predict the circadian phase marker dim-light melatonin onset (DLMO) show promise. Alternatively, there are limited attempts using metabolomics to predict DLMO and no known omics-based biomarkers predict dim-light melatonin offset (DLMOff). We analyzed the human

Home dim light melatonin onsets with measures of compliance in delayed sleep phase disorder.: The dim light melatonin onset (DLMO) assists with the diagnosis and treatment of circadian rhythm sleep disorders. Home DLMOs are attractive for cost savings and convenience, but can be confounded by home lighting and sample timing errors. We developed a home saliva collection kit with objective measures of light exposure and sample timing. We report on our first test of the kit in a clinical population. Thirty-two participants with delayed sleep phase disorder (DSPD; 17 women, aged 18-52 years)

A randomized controlled trial with bright light and melatonin for the treatment of delayed sleep phase disorder: effects on subjective and objective sleepiness and cognitive function.: Delayed sleep phase disorder (DSPD) is a circadian rhythm sleep disorder. Patients with DSPD have problems initiating sleep if they go to bed at a conventional time, and they often have problems waking at desired times. If they rise early in the morning, they usually experience severe sleepiness during morning hours. In the present study, we investigated the short- and long-term effects on measures of subjective and objective sleepiness and cognitive function of bright light and melatonin treatm

Light-induced changes of the circadian clock of humans: increasing duration is more effective than increasing light intensity.: Study objectives: To evaluate the effect of increasing the intensity and/or duration of exposure on light-induced changes in the timing of the circadian clock of humans. Design: Multifactorial randomized controlled trial, between and within subject design Setting: General Clinical Research Center (GCRC) of an academic medical center Participants: 56 healthy young subjects (20-40 years of age) Interventions: Research subjects were admitted for 2 independent stays of 4 nights/3 days for treatment

Changes in the diurnal rhythms during a 45-day head-down bed rest.

In spaceflight human circadian rhythms and sleep patterns are likely subject to change, which consequently disturbs human physiology, cognitive abilities and performance efficiency. However, the influence of microgravity on sleep and circadian clock as well as the underlying mechanisms remain largely unknown. Placing volunteers in a prone position, whereby their heads rest at an angle of -6° below horizontal, mimics the microgravity environment in orbital flight. Such positioning is termed head-down bed rest (HDBR). In this work, we analysed the influence of a 45-day HDBR on physiological diurnal rhythms. We examined urinary electrolyte and hormone excretion, and the results show a dramatic elevation of cortisol levels during HDBR and recovery. Increased diuresis, melatonin and testosterone were observed at certain periods during HDBR. In addition, we investigated the changes in urinatio…

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Environmental perturbation of the circadian clock disrupts pregnancy in the mouse.

Background: The circadian clock has been linked to reproduction at many levels in mammals. Epidemiological studies of female shift workers have reported increased rates of reproductive abnormalities and adverse pregnancy outcomes, although whether the cause is circadian disruption or another factor associated with shift work is unknown. Here we test whether environmental disruption of circadian rhythms, using repeated shifts of the light:dark (LD) cycle, adversely affects reproductive success in mice. Methodology/principal findings: Young adult female C57BL/6J (B6) mice were paired with B6 males until copulation was verified by visual identification of vaginal plug formation. Females were then randomly assigned to one of three groups: control, phase-delay or phase-advance. Controls remained on a constant 12-hr light:12-hr dark cycle, whereas phase-delayed and phase-advanced mice were sub…

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Circadian regulation of intracellular G-protein signalling mediates intercellular synchrony and rhythmicity in the suprachiasmatic nucleus.

Synchronous oscillations of thousands of cellular clocks in the suprachiasmatic nucleus (SCN), the circadian centre, are coordinated by precisely timed cell-cell communication, the principle of which is largely unknown. Here we show that the amount of RGS16 (regulator of G protein signalling 16), a protein known to inactivate Gαi, increases at a selective circadian time to allow time-dependent activation of intracellular cyclic AMP signalling in the SCN. Gene ablation of Rgs16 leads to the loss of circadian production of cAMP and as a result lengthens circadian period of behavioural rhythm. The temporally precise regulation of the cAMP signal by clock-controlled RGS16 is needed for the dorsomedial SCN to maintain a normal phase-relationship to the ventrolateral SCN. Thus, RGS16-dependent temporal regulation of intracellular G protein signalling coordinates the intercellular synchrony of …

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Effect of intermittent fasting on circadian rhythms in mice depends on feeding time.

Calorie restriction (CR) resets circadian rhythms and extends life span. Intermittent fasting (IF) also extends life span, but its affect on circadian rhythms has not been studied. To study the effect of IF alongside CR, we imposed IF in FVB/N mice or IF combined with CR using the transgenic FVB/N alphaMUPA mice that, when fed ad libitum, exhibit spontaneously reduced eating and extended life span. Our results show that when food was introduced during the light period, body temperature peak was not disrupted. In contrast, IF caused almost arrhythmicity in clock gene expression in the liver and advanced mPer2 and mClock expression. However, IF restored the amplitudes of clock gene expression under disruptive light condition regardless whether the animals were calorically restricted or not. Unlike daytime feeding, nighttime feeding yielded rhythms similar to those generated during ad libit…

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Sleep and sensorimotor integration during early vocal learning in a songbird.

Behavioural studies widely implicate sleep in memory consolidation in the learning of a broad range of behaviours. During sleep, brain regions are reactivated, and specific patterns of neural activity are replayed, consistent with patterns observed in previous waking behaviour. Birdsong learning is a paradigmatic model system for skill learning. Song development in juvenile zebra finches (Taeniopygia guttata) is characterized by sleep-dependent circadian fluctuations in singing behaviour, with immediate post-sleep deterioration in song structure followed by recovery later in the day. In sleeping adult birds, spontaneous bursting activity of forebrain premotor neurons in the robust nucleus of the arcopallium (RA) carries information about daytime singing. Here we show that, in juvenile zebra finches, playback during the day of an adult 'tutor' song induced profound and tutor-song-specific…

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Healthy older adults better tolerate sleep deprivation than young adults.

Objectives: To determine whether healthy aging is associated with increased sleepiness and whether healthy older adults experience more sleepiness when acutely sleep deprived. Design: A 5-day inpatient circadian rhythm-sleep study consisting of 3 baseline nights followed by an extended 26-hour wake episode under constant conditions. Setting: Intensive Physiological Monitoring Unit, General Clinical Research Center, Brigham and Women's Hospital. Participants: Thirty-seven healthy participants without medical, psychological, or sleep disorders: 26 young (7 women, 19 men; mean age 21.9 +/- 3.3, range 18-29) and 11 "young-old" adults (3 women, 8 men; mean age 68.1 +/- 3.6, range 65-76). Intervention: An extended 26-hour wake episode under constant conditions. Measurements: Electroencephalographic-verified wakefulness, slow eye movements, sustained attention, subjective sleepiness. Results: D…

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Shift work disorder among oil rig workers in the North Sea.

Study objectives: Shift work disorder (SWD) is a circadian rhythm sleep disorder caused by work hours during the usual sleep period. The main symptoms are excessive sleepiness and insomnia temporally associated with the working schedule. The aim of the present study was to examine SWD among shift workers in the North Sea. Design and participants: A total of 103 shift workers (2 weeks on 7 nights/7days, 12-h shifts, 4 weeks off), mean age 39.8 years, working at an oil rig in the North Sea responded to a questionnaire about SWD. They also completed the Pittsburgh Sleep Quality Index, Bergen Insomnia Scale, Epworth Sleepiness Scale, Composite Morningness Questionnaire, Subjective Health Complaint Inventory, Demand/Control, and Instrumental Mastery Oriented Coping (based on the Utrecht Coping list). Most of these instruments were administered during the first day of the 2-week working period…

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Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in irritable bowel syndrome.

Enhanced stress responsiveness has been implicated as a potential mechanism contributing to the pathophysiology of irritable bowel syndrome (IBS), and should be reflected in altered function of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system. Both of these systems can modulate mucosal immune function. The aims of this study were: (i) to characterize the basal circadian rhythm of adrenocorticotropin hormone (ACTH) and cortisol in IBS vs healthy controls; (ii) to compare stimulated ACTH, cortisol and noradrenaline responses to a pelvic visceral stressor (sigmoidoscopy) in IBS and controls; and (iii) to correlate neuroendocrine responses with colonic mucosal cytokine expression and symptoms in IBS. Two separate studies were conducted in women. In Study 1, basal cortisol levels were analysed in 41 IBS and 25 controls using 24-h collections of plasma ACTH and …

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The prevalence of probable delayed-sleep-phase syndrome in students from junior high school to university in Tottori, Japan.

Delayed sleep phase syndrome (DSPS) is a circadian rhythm sleep disorder with a typical onset in the second decade of life. DSPS is characterized by the sleep-onset insomnia and the difficulty in waking at the desired time in the morning. Although DSPS is associated with inability to attend school, the prevalence has been controversial. To elucidate a change in the prevalence of DSPS among young population, epidemiological survey was conducted on Japanese students. A total of 4,971 students of junior high school, senior high school, and university were enrolled in this cross sectional study in Tottori Prefecture. They answered anonymous screening questionnaire regarding school schedule, sleep hygiene and symptomatic items of sleep disorders. The prevalence of probable DSPS was estimated at 0.48% among the total subject students without gender difference. In university, the prevalence of …

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Circadian rhythm disorganization produces profound cardiovascular and renal disease in hamsters.

Sleep deprivation, shift work, and jet lag all disrupt normal biological rhythms and have major impacts on health; however, circadian disorganization has never been shown as a causal risk factor in organ disease. We now demonstrate devastating effects of rhythm disorganization on cardiovascular and renal integrity and that interventions based on circadian principles prevent disease pathology caused by a short-period mutation (tau) of the circadian system in hamsters. The point mutation in the circadian regulatory gene, casein kinase-1epsilon, produces early onset circadian entrainment with fragmented patterns of behavior in +/tau heterozygotes. Animals die at a younger age with cardiomyopathy, extensive fibrosis, and severely impaired contractility; they also have severe renal disease with proteinuria, tubular dilation, and cellular apoptosis. On light cycles appropriate for their genoty…

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PPARalpha is a potential therapeutic target of drugs to treat circadian rhythm sleep disorders.

Recent progress at the molecular level has revealed that nuclear receptors play an important role in the generation of mammalian circadian rhythms. To examine whether peroxisome proliferator-activated receptor alpha (PPARalpha) is involved in the regulation of circadian behavioral rhythms in mammals, we evaluated the locomotor activity of mice administered with the hypolipidemic PPARalpha ligand, bezafibrate. Circadian locomotor activity was phase-advanced about 3h in mice given bezafibrate under light-dark (LD) conditions. Transfer from LD to constant darkness did not change the onset of activity in these mice, suggesting that bezafibrate advanced the phase of the endogenous clock. Surprisingly, bezafibrate also advanced the phase in mice with lesions of the suprachiasmatic nucleus (SCN; the central clock in mammals). The circadian expression of clock genes such as period2, BMAL1, and R…

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Factors influencing the magnitude and reproducibility of corticomotor excitability changes induced by paired associative stimulation.

Several paired-associative stimulation (PAS) protocols induce neuroplastic changes in human motor cortex (M1). To understand better the inherent variability of responses to PAS, we investigated the effectiveness and reproducibility of two PAS paradigms, and neurophysiological and experimental variables that may influence this. Motor evoked potentials (MEPs) were elicited by transcranial magnetic stimulation (TMS) of right M1, and recorded from surface EMG of left abductor pollicis brevis (APB) and first dorsal interosseous before and after PAS. PAS consisted of electrical stimulation of left median nerve paired with TMS over right M1 25 ms later. Twenty subjects were given one of two PAS protocols: short (132 paired stimuli at 0.2 Hz) or long (90 paired stimuli at 0.05 Hz), and were re-tested with the same protocol on 3 separate occasions, with 11 subjects tested in the morning and 9 in …

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Biochemical, molecular and behavioral phenotypes of Rab3A mutations in the mouse.

Ras-associated binding (Rab) protein 3A is a neuronal guanosine triphosphate (GTP)-binding protein that binds synaptic vesicles and regulates synaptic transmission. A mouse mutant, earlybird (Ebd), with a point mutation in the GTP-binding domain of Rab3A (D77G), exhibits anomalies in circadian behavior and homeostatic response to sleep loss. Here, we show that the D77G substitution in the Ebd allele causes reduced GTP and GDP binding, whereas GTPase activity remains intact, leading to reduced protein levels of both Rab3A and rabphilin3A. Expression profiling of the cortex and hippocampus of Ebd and Rab3a-deficient mice revealed subtle differences between wild-type and mutant mice. Although mice were backcrossed for three generations to a C57BL/6J background, the most robust changes at the transcriptional level between Rab3a(-/-) and Rab3a(+/+) mice were represented by genes from the 129/…

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Suggestive evidence for association of the circadian genes PERIOD3 and ARNTL with bipolar disorder.

Bipolar affective disorder (BPAD) is suspected to arise in part from malfunctions of the circadian system, a system that enables adaptation to a daily and seasonally cycling environment. Genetic variations altering functions of genes involved with the input to the circadian clock, in the molecular feedback loops constituting the circadian oscillatory mechanism itself, or in the regulatory output systems could influence BPAD as a result. Several human circadian system genes have been identified and localized recently, and a comparison with linkage hotspots for BPAD has revealed some correspondences. We have assessed evidence for linkage and association involving polymorphisms in 10 circadian clock genes (ARNTL, CLOCK, CRY2, CSNK1epsilon, DBP, GSK3beta, NPAS2, PER1, PER2, and PER3) to BPAD. Linkage analysis in 52 affected families showed suggestive evidence for linkage to CSNK1epsilon. Thi…

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Effect of aripiprazole on non-24-hour sleep-wake rhythm disorder comorbid with major depressive disorder: a case report.

Background: Patients with non-24-hour sleep-wake rhythm disorder (N24SWD) exhibit a sleep pattern that is asynchronous with the external light-dark cycle, typically involving a cycling, relapsing-remitting pattern of sleep disturbances, including nighttime insomnia and daytime sleepiness. Here, we report the case of a patient with N24SWD comorbid with major depressive disorder, who was successfully treated with a low dose of aripiprazole. Case presentation: A 47-year-old female presented with an 8-year complaint of difficulty falling asleep and waking up in the morning. The patient was diagnosed with major depressive disorder at the age of 35 years and was treated with various antidepressants since that time. At the age of 40 years, the patient's sleep-wake cycle began to extend without exacerbation of depressive symptoms. The patient was diagnosed with N24SWD at the age of 43 years. Ram…

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Non-24-Hour Sleep-Wake Disorder Revisited - A Case Study.

The human sleep-wake cycle is governed by two major factors: a homeostatic hourglass process (process S), which rises linearly during the day, and a circadian process C, which determines the timing of sleep in a ~24-h rhythm in accordance to the external light-dark (LD) cycle. While both individual processes are fairly well characterized, the exact nature of their interaction remains unclear. The circadian rhythm is generated by the suprachiasmatic nucleus ("master clock") of the anterior hypothalamus, through cell-autonomous feedback loops of DNA transcription and translation. While the phase length (tau) of the cycle is relatively stable and genetically determined, the phase of the clock is reset by external stimuli ("zeitgebers"), the most important being the LD cycle. Misalignments of the internal rhythm with the LD cycle can lead to various somatic complaints and to the development …

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Sleep disturbances in obsessive-compulsive disorder: Association with non-response to repetitive transcranial magnetic stimulation (rTMS).

Background Repetitive transcranial magnetic stimulation (rTMS) is a promising augmentation strategy for treatment-refractory OCD. However, a substantial group still fails to respond. Sleep disorders, e.g. circadian rhythm sleep disorders (CRSD), are highly prevalent in OCD and might mediate treatment response. The aims of the current study were to compare sleep disturbances between OCD patients and healthy subjects as well as between rTMS responders and non-responders, and most importantly to determine sleep-related predictors of rTMS non-response. Methods 22 OCD patients received at least 10 sessions rTMS combined with psychotherapy. Sleep disturbances were measured using questionnaires and actigraphy. Sleep in patients was compared to healthy subjects. Treatment response was defined as >35% reduction on YBOCS. Treatment response prediction models were based on measures of CRSD and inso…

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Development and Validation of an LC-MS/MS-Based Method for Quantifying Urinary Endogenous 6-Hydroxymelatonin.

Evaluation of endogenous melatonin (MEL) secretion using its urinary metabolites is useful for the treatment of circadian rhythm sleep disorders. The primary melatonin metabolites excreted in the urine are 6-hydroxymelatonin (6-O-MEL) sulfate (S-O-MEL) and 6-O-MEL glucuronate, which result from sequential MEL metabolism by phases I and II drug metabolizing enzymes. To determine the accurate MEL secretion level, these urinary metabolites should be enzymatically deconjugated and converted into MEL. Furthermore, the use of LC-tandem mass spectrometry (LC-MS/MS) is preferable for the precision of this determination. Therefore, as part of our ongoing efforts to ultimately determine the level of MEL secretion, we herein aimed to develop an LC-MS/MS-based quantification method for 6-O-MEL and optimize deconjugation conditions. We determined the LC-MS/MS conditions of 6-O-MEL measurement and opt…

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Pharmacological characterization of a highly selective and potent partial agonist of the MT₂ melatonin receptor.

Background/aims: The MT₂ melatonin receptor is a potential target for treating circadian rhythm sleep disorders. This study aims to characterize the recently identified MT₂ melatonin receptor agonist. Methods: The pharmacological properties of the MT₂ melatonin receptor-selective agonist as exemplified by compound 1 [N-(2-[7-benzyl-1,6-dihydro-2H-indeno(5,4-b)furan-8-yl]ethyl)acetamide] were evaluated by use of cell-free binding and cell-based functional assays. Results: Competition binding assays using 2-[(125)I]iodomelatonin revealed rapid, reversible, and high-affinity binding of compound 1 to human, mouse, and rat MT₂ melatonin receptors. cAMP, ERK1/2, and PathHunter β-arrestin recruitment assays revealed partial agonist activities. However, compound 1 induced a more intense internalization of human MT₂ melatonin receptor than melatonin. Based on studies using structurally related an…

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Single-nucleotide polymorphisms and mRNA expression for melatonin synthesis rate-limiting enzyme in recurrent depressive disorder.

Depressive disorder (DD) is characterised by disturbances in blood melatonin concentration. It is well known that melatonin is involved in the control of circadian rhythms, sleep included. The use of melatonin and its analogues has been found to be effective in depression therapy. Melatonin synthesis is a multistage process, where the last stage is catalysed by acetylserotonin methyltransferase (ASMT), the reported rate-limiting melatonin synthesis enzyme. Taking into account the significance of genetic factors in depression development, the gene for ASMT may become an interesting focus for studies in patients with recurrent DD. The goal of the study was to evaluate two single-nucleotide polymorphisms (SNPs) (rs4446909; rs5989681) of the ASMT gene, as well as mRNA expression for ASMT in recurrent DD-affected patients. We genotyped two polymorphisms in a group of 181 recurrent DD patients…

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Perceived stress is linked to heightened biomarkers of inflammation via diurnal cortisol in a national sample of adults.

Exposure to and perceptions of stress have been associated with altered systemic inflammation, but the intermediate processes by which stress links to inflammation are not fully understood. Diurnal cortisol slopes were examined as a pathway by which self-reported psychosocial stress is associated with inflammation [i.e., C-reactive protein (CRP), interleukin-6 (IL-6), fibrinogen, E-Selectin, and Intercellular Adhesion Molecule-1 (ICAM-1)] in a large sample of adults (the Midlife in the US study; N = 914; 55.9% female; aged 34-84 years). Structural equation modeling indicated that perceived psychological stress was associated with flattened diurnal cortisol slopes and flatter diurnal cortisol slopes were, in turn, associated with heightened inflammation in these cross-sectional analyses (index of indirect pathway, ω = 0.003, 95% CI [0.001, 0.004], ωSTD = 0.027; with covariates, ω = 0.001,…

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Long work hours, prolonged daytime naps, and decreased cognitive performance in older adults.

In the United States, labor force market projections show significant growth in older ages. With postponed retirement and age-related health changes, attention to work times and recuperative strategies related to cognitive performance remains necessary for safe practice. The purpose of this study was to explore the relationships between long work hours, daytime naps, and cognitive performance in older adults. Cross-sectional data were obtained from 2013-2014 waves of the National Health and Aging Trends Study. A total sample of 308 workers were identified that had data on work hours, sleep-related parameters, and cognitive functioning. Around 42% of older adults were 70 to 74 years of age, and almost 73% of the sample worked < 40 hours/week. Workers on average slept 6.87 ± 1.27 hours, and nearly 43% reported daytime napping, with most naps being brief (≤ 45 minutes). Around 78% of the sa…

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Marriage and Gut (Microbiome) Feelings: Tracing Novel Dyadic Pathways to Accelerated Aging.

Within a couple, partners influence each other's mental and physical health. This review focuses on how couples' relationships, the partners' individual and joint vulnerabilities, and their health behaviors influence health through changes in the gut microbiota, metabolism, and immune function. Couples' shared stressors and emotions and their intertwined lifestyles and routines serve to promote common disease risks in part through parallel changes in their gut microbiotas. Marital discord, stress, and depression have strong bidirectional links, fueling one another. Chronic marital stress and depression can elevate the risk for obesity, metabolic syndrome, and cardiovascular disease by altering resting energy expenditure, insulin production, and triglyceride responses after unhealthy meals. During stressful times, health behaviors typically suffer-and sleep disturbances, poor diets, and s…

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Marital status as a predictor of diurnal salivary cortisol levels and slopes in a community sample of healthy adults.

Married people tend to be healthier than both the previously (bereaved, divorced, and separated) and never married, but the mechanisms through which this occurs remain unclear. To this end, research has increasingly focused on how psychological stress experienced by unmarried versus married individuals may differentially impact physiological systems related to health. One key system that is modulated by stress is the hypothalamic-pituitary-adrenal (HPA) axis, of which cortisol is a key hormonal product. Increased cortisol production and disruption of cortisol's daily rhythm have been linked to poorer health outcomes. This study examined the association between current marital status and these two indices of cortisol in a community sample of 572 healthy men and women aged 21-55. It also tested whether marriage buffers against the effect of stress (perceived stress by marital status intera…

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The Cortisol Awakening Response Mediates the Relationship Between Acculturative Stress and Self-Reported Health in Mexican Americans.

Background: The assessment of acculturative stress as synonymous with acculturation level overlooks the dynamic, interactive, and developmental nature of the acculturation process. An individual's unique perception and response to a range of stressors at each stage of the dynamic process of acculturation may be associated with stress-induced alterations in important biological response systems that mediate health outcomes. Evidence suggests the cortisol awakening response (CAR) is a promising pre-clinical biomarker of stress exposure that may link acculturative stress to self-reported health in Mexican Americans. Purpose: The aim of the current study was to examine whether alterations in the CAR mediate the relationship between acculturative stress and self-reported health in Mexican Americans. Methods: Salivary cortisol samples were collected at awakening, 30, 45, and 60 min thereafter,…

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